研究者詳細 - 伊藤　裕

論文 - 伊藤　裕

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DNA damage in proximal tubules triggers systemic metabolic dysfunction through epigenetically altered macrophages

Nishimura E.S., Hishikawa A., Nakamichi R., Akashio R., Chikuma S., Hashiguchi A., Yoshimoto N., Hama E.Y., Maruki T., Itoh W., Yamaguchi S., Yoshino J., Itoh H., Hayashi K.

Nature Communications 16 （ 1 ） 3958 2025年12月

DNA damage repair is a critical physiological process closely linked to aging. The accumulation of DNA damage in renal proximal tubular epithelial cells (PTEC) is related to a decline in kidney function. Here, we report that DNA double-strand breaks in PTECs lead to systemic metabolic dysfunction, including weight loss, reduced fat mass, impaired glucose tolerance with mitochondrial dysfunction, and increased inflammation in adipose tissues and the liver. Single-cell RNA sequencing analysis reveals expansion of CD11c+ Ccr2+ macrophages in the kidney cortex, liver, and adipose tissues and Ly6Chi monocytes in peripheral blood. DNA damage in PTECs is associated with hypomethylation of macrophage activation genes, including Gasdermin D, in peripheral blood cells, which is linked to reduced DNA methylation at KLF9-binding motifs. Macrophage depletion ameliorates metabolic abnormalities. These findings highlight the impact of kidney DNA damage on systemic metabolic homeostasis, revealing a kidney-blood-metabolism axis mediated by epigenetic changes in macrophages.

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Patient education status regarding peritoneal dialysis: a questionnaire-based survey study

Ryuzaki M., Inoue S., Morimoto K., Wakabayashi K., Yoshifuji A., Komatsu M., Fujii K., Kato A., Honjoh H., Wakino S., Uchiyama K., Itoh H.

Renal Replacement Therapy 11 （ 1 ） 2025年12月

Background: The number of patients undergoing peritoneal dialysis (PD) in Japan has recently increased. However, Japanese guidelines for such patients’ education are not yet available. Therefore, we aimed to investigate the present status of patient education regarding PD in Japan. Methods: We used one questionnaire to perform two rounds of surveys (2019 and 2021) at institutes that managed ten patients or more on PD at the end of each year. We evaluated the facilities’ characteristics, catheter placement, PD guidance, educational content, education management, home-care environment, care of exit site, and bathing and retraining. Results: A total of 76 facilities (response rate: 26.8%) responded to the first survey, and 86 (response rate: 28.3%) to the second. The incidence of peritonitis in the valid responding institutes was 0.21 per patient-year in 2019 and 0.19 per patient-year in 2021, similar to the incidence of 0.20 per patient-year in 2022 reported by the Japanese Society for Dialysis Therapy Renal Data Registry. This indicates that the valid responding institutes may have been representative of the typical Japanese clinical level in terms of PD. In terms of catheter placement, exit-site positions were preoperatively marked by nurse in 41% of facilities in 2019 and in 37% in 2021. In terms of PD guidance, regarding the timing of the education’s initiation, the periods before PD catheter placement or during catheter embedding were more common than 1–6 days after placement in both years. In terms of the duration, 30-min to 1-h education sessions were most common, and the majority of facilities provided guidance for more than 7 days in both years. These results were different from the schedules recommended by the International Society for Peritoneal Dialysis (3 h per session for more than 5 days, initiated 10 days after the operation). Regarding educational content, most facilities provided education on PD procedures and bathing; however, in some facilities, the content did not include dietary guidance, the importance of residual kidney function, medications, laboratory data, troubleshooting, medical security, or social resources. In both years, approximately 70% of the instructional items comprised the PD procedure, exit-site care, bathing, and infection prevention. Regarding education management, the patients’ levels of understanding were evaluated via manual or oral tests in most of the facilities. Regarding the method of demonstration, the entire procedure was explained during the demonstration in almost all institutes. Nurses in > 50% of facilities visited the patients’ homes either when PD was introduced or as needed. The majority of facilities did not use cognitive-function tests when PD was introduced to older adults. Regarding exit-site care and bathing, no consensus existed. Almost half of facilities performed regular, scheduled retraining. Conclusions: In this study, patients’ PD-related educational situations differed from those recommended by the International Society for Peritoneal Dialysis, and no consensus for exit-site care or bathing existed. To improve the clinical level of PD practice in Japan, original Japanese guidelines for patients’ PD education are required, for which our results may serve as the foundation.

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Effect of administration and withdrawal of the sodium-glucose cotransporter 2 inhibitor, tofogliflozin, on renal protection in individuals with type 2 diabetes mellitus and diabetic nephropathy: A multicenter, single-arm study (RESTORE-nephropathy study)

Shigeta A., Tanaka M., Meguro S., Morimoto J., Imai T., Yamauchi A., Kanazawa Y., Kawai T., Azuma K., Yamada S., Endo S., Itoh H., Hayashi K.

Journal of Diabetes Investigation 16 （ 5 ） 817 - 826 2025年05月

ISSN 20401116

Aims/Introduction: The mechanisms of the renoprotective effects of sodium-glucose cotransporter 2 inhibitors are unknown. This study aimed to explore the effect and mechanism of tofogliflozin on urinary albumin by administration, withdrawal, and re-administration. Materials and Methods: Individuals with type 2 diabetes mellitus and stage 2 or 3 diabetic nephropathy were enrolled. Tofogliflozin was administered for 24 weeks, withdrawn for 12 weeks (withdrawal period), and re-administered for 24 weeks. The primary endpoint was the change in urinary albumin/creatinine ratio (UACR). The secondary endpoints included hemoglobin A1c (HbA1c), hepatic biomarkers, lipid profiles, physical examinations, and blood counts. Results: A total of 47 individuals were enrolled. UACR significantly decreased throughout the observation period. It also significantly decreased, increased, and again decreased during the period of the 1st administration, withdrawal, and re-administration, respectively. HbA1c, body weight, waist circumference, and systolic blood pressure also showed the same tendency. Aspartate aminotransferase and alanine aminotransferase significantly decreased throughout the observation period, but did not increase during the withdrawal period. Conclusions: Urinary albumin improved during the administration of tofogliflozin and worsened during its withdrawal, suggesting the reversibility of its renoprotective effect. The administration of tofogliflozin should be continued to avoid the reversal of glycemic control, renoprotective effects, and other beneficial effects.

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A Randomized Clinical Trial of ICT-based Interventions for Sodium and Potassium Regulation in Healthy Adults.

Yano Y, Kitaoka K, Ohkubo T, Okamura T, Kanegae H, Yoshita K, Tsukinoki R, Okami Y, Node K, Rakugi H, Itoh H, Miura K

American journal of hypertension 2025年04月

ISSN 0895-7061

BACKGROUND: There is limited knowledge regarding effective strategies, including information and communication technology (ICT)-based interventions, to reduce sodium intake and increase potassium intake in healthy individuals. METHODS: We conducted a three-month randomized controlled trial involving healthy adult employees with spot urine sodium-to-potassium ratios (spot UNa/UK) ≥4.0 or estimated 24-hour salt intake ≥10g. Estimated 24-hour UNa and UK were calculated using the Tanaka formula. Participants were assigned to one of four groups: (1) online education, where participants monitored their spot UNa/UK and received feedback from dieticians (n=84); (2) messaging, with similar self-monitoring and dietician messages (n=84); (3) self-learning, provided with an educational leaflet (n=87); and (4) a control group (n=87). The primary outcome was the change in spot UNa/UK ratios, and secondary outcomes included changes in estimated 24-hour UNa and UK. The trial protocol specified a hierarchical order for testing the interventions, anticipating the highest efficacy in the online education group. RESULTS: After the intervention, the online education group showed a decrease in spot UNa/UK ratios (mean -0.9 [95% CI -1.8 to 0.0], p=0.052) compared to the control group. The increase in estimated 24-hour UK excretion was larger in the online education compared to control group (mean +2.5 mmol/day [95% CI -0.3 to 5.3], p=0.085). The difference in estimated 24-hour UNa excretion between the online education and control groups was -4.3 mmol/day (95% CI -15.5 to 6.9, p=0.45). CONCLUSIONS: Combining self-monitoring of sodium and potassium intake with ICT-based interventions, including online nutritional education, was associated with a modest reduction in the estimated ratios of sodium and potassium intake in healthy individuals.

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Efficacy of Esaxerenone Plus a Renin-Angiotensin System Inhibitor or Calcium Channel Blocker for Nocturnal Hypertension: A Post Hoc Analysis.

Kario K, Ito S, Itoh H, Rakugi H, Okuda Y, Yamakawa S

American journal of hypertension 2025年04月

ISSN 0895-7061

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Effective calcineurin inhibitor treatment in adult-onset steroid-resistant nephrotic syndrome with a novel splice donor site variant of TRPC6: a case report

Nagasaka T., Uchiyama K., Hama E.Y., Kojima D., Kaneko K., Yoshimoto N., Yasuda I., Yamada M., Miya F., Suzuki H., Tajima T., Yamaguchi S., Hayashi K., Kanda T., Hashiguchi A., Kosaki K., Itoh H.

CEN Case Reports 14 （ 2 ） 208 - 216 2025年04月

Transient receptor potential canonical 6 (TRPC6) variants, which were initially detected in adult-onset familial focal segmental glomerulosclerosis (FSGS), were also identified in pediatric-onset one. Here, we present a patient with adult-onset steroid-resistant nephrotic syndrome (SRNS) who harbored a likely pathogenic TRPC6 variant and partially responded to calcineurin inhibitors (CNIs). A 44-year-old woman with stable rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome was presented with nephrotic syndrome. Her renal biopsy results showed minor glomerular abnormalities. Upon admission, she was treated with steroids for around 4 weeks, but it was ineffective. After 1–2 weeks of cyclosporine A (CyA) administration, urine output increased, renal function improved without a decrease in proteinuria, and she was discharged. Her renal function was maintained for 2 months, but after a CyA dose reduction, she was again admitted to the hospital due to relapsing edema, decreased urine output, and worsening renal function. CyA was replaced by tacrolimus (TAC). A second renal biopsy showed nearly the same findings as the first except for tubulointerstitial lesions. After 1–2 weeks of TAC administration, urine output increased, and renal function improved. However, urinary protein levels did not decrease as before. After discharge, a whole exome analysis revealed a heterozygous splice donor site variant NM_004621.6;c.2644 + 1G > A in TRPC6. Genetic testing identified a novel splice donor site variant of TRPC6 in a patient with adult-onset SRNS, which prevented unnecessary steroid continuation. The safety and efficacy of CNI in TRPC6 glomerulopathy must be evaluated in future larger studies with longer follow-up.

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Open-Label, Randomized, Controlled, Crossover Trial on the Effect of Dapagliflozin in Patients With ADPKD Receiving Tolvaptan

Uchiyama K., Kamano D., Nagasaka T., Hama E.Y., Shirai R., Sumura R., Kusahana E., Yanai A., Nakayama T., Kimura T., Takahashi R., Kasai T., Tajima T., Hosoya K., Azegami T., Yamaguchi S., Yoshino J., Ito J., Hayashi M., Kanda T., Ishibashi Y., Washida N., Itoh H., Hayashi K.

Kidney International Reports 10 （ 4 ） 1063 - 1075 2025年04月

ISSN 24680249

Introduction: Although dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, delays the progression of chronic kidney disease (CKD), its effect on patients with autosomal dominant polycystic kidney disease (ADPKD) has not been established. We conducted an open-label, randomized controlled crossover trial to evaluate the additive effects of dapagliflozin in patients with ADPKD receiving tolvaptan. Methods: A total of 27 patients were randomly counterbalanced to receive dapagliflozin 10 mg or usual care without dapagliflozin for 6 months. The primary endpoint was the slope of the estimated glomerular filtration rate (eGFR) determined by linear regression from 1 to 6 months, and the secondary endpoints included changes in total kidney volume (TKV). eGFR was calculated based on creatinine levels (eGFR<inf>cr</inf>), cystatin C levels (eGFR<inf>cys</inf>), and the mean of eGFR<inf>cr</inf> and eGFR<inf>cys</inf> (eGFR<inf>cr-cys</inf>). Results: There were significant attenuations in the eGFR<inf>cr-cys</inf> and eGFR<inf>cys</inf> slopes during the dapagliflozin trial compared with the one without dapagliflozin (2.57 ± 7.88 vs. −5.65 ± 9.57 ml/min per 1.73 m2 per year, P = 0.002; 3.91 ± 11.40 vs. −8.43 ± 13.44 ml/min per 1.73 m2 per year, P = 0.003, respectively). Meanwhile, the eGFR<inf>cr</inf> slope was potentially moderate during the trial with dapagliflozin (1.03 ± 10.78 vs. −3.66 ± 8.88 ml/min per 1.73 m2 per year, P = 0.06). The 6-month change in TKV was significantly attenuated during the trial with dapagliflozin compared with the one without dapagliflozin (−0.44 ± 4.91% vs. 5.04 ± 8.09%, P = 0.01). Conclusion: In patients with ADPKD treated with tolvaptan, dapagliflozin may have an additive effect in slowing ADPKD progression.

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Maternal circadian rhythms during pregnancy dictate metabolic plasticity in offspring

Yao N., Kinouchi K., Katoh M., Ashtiani K.C., Abdelkarim S., Morimoto H., Torimitsu T., Kozuma T., Iwahara A., Kosugi S., Komuro J., Kato K., Tonomura S., Nakamura T., Itoh A., Yamaguchi S., Yoshino J., Irie J., Hashimoto H., Yuasa S., Satoh A., Mikami Y., Uchida S., Ueki T., Nomura S., Baldi P., Hayashi K., Itoh H.

Cell Metabolism 37 （ 2 ） 395 - 412.e6 2025年02月

ISSN 15504131

Tissue-level oscillation is achieved by tissue-intrinsic clocks along with network-dependent signals originating from distal organs and organismal behavior. Yet, it remains unexplored whether maternal circadian rhythms during pregnancy influence fetal rhythms and impact long-term susceptibility to dietary challenges in offspring. Here, we demonstrate that circadian disruption during pregnancy decreased placental and neonatal weight yet retained transcriptional and structural maturation. Intriguingly, diet-induced obesity was exacerbated in parallel with arrhythmic feeding behavior, hypothalamic leptin resistance, and hepatic circadian reprogramming in offspring of chronodisrupted mothers. In utero circadian desynchrony altered the phase-relationship between the mother and fetus and impacted placental efficiency. Temporal feeding restriction in offspring failed to fully prevent obesity, whereas the circadian alignment of caloric restriction with the onset of the active phase virtually ameliorated the phenotype. Thus, maternal circadian rhythms during pregnancy confer adaptive properties to metabolic functions in offspring and provide insights into the developmental origins of health and disease.

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A machine learning model for predicting worsening renal function using one-year time series data in patients with type 2 diabetes

Watanabe M., Meguro S., Kimura K., Furukoshi M., Masuda T., Enomoto M., Itoh H.

Journal of Diabetes Investigation 16 （ 1 ） 93 - 99 2025年01月

ISSN 20401116

Background and Aims: To prevent end-stage renal disease caused by diabetic kidney disease, we created a predictive model for high-risk patients using machine learning. Methods and Results: The reference point was the time at which each patient's estimated glomerular filtration rate (eGFR) first fell below 60 mL/min/1.73 m2. The input period spanned the reference point to 1 year prior. The primary endpoint was a 50% decrease in eGFR from the mean of the input period over the 3 year evaluation period. We created predictive models for patients’ primary endpoints using time series data of various variables over the input period. Among 2,533 total patients, 1,409 had reference points, 31 had records for their input and evaluation periods and had reached their primary endpoints, and 317 patients had not. The area under the curve (AUC) of the predictive model peaked (0.81) when the minimum eGFR, the difference between maximum and minimum eGFR, and both maximum and minimum urinary protein values were included in the features. Conclusion: The accuracy of prognosis prediction can be improved by considering the variable components of urinary protein and eGFR levels. This model will allow us to identify patients whose renal functions are relatively preserved with eGFR of more than 60 mL/min/1.73 m2 and are likely to benefit clinically from immediate treatment intensification.

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Ghrelin Promotes Lipid Uptake into White Adipose Tissue via Endothelial Growth Hormone Secretagogue-Receptor in Mice

Urai H., Azegami T., Komatsu M., Takahashi R., Kubota Y., Hasegawa K., Tokuyama H., Wakino S., Hayashi K., Kanda T., Itoh H.

Nutrients 17 （ 1 ） 2025年01月

Background/Objectives: Endothelial peroxisome proliferator-activated receptor gamma (PPARγ) regulates adipose tissue by facilitating lipid uptake into white adipocytes, but the role of endothelial lipid transport in systemic energy balance remains unclear. Ghrelin conveys nutritional information through the central nervous system and increases adiposity, while deficiency in its receptor, growth hormone secretagogue-receptor (GHSR), suppresses adiposity on a high-fat diet. This study aims to examine the effect of ghrelin/GHSR signaling in the endothelium on lipid metabolism. Methods: We compared the effects of ghrelin on adiposity and lipid uptake into adipocytes in wild-type and GHSR-null mice. Transgenic mice expressing GHSR selectively in endothelial cells were also generated and compared with global GHSR-null and wild-type mice. The impact of ghrelin on lipid uptake-related genes was assessed in cultured endothelial cells. Results: Ghrelin increased adiposity and triglyceride clearance in wild-type but not in GHSR-null mice. GHSR-null mice showed higher serum triglyceride after olive oil gavage and lower white adipose tissue (WAT) weight on a high-fat diet, suggesting impaired lipid uptake. Restoring GHSR expression in endothelial cells increased lipoprotein lipase activity, lipid uptake into WAT, and WAT weight. Ghrelin enhanced free fatty acid uptake and the expression of lipid uptake genes in cultured endothelial cells, whereas these effects were absent in GHSR-null mice-derived endothelial cells. Knockdown of PPARγ revealed that ghrelin/GHSR signaling in endothelial cells promoted lipid uptake via endothelial PPARγ. Conclusions: Endothelial GHSR is key for regulating lipid metabolism via PPARγ in response to ghrelin and for the role of endothelium in regulating white adipocyte metabolism. Targeting endothelial ghrelin signaling may be a promising therapeutic approach for managing excessive adiposity and associated metabolic disorders.

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Pancreatic cancer risk in diabetic patients using the Japanese Regional Insurance Claims

Satoh T., Nakatani E., Ariyasu H., Kawaguchi S., Ohno K., Itoh H., Hayashi K., Usui T.

Scientific Reports 14 （ 1 ） 16958 2024年12月

Pancreatic cancer presents a critical health issue characterized by low survival rates. Identifying risk factors in specific populations, such as those with diabetes, is crucial for early detection and improved outcomes. This study aimed to identify risk factors for pancreatic cancer in diabetic patients using a longitudinal cohort from the Shizuoka Kokuho database, spanning April 2012 to September 2021. Diabetic patients were identified and monitored for the onset of pancreatic cancer. Factors analyzed included age, sex, the Elixhauser comorbidity index, and specific comorbidities. Statistical analyses involved univariate and multivariate Cox proportional hazards regression. The study identified 212,775 as diabetic patients and 1755 developed pancreatic cancer during the period. The annual incidence rate of pancreatic cancer in this group was 166.7 cases per 100,000 person-years. The study identified older age, male sex, a history of liver disease, chronic pancreatitis, and pancreatic cystic lesions as significant risk factors for pancreatic cancer in diabetic patients. The study also highlighted the absence of a significant association between diabetes type or diabetic complications and the onset of pancreatic cancer. These findings may aid in the early diagnosis of pancreatic cancer in diabetic patients and may inform revisions in screening practices in diabetic patients.

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Predicting exacerbation of renal function by DNA methylation clock and DNA damage of urinary shedding cells: a pilot study

Hishikawa A., Nishimura E.S., Yoshimoto N., Nakamichi R., Hama E.Y., Ito W., Maruki T., Nagashima K., Shimizu-Hirota R., Takaishi H., Itoh H., Hayashi K.

Scientific Reports 14 （ 1 ） 11530 - 11530 2024年12月

Recent reports have shown the feasibility of measuring biological age from DNA methylation levels in blood cells from specific regions identified by machine learning, collectively known as the epigenetic clock or DNA methylation clock. While extensive research has explored the association of the DNA methylation clock with cardiovascular diseases, cancer, and Alzheimer's disease, its relationship with kidney diseases remains largely unexplored. In particular, it is unclear whether the DNA methylation clock could serve as a predictor of worsening kidney function. In this pilot study involving 20 subjects, we investigated the association between the DNA methylation clock and subsequent deterioration of renal function. Additionally, we noninvasively evaluated DNA damage in urinary shedding cells using a previously reported method to examine the correlation with the DNA methylation clock and worsening kidney function. Our findings revealed that patients with an accelerated DNA methylation clock exhibited increased DNA damage in urinary shedding cells, along with a higher rate of eGFR decline. Moreover, in cases of advanced CKD (G4-5), the DNA damage in urinary shedding cells was significantly increased, highlighting the interplay between elevated DNA damage and eGFR decline. This study suggests the potential role of the DNA methylation clock and urinary DNA damage as predictive markers for the progression of chronic kidney disease.

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Diurnal variation in the association between the scan frequency of isCGM and CGM metrics: post hoc analysis of the ISCHIA study

Meguro S., Sakane N., Hosoda K., Hirota Y., Itoh A., Kato K., Kodani N., Kuroda A., Matsuhisa M., Miura J., Shimada A., Tone A., Toyoda M., Murata T., Fukunaga M., Kouyama K., Tanaka T., Tenta M., Matsushita Y., Takeda M., Iseda I., Hida K., Nagao T., Taniguchi R., Tanaka N., Abe K., Hitaka Y., Matoba Y., Katsuno T., Kusunoki Y., Fukuda T., Shimizu I., Tsuchiya T., Yagi K., Sugiyama K., Yamaguchi S., Kinouchi K., Inaishi J., Nakajima Y., Mitsuishi M., Tanaka M., Irie J., Saisho Y., Itoh H., Kawashima S., Haisa A., Satomura A., Oikawa Y., Saito N., Kimura M., Tsuchida Y., Shimura K., Hoshina S., Takagi S., Kobayashi H., Shen Z., Suganuma A., Watanabe T., Ito Y., Suzuki S., Kasama S., Kasahara M., Kouyama R., Satoh-Asahara N., Miyamoto Y., Nishimura K.

Diabetology International 15 （ 4 ） 828 - 836 2024年10月

ISSN 21901678

Background and aims: To investigate the association between the frequency of intermittent-scanning continuous glucose monitoring (isCGM) and diurnal variation of time in range (TIR), time above range (TAR), and time below range (TBR), we performed a post hoc analysis of the ISCHIA study, a multicenter, prospective, open-label, randomized crossover study of patients with type 1 diabetes mellitus. Method: Data of 93 people who completed the ISCHIA study were used. We calculated scan frequency, TAR, TIR, and TBR of four approximately 6-h intervals: 6:00–11:59 (morning), 12:00–17:59 (afternoon), 18:00–23:59 (evening), and 0:00–5:59 (night). The correlation between scan frequency and diurnal variation of CGM metrics was analyzed using nonparametric Spearman correlation analysis. Results: More frequent scanning was associated with higher TIR in the afternoon (rho = 0.343, P < 0.001), evening (rho = 0.243, P = 0.019), and night (rho = 0.218, P = 0.036); furthermore, it was associated with lower TAR in the afternoon (rho = -0.275, P = 0.008) and TBR in the evening (rho = -0.235, P = 0.024). Concern about the effect of blood glucose fluctuation on social communication affected the number of scans during the day. Concerns about loneliness and hypoglycemia when alone also influenced the number of nighttime scans. Conclusion: Scan frequency is influenced by psychological factors. Afternoon scans were associated with the highest increase in TIR and decrease in TAR. Evening scans were linked to a reduction in TBR.

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Impact of dietary habits on renal function in Saku, a rural Japanese town: a cohort study

Adachi K., Yasuda M., Ida M., Kanda T., Morita A., Wakino S., Watanabe S., Itoh H.

Clinical and Experimental Nephrology 28 （ 8 ） 751 - 763 2024年08月

ISSN 13421751

Background: High protein intake leads to a decline in renal function in the advanced stages of chronic kidney disease (CKD). An effective diet for maintaining renal function in healthy individuals or patients in the early stages of CKD has not been established. This cohort study was conducted in Saku, Nagano Prefecture, Japan, to investigate the impact of dietary habits on renal function. Methods: In this cross-sectional cohort study, we used the Saku Control Obesity Program (UMIN000016892), including 4,446 participants who submitted a brief-type self-administered diet history questionnaire and underwent routine physical examination. The amount of food intake was divided into quartiles. After adjusting for age and sex, multivariate logistic regression analysis was used to calculate the odds ratio (OR) for the risk of developing CKD (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2). Results: In total, 3,899 participants were analyzed. The overall prevalence of patients with eGFR < 60 mL/min/1.73 m2 was 11% (n = 434, male; 7.1%, female; 4.1%). The groups with a high intake of chicken (approximately 63.4 g/day, adjusted OR: 0.632, P = 0.003), natto (fermented bean; approximately 21.7 g/day, adjusted OR: 0.679, P = 0.01), and plant protein (approximately 0.8 g/ideal body weight/day, adjusted OR: 0.695, P = 0.042) showed a low risk of developing CKD compared to the group with the lowest intake. Conclusions: Our cross-sectional study showed that the intake of chicken meat, natto, and plant protein was associated with high eGFR levels. This information can be of value for preventing CKD incidence in healthy Japanese individuals.

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A sensor-augmented pump with a predictive low-glucose suspend system could lead to an optimal time in target range during pregnancy in Japanese women with type 1 diabetes

Tamura R.K., Kodani N., Itoh A., Meguro S., Kajio H., Itoh H.

Diabetology International 15 （ 3 ） 447 - 455 2024年07月

ISSN 21901678

Introduction: It is challenging for pregnant women with type 1 diabetes to maintain optimum glucose level to attain good neonatal outcomes. This study evaluated the efficacy of sensor-augmented insulin pump (SAP) with a predictive low-glucose suspend (PLGS) system in pregnant Japanese women with type 1 diabetes. Materials and methods: SAP with PLGS was used in 11 of the 22 women with type 1 diabetes who delivered between 2011 and 2021 at the two medical institutions in Japan. Glucose management, insulin delivery suspension time (IST) and neonatal outcomes were retrospectively studied. Results: In SAP with PLGS cases (n = 11), average glycated hemoglobin levels were < 6.5% throughout the pregnancy, and the time in range (TIR, 63–140 mg/dl) was > 70% in the second and third trimesters. PLGS was safely used without inducing ketoacidosis. Positive correlation was observed between IST and TIR (r = 0.62, p < 0.01). Negative correlation was observed between IST and time below range (TBR) (r = − 0.40, p = 0.02), and IST and time above range (TAR) (r = − 0.45, p = 0.01). Total daily insulin dose was adequately increased without increasing hypoglycemia. There was only one heavy-for-date HFD) infant among the 11 newborns in SAP with PLGS cases. In cases without SAP (n = 11), target glycemic levels were difficult to achieve and there were 5 HFD infants among the 11 newborns. Conclusion: SAP with PLGS was safely and effectively used in pregnant women with type 1 diabetes to achieve target glucose levels without increasing the risk of hypoglycemia, which may have led to good neonatal outcomes.

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Predictors of the effectiveness of isCGM usage in adults with type 1 diabetes mellitus: post-hoc analysis of the ISCHIA study

Fukunaga M., Kouyama K., Tanaka T., Tenta M., Matsushita Y., Takeda M., Iseda I., Hida K., Nagao T., Taniguchi R., Tanaka N., Abe K., Hitaka Y., Matoba Y., Katsuno T., Kusunoki Y., Fukuda T., Shimizu I., Kodani N., Tsuchiya T., Yagi K., Sugiyama K., Itoh A., Yamaguchi S., Kinouchi K., Inaishi J., Nakajima Y., Mitsuishi M., Tanaka M., Irie J., Saisho Y., Itoh H., Meguro S., Kawashima S., Haisa A., Satomura A., Oikawa Y., Shimada A., Saito N., Kimura M., Tsuchida Y., Shimura K., Hoshina S., Takagi S., Kobayashi H., Shen Z., Suganuma A., Watanabe T., Ito Y., Suzuki S., Kasama S., Kasahara M., Tone A., Miura J., Kouyama R., Kato K., Kuroda A., Matsuhisa M., Hirota Y., Toyoda M., Satoh-Asahara N., Sakane N., Miyamoto Y., Nishimura K., Hosoda K., Murata T.

Diabetology International 15 （ 3 ） 400 - 405 2024年07月

ISSN 21901678

Aim: The Effect of Intermittent-Scanning Continuous Glucose Monitoring to Glycemic Control Including Hypoglycemia and Quality of Life of Patients with Type 1 Diabetes Mellitus (ISCHIA) study was a randomized, crossover trial that reported the decrease in time below range (TBR) by the use of intermittent-scanning continuous glucose monitoring (isCGM) combined with structured education in adults with type 1 diabetes (T1D) treated by multiple daily injections. The participants were instructed to perform frequent scanning of the isCGM sensor (10 times a day or more) and ingest sugar when impending hypoglycemia is suspected by tracking the sensor glucose levels and the trend arrow. We conducted post-hoc analysis to identify factors affecting difference in TBR (∆TBR), in time in range (∆TIR), and in time above range (∆TAR). Participants and methods: Data from 93 participants who completed the ISCHIA study were used. Multiple regression analyses were performed to identify factors affecting CGM metrics. Results: Pearson’s correlation analysis showed the negative association between log-transformed scan frequency and with ∆TBR (r = − 0.255, P = 0.015), while there was no significant association of log-transformed scan frequency with ∆TIR (r = 0.172, P = 0.102) and ∆TAR (r = 0.032, P = 0.761), respectively. The log-transformed scan frequency was an independent predictor of ∆TBR (Beta = − 7.712, P = 0.022), but not of ∆TIR(Beta = 7.203, P = 0.091) and of ∆TAR (Beta = 0.514, P = 0.925). Conclusions: Our findings suggest that more frequent scanning of isCGM may be beneficial to reduce TBR in T1D adults.

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Podocyte Ercc1 is indispensable for glomerular integrity

Hama E.Y., Nakamichi R., Hishikawa A., Kihara M., Abe T., Yoshimoto N., Nishimura E.S., Itoh H., Hayashi K.

Biochemical and Biophysical Research Communications 704 149713 - 149713 2024年04月

ISSN 0006291X

As life expectancy continues to increase, age-related kidney diseases are becoming more prevalent. Chronic kidney disease (CKD) is not only a consequence of aging but also a potential accelerator of aging process. Here we report the pivotal role of podocyte ERCC1, a DNA repair factor, in maintaining glomerular integrity and a potential effect on multiple organs. Podocyte-specific ERCC1-knockout mice developed severe proteinuria, glomerulosclerosis, and renal failure, accompanied by a significant increase in glomerular DNA single-strand breaks (SSBs) and double-strand breaks (DSBs). ERCC1 gene transfer experiment in the knockout mice attenuated proteinuria and glomerulosclerosis with reduced DNA damage. Notably, CD44+CD8+ memory T cells, indicative of T-cell senescence, were already elevated in the peripheral blood of knockout mice at 10 weeks old. Additionally, levels of senescence-associated secretory phenotype (SASP) factors were significantly increased in both the circulation and multiple organs of the knockout mice. In older mice and human patients, we observed an accumulation of DSBs and an even greater buildup of SSBs in glomeruli, despite no significant reduction in ERCC1 expression with age in mice. Collectively, our findings highlight the crucial role of ERCC1 in repairing podocyte DNA damage, with potential implications for inflammation in various organs.

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Antimicrobial Prophylaxis With Ampicillin-sulbactam Compared With Cefazolin for Esophagectomy: Nationwide Inpatient Database Study in Japan.

Hirano Y, Konishi T, Kaneko H, Itoh H, Matsuda S, Kawakubo H, Uda K, Matsui H, Fushimi K, Daiko H, Itano O, Yasunaga H, Kitagawa Y

Annals of surgery 279 （ 4 ） 640 - 647 2024年04月

ISSN 0003-4932

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3）Deep Medicine：生活習慣病克服のためのSDGs（Sustainable Development Goals）

伊藤裕

日本内科学会雑誌（一般社団法人日本内科学会） 113 （ 3 ） 391 - 395 2024年03月

ISSN 00215384

Renal sinus fat is associated with intrarenal hemodynamic abnormalities independent of visceral fat in patients with chronic kidney disease

Kaneko K., Mitsuno R., Kojima D., Azegami T., Kosugi S., Nakamura T., Hashiguchi A., Yamada Y., Jinzaki M., Yamaguchi S., Itoh H., Yoshino J., Hayashi K.

Obesity Research and Clinical Practice 18 （ 2 ） 118 - 123 2024年03月

ISSN 1871403X

Objective: Obesity is a risk factor of chronic kidney disease (CKD), contributing to the rising incidence of cardiometabolic diseases. Renal sinus fat (RSF) is an ectopic fat depot located at the renal cavity that could impair renal function and hemodynamic through compression of renal structures. The major purpose of this study was to explore the relationship between RSF accumulation and renal dysfunction in CKD patients. Methods: We evaluated the associations between computed tomography measured RSF volume and key clinical and histologic parameters involved in renal function and hemodynamics in 132 well-characterized CKD patients who underwent renal biopsy (median age: 62 years; 63.6% men). Results: RSF volume normalized by renal volume (RSF%) positively correlated with obesity-related traits such body mass index and visceral fat volume (VFV) (all P < 0.001) whereas it negatively correlated with estimated glomerular filtration rate (eGFR) (ρ = −0.42, P < 0.001) and 24-h urinary creatinine clearance (CCr) (ρ = −0.34, P < 0.001). Notably, we found robust positive correlations between RSF% and renal resistive index (RRI) measured by the Doppler ultrasound (ρ = 0.40, P < 0.001), and the histological severity of global glomerular sclerosis (ρ = 0.48, P < 0.001) and interstitial fibrosis and tubular atrophy (IFTA) (ρ = 0.35, P < 0.001). In the multivariate linear regression models, after accounting for potential confounders including VFV, RSF% remained significantly associated with CCr (β = −0.26, P < 0.001), RRI (β = 0.17, P = 0.022), global glomerular sclerosis (β = 0.21, P = 0.002), and IFTA (β = 0.17, P = 0.012). Conclusion: RSF accumulation is associated with renal dysfunction and hemodynamic abnormalities independent of visceral adiposity. Our results suggest that RSF may have a potential unique role in the pathogenesis of CKD.

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Safety and efficacy of long-term nicotinamide mononucleotide supplementation on metabolism, sleep, and nicotinamide adenine dinucleotide biosynthesis in healthy, middle-aged Japanese men

Yamaguchi S., Irie J., Mitsuishi M., Uchino Y., Nakaya H., Takemura R., Inagaki E., Kosugi S., Okano H., Yasui M., Tsubota K., Hayashi K., Yoshino J., Itoh H.

Endocrine Journal （一般社団法人日本内分泌学会） 71 （ 2 ） 153 - 169 2024年

ISSN 09188959

Obesity and aging are major risk factors for several life-threatening diseases. Accumulating evidence from both rodents and humans suggests that the levels of nicotinamide adenine dinucleotide (NAD+), a regulator of many biological processes, declines in multiple organs and tissues with aging and obesity. Administration of an NAD+ intermediate, nicotinamide mononucleotide (NMN), replenishes intracellular NAD+ levels and mitigates aging-and obesity-associated derangements in animal models. In this human clinical study, we aimed to investigate the safety and effects of 8-week oral administration of NMN on biochemical, metabolic, ophthalmologic, and sleep quality parameters as well as on chronological alterations in NAD+ content in peripheral tissues. An 8-week, single-center, single-arm, open-label clinical trial was conducted. Eleven healthy, middle-aged Japanese men received two 125-mg NMN capsules once daily before breakfast. The 8-week NMN supplementation regimen was well-tolerated; NAD+ levels in peripheral blood mononuclear cells increased over the course of NMN administration. In participants with insulin oversecretion after oral glucose loading, NMN modestly attenuated postprandial hyperinsulinemia, a risk factor for coronary artery disease (n = 3). In conclusion, NMN overall safely and effectively boosted NAD+ biosynthesis in healthy, middle-aged Japanese men, showing its potential for alleviating postprandial hyperinsulinemia.

Clinical significance of serum urea-to-creatinine ratio in patients undergoing peritoneal dialysis

Tonomura S., Uchiyama K., Nakayama T., Mitsuno R., Kojima D., Hama E.Y., Nagasaka T., Nishimura E.S., Kusahana E., Takahashi R., Yoshimoto N., Yamaguchi S., Morimoto K., Yoshida T., Hayashi K., Kanda T., Washida N., Itoh H.

Therapeutic Apheresis and Dialysis 27 （ 6 ） 1103 - 1112 2023年12月

ISSN 17449979

Introduction: We aimed to determine the correlation between the serum urea-to-creatinine ratio and residual kidney function (RKF) in patients undergoing peritoneal dialysis (PD), as well as its predictive value for PD-related outcomes. Methods: This study included a cross-sectional study to assess the correlation between serum urea-to-creatinine ratio and RKF in 50 patients on PD and a retrospective cohort study to assess the association between serum urea-to-creatinine ratio and PD-related outcomes in 122 patients who initiated PD. Results: Serum urea-to-creatinine ratios had significant positive correlations with renal Kt/V and creatinine clearance values (r = 0.60, p < 0.001 and r = 0.61, p < 0.001, respectively). Additionally, serum urea-to-creatinine ratio was significantly associated with a lower risk of transfer to hemodialysis or PD/hemodialysis hybrid therapy (hazard ratio: 0.84, 95% confidence interval: 0.75–0.95). Conclusion: The serum urea-to-creatinine ratio can be an indicator of RKF and a prognostic factor in patients undergoing PD.

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Comparison of the effects of angiotensin receptor–neprilysin inhibitors and thiazide diuretic/renin–angiotensin system inhibitor combination therapy in hypertensive patients: a retrospective cohort study

Mitsuno R., Uchiyama K., Nakayama T., Takahashi R., Yoshimoto N., Yamaguchi S., Washida N., Kanda T., Hayashi K., Itoh H.

Journal of Human Hypertension 37 （ 12 ） 1049 - 1055 2023年12月

ISSN 09509240

Angiotensin receptor–neprilysin inhibitors (ARNIs) have been approved as antihypertensive agents in Japan, and thiazide diuretics (TZDs) are widely used concomitantly with renin–angiotensin system inhibitors (RASIs) for hypertension. This retrospective study included patients with hypertension who switched from RASI to ARNI therapy (ARNI group) and those who were prescribed TZDs with RASIs (TZD/RASI group). Drug-related changes in the estimated glomerular filtration rate (eGFR), blood pressure (BP), body weight (BW), serum electrolytes, uric acid (UA), and triglyceride levels were compared between the two groups. Overall, 70 participants (31 and 39 in the ARNI and TZD/RASI groups, respectively) were enrolled and observed for a median of 2 months. According to linear mixed models, compared with the TZD/RASI group, the ARNI group exhibited a significant change in mean eGFR of 3.71 mL/min/1.73 m2 [95% confidence interval (CI), 0.57–6.84; P = 0.02] from the time of switching drug to the next outpatient visit. Further, compared with the TZD/RASI group, the ARNI group exhibited significant changes in mean serum UA (−1.27; 95% CI, −1.66 to −0.88), sodium (1.22; 95% CI, 0.12 to −2.32), chloride (2.14; 95% CI, 0.75–3.52), and triglyceride (−52.1; 95% CI, −100.9 to −3.29) levels. Conversely, serum potassium levels, BW, and systolic and diastolic BP did not differ significantly between the two groups (P = 0.69, 0.44, 0.49, and 0.66, respectively). Compared with the combination therapy of TZD and RASI, ARNI therapy causes less renal dysfunction, hyperuricemia, and hypertriglyceridemia with fewer electrolyte abnormalities and no significant difference in antihypertensive effects.

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Dietary protein intake and all-cause mortality: results from The Kawasaki Aging and Wellbeing Project

Kurata H., Meguro S., Abe Y., Sasaki T., Asakura K., Arai Y., Itoh H.

BMC Geriatrics 23 （ 1 ） 479 - 479 2023年12月

Background: Increased protein intake has been recommended to prevent sarcopenia/frailty, reports on the quantity and quality of protein intake needed and the associated prognosis, particularly in the aging population of Asia, are limited. In this study, we aimed to investigate the relationship between protein intake and mortality in Japanese individuals, aged 85 years and older. Methods: The data were obtained from The Kawasaki Aging and Wellbeing Project, which is a prospective cohort study of older adults aged between 85 and 89 years with no physical disability at baseline. Of the 1,026 adults in the cohort, 833 were included in the analysis, after excluding those who had not completed a brief, self-administered diet history questionnaire or those who scored less than 24 on the Mini-Mental State Examination. The participants were grouped into quartiles based on protein intake: Q1 (protein < 14.7, %Energy), Q2 (14.7 ≤ protein < 16.7, %Energy), Q3 (16.7 ≤ protein < 19.1, %Energy), and Q4 (≥ 19.1, %Energy). Multivariate Cox proportional hazards models were utilized to evaluate the association between protein intake and all-cause mortality. Kaplan–Meier survival curves were employed to investigate the relationship between protein intake and all-cause mortality. Results: The mean protein intake of our study population was 17.0% of total energy. Animal protein intake, particularly fish intake, increased significantly along with total protein intake. The study had an average observation period of 1,218 days and recorded 89 deaths. After adjusting for age, sex, skeletal muscle mass index, cardiovascular disease, cancer, education, and serum albumin levels, a lower risk of all-cause mortality was observed in the highest protein intake (Q4) group than in the lowest protein intake (Q1) group (hazard ratio: 0.44, 95% confidence interval: 0.22–0.90, p-value: 0.020). Conclusion: Protein intake is associated with a reduced risk of all-cause mortality in older adults (aged ≥ 85 years) who engage in independent activities of daily living. This association may impact all-cause mortality independent of muscle mass.

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Peritoneal dialysis-related peritonitis with encapsulated ascites due to Mycobacterium abscessus subsp. massilience and subsp. bolletii: a case series and literature review

Nagasaka T., Uchiyama K., Shirai R., Mitsuno R., Maruki T., Hama E.Y., Sugita E., Kusahana E., Sumura R., Nakayama T., Kinugasa S., Morimoto K., Ishibashi Y., Washida N., Itoh H.

Renal Replacement Therapy 9 （ 1 ） 2023年12月

Background: As there is no established standard of care for non-tuberculous mycobacterium (NTM) peritoneal dialysis (PD)-related peritonitis, its treatments have to be case-dependent, which is often difficult. Additionally, several reported cases were accompanied by encapsulated ascites, adhesive ileus, and encapsulating peritoneal sclerosis, suggesting treatment difficulties. We report two cases of PD-related peritonitis with encapsulated ascites due to Mycobacterium abscessus subsp. massilience and subsp. bolletii. To the best of our knowledge, this is the first case series to report PD-related peritonitis caused by Mycobacterium abscessus subsp. bolletii. Case presentation: The first case is that of a 74-year-old male patient who started PD six years ago for end-stage renal failure due to diabetic nephropathy. In February 2021, he presented with signs of infection at the exit-site and swelling of the tunnel. Mycobacterium abscessus subsp. massilience was detected in the culture of the exit-site exudate; thus, he was diagnosed with tunnel infection (caused by NTM). Subsequently, fever, abdominal pain, and increased cell counts in the PD drainage fluid were observed, and he was judged to have NTM peritonitis. His general condition improved after PD catheter removal in addition to antimicrobial treatment and encapsulated ascites drainage. The second case is that of a 52-year-old man who commenced PD for end-stage renal failure due to nephrosclerosis 12 years ago. In May 2022, he was diagnosed with PD-related peritonitis based on signs of infection at the exit-site, encapsulated ascites on computed tomography, and a cloudy PD drainage fluid. Mycobacterium abscessus subsp. bolletii was detected in the culture of the exit-site exudate, which led to the diagnosis of NTM peritonitis. In addition to antimicrobial treatment, PD catheter removal and encapsulated ascites drainage were performed. The patient also had adhesive bowel obstruction due to peritonitis and required decompression therapy with the insertion of a gastric tube. Conclusions: PD catheter removal and encapsulated ascites drainage might have improved inflammation and treatment outcomes. Additionally, Mycobacterium abscessus might be prone to forming encapsulated cavities and/or intestinal adhesions; however, further accumulation of cases clarifying “subspecies” of Mycobacterium abscessus is necessary to confirm this hypothesis.

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Plasminogen activator inhibitor 1 is not a major causative factor for exacerbation in a mouse model of SARS-CoV-2 infection

Nakayama T., Azegami T., Kiso M., Imai M., Uraki R., Hayashi K., Hishikawa A., Yoshimoto N., Nakamichi R., Sugita-Nishimura E., Yoshida-Hama E., Kawaoka Y., Itoh H.

Scientific Reports 13 （ 1 ） 3103 - 3103 2023年12月

Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global pandemic. Although several vaccines targeting SARS-CoV-2 spike proteins protect against COVID-19 infection, mutations affecting virus transmissibility and immune evasion potential have reduced their efficacy, leading to the need for a more efficient strategy. Available clinical evidence regarding COVID-19 suggests that endothelial dysfunction with thrombosis is a central pathogenesis of progression to systemic disease, in which overexpression of plasminogen activator inhibitor-1 (PAI-1) may be important. Here we developed a novel peptide vaccine against PAI-1 and evaluated its effect on lipopolysaccharide (LPS)-induced sepsis and SARS-CoV-2 infection in mice. Administration of LPS and mouse-adapted SARS-CoV-2 increased serum PAI-1 levels, although the latter showed smaller levels. In an LPS-induced sepsis model, mice immunized with PAI-1 vaccine showed reduced organ damage and microvascular thrombosis and improved survival compared with vehicle-treated mice. In plasma clot lysis assays, vaccination-induced serum IgG antibodies were fibrinolytic. However, in a SARS-CoV-2 infection model, survival and symptom severity (i.e., body weight reduction) did not differ between vaccine- and vehicle-treated groups. These results indicate that although PAI-1 may promote the severity of sepsis by increasing thrombus formation, it might not be a major contributor to COVID-19 exacerbation.

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Efficacy and safety of a telemedicine system in subjects with gestational diabetes mellitus (TELEGLAM): Study protocol for a randomized controlled trial

Aoyama K., Nakajima Y., Meguro S., Sato Y., Goto R., Hida M., Arimitsu T., Kasuga Y., Tanaka M., Itoh H.

Heliyon 9 （ 11 ） e22504 2023年11月

ISSN 24058440

Background: Strict glycemic control is important to prevent perinatal complications in patients with gestational diabetes mellitus (GDM). Patients often require insulin injection, and frequent hospital visits are necessary to adjust the dose of insulin, which is considered burdensome for pregnant patients. Telemedicine may reduce the burden of hospital visits, and previous studies have reported its safety in GDM patients. This study aimed to evaluate the efficacy of telemedicine in GDM patients, focusing on patient satisfaction and health economic indicators. Methods: This is a single-center, two-arm, randomized, open-label parallel-group study. Subjects will be selected from the patient population attending the Department of Endocrinology, Metabolism, and Nephrology, Keio University School of Medicine, Japan. Patients diagnosed with GDM by an oral glucose tolerance test (OGTT) by 29 weeks and 6 days of gestation who have undergone self-monitoring of blood glucose (SMBG) and insulin injection are eligible for inclusion. In the intervention group, telemedicine will be administered using the MeDaCa telemedicine system developed by the Medical Data Card, Inc., Tokyo, Japan. Subjects in the control group will be examined face-to-face every 2–3 weeks, as usual. We set health economic indicators and patient satisfaction as the primary endpoints, and will perform a cost-consequence analysis. Glycemic control indicators and perinatal outcomes will be evaluated as secondary endpoints. Conclusions: Eligible patients are currently being recruited. Recruitment will be completed when the expected number of patients are enrolled.

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N-methyl-2-pyridone-5-carboxamide (N-Me-2PY) has potent anti-fibrotic and anti-inflammatory activity in a fibrotic kidney model: is it an old uremic toxin?

Yoshimura N., Yamada K., Ono T., Notoya M., Yukioka H., Takahashi R., Wakino S., Kanda T., Itoh H.

Clinical and Experimental Nephrology 27 （ 11 ） 901 - 911 2023年11月

ISSN 13421751

Background: Uremic toxins accumulate in renal tissues and cells due to chronic kidney disease (CKD). Abnormalities in nicotinamide adenine dinucleotide (NAD +) metabolism lead to the progression of CKD. NAD + metabolites, such as N-methyl-2-pyridone-5-carboxamide (N-Me-2PY) and N-methyl-4-pyridone-5-carboxamide (N-Me-4PY), have been recognized as uremic toxins. However, no reports have validated whether they are actually harmful to the body. Therefore, we focused on the structural similarity of these metabolites to the anti-fibrotic drug pirfenidone and evaluated their effects on renal fibrosis. Methods: Each NAD + metabolite was treated with TGFβ1 to kidney fibroblasts or tubular epithelial cells, and quantitative RT-PCR and Western blot analysis were conducted. N-Me-2PY was orally administered to a ligated murine kidney fibrosis model (UUO) to evaluate its anti-fibrotic and toxic effects on the body. Results: N-Me-2PY, N-Me-4PY, and nicotinamide N-oxide (NNO) inhibited TGFβ1-induced fibrosis and inflammatory gene expression in kidney fibroblasts. N-Me-2PY strongly suppressed the expression of types I and III collagen, αSMA, and IL-6. N-Me-2PY also suppressed TGFβ1-induced type I collagen and IL-6 expression in renal tubular epithelial cells. No toxic effect was observed with N-Me-2PY treatment, while attenuating renal fibrosis and tubular dilation in UUO mice. Suppression of various fibrosis- and inflammation-related genes was also observed. N-Me-2PY did not inhibit TGFβ1-induced Smad3 phosphorylation but inhibited Akt phosphorylation, suggesting that N-Me-2PY exerts anti-fibrotic and anti-inflammatory effects through Akt inhibition, similar to pirfenidone. Conclusions: NAD + metabolites, such as N-Me-2PY, are not uremic toxins but are potential therapeutic agents that have anti-fibrotic effects in CKD.

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Pediatric blood pressure category predicts longitudinal blood pressure change in adolescence and early adulthood

Azegami T., Uchida K., Sato Y., Murai-Takeda A., Inokuchi M., Itoh H., Mori M.

Pediatric Research 94 （ 5 ） 1731 - 1737 2023年11月

ISSN 00313998

Background: Patterns of blood pressure (BP) change from early adolescence to young adulthood have not been well-described. The objective of this study was to examine the predictive value of pediatric BP classification on BP change and identify subpopulations with large BP increases during adolescence and early adulthood. Methods: Baseline data were obtained from medical checkups of Japanese adolescents aged 12–13 years in 2009 or 2010 and subsequent BP values were followed for a 9-year period. Mixed-effects models were used to estimate the effects of baseline factors on subsequent BP changes. Results: Hypertensive and elevated BP group consistently had higher BP values than normal BP group throughout the observation period. Multivariate mixed-effects model analyses revealed group-by-time interactions between systolic BP change and BP category in males and uric acid category in females, and between diastolic BP change and white blood cell count in males and obesity and high-density lipoprotein cholesterol in females; however, these factors had limited effects on the rate of BP increase, indicating that they are not suitable as clinical predictors of BP increase. Conclusions: Pediatric BP category predicted BP values, but there was no factor that identified subpopulations with large BP increases in adolescence and early adulthood. Impact: Blood pressure category in the American Academy of Pediatrics clinical practice guideline at age 12–13 years predicted subsequent blood pressure values during adolescence and early adulthood.No baseline factor that identified a subpopulation with large increase in blood pressure during adolescence and early adulthood in clinical practice was found.Our study contributes to the existing literature by demonstrating the usefulness of the American Academy of Pediatrics clinical practice guideline for blood pressure classification in a Japanese population.

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Proportion of early extubation and short-term outcomes after esophagectomy: a retrospective cohort study.

Hirano Y, Konishi T, Kaneko H, Itoh H, Matsuda S, Kawakubo H, Uda K, Matsui H, Fushimi K, Daiko H, Itano O, Yasunaga H, Kitagawa Y

International journal of surgery (London, England) 109 （ 10 ） 3097 - 3106 2023年10月

ISSN 1743-9191

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Adipocyte NMNAT1 expression is essential for nuclear NAD+ biosynthesis but dispensable for regulating thermogenesis and whole-body energy metabolism

Yamaguchi S., Kojima D., Iqbal T., Kosugi S., Franczyk M.P., Qi N., Sasaki Y., Yaku K., Kaneko K., Kinouchi K., Itoh H., Hayashi K., Nakagawa T., Yoshino J.

Biochemical and Biophysical Research Communications 674 162 - 169 2023年09月

ISSN 0006291X

Nicotinamide adenine dinucleotide (NAD+) functions as an essential cofactor regulating a variety of biological processes. The purpose of the present study was to determine the role of nuclear NAD+ biosynthesis, mediated by nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), in thermogenesis and whole-body energy metabolism. We first evaluated the relationship between NMNAT1 expression and thermogenic activity in brown adipose tissue (BAT), a key organ for non-shivering thermogenesis. We found that reduced BAT NMNAT1expression was associated with inactivation of thermogenic gene program induced by obesity and thermoneutrality. Next, we generated and characterized adiponectin-Cre-driven adipocyte-specific Nmnat1 knockout (ANMT1KO) mice. Loss of NMNAT1 markedly reduced nuclear NAD+ concentration by approximately 70% in BAT. Nonetheless, adipocyte-specific Nmnat1 deletion had no impact on thermogenic (rectal temperature, BAT temperature and whole-body oxygen consumption) responses to β-adrenergic ligand norepinephrine administration and acute cold exposure, adrenergic-mediated lipolytic activity, and metabolic responses to obesogenic high-fat diet feeding. In addition, loss of NMNAT1 did not affect nuclear lysine acetylation or thermogenic gene program in BAT. These results demonstrate that adipocyte NMNAT1 expression is required for maintaining nuclear NAD+ concentration, but not for regulating BAT thermogenesis or whole-body energy homeostasis.

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Associated factors and effects of comorbid atrial fibrillation in hypertensive patients due to primary aldosteronism

Sakaguchi S., Okamoto R., Inoue C., Akao M., Kamemura K., Kurihara I., Takeda Y., Ohno Y., Inagaki N., Rakugi H., Katabami T., Tsuiki M., Tanabe A., Tamura K., Fujita S., Yano Y., Dohi K., Abe M., Chiba Y., Fujii Y., Fujita M., Fukui M., Fukuoka T., Goto H., Hasegawa T., Hashimoto S., Haze T., Ichijo T., Itoh H., Iwamoto T., Izawa S., Kai T., Kawaguchi T., Kawamura T., Kawashima J., Kimura N., Kobayashi H., Matsuda F., Matsuda Y., Miyauchi S., Nakamura Y., Nishimoto K., Ogawa O., Ogawa Y., Ogo A., Okamura S., Okumura A., Otsuki M., Sakamoto R., Shimbo T., Sone M., Sugiyama T., Suzuki A., Suzuki T., Takahashi K., Takura T., Tanaka T., Wada N., Watanabe M., Watanabe T., Yamada M., Yamamoto K., Yamasaki T., Yanase T., Yoneda T., Yoshikawa Y., Yoshimoto T., Naruse M.

Journal of Human Hypertension 37 （ 9 ） 757 - 766 2023年09月

ISSN 09509240

The incidence of atrial fibrillation (AF) and risk of cardiovascular events are reportedly higher in patients with primary aldosteronism (PA) than essential hypertension. However, associated factors of comorbid AF and cardiovascular events in PA patients after PA treatment remain unclear. This nationwide registration study included PA patients ≥20 years old. Incident cardiovascular events were observed with a mean follow-up of approximately 3 years. A total of 3654 patients with PA were included at the time of analysis. Prevalence of AF was 2.4%. PA patients with AF were older, more frequently male and had longer duration of hypertension than those without AF. No significant difference in basal plasma and adrenal venous aldosterone concentration, renin activity, potassium concentration, confirmatory tests of PA, laterality or surgery rate were seen between groups. Logistic regression analysis showed age, male sex, cardiothoracic ratio, past history of coronary artery disease and heart failure were independent factors associated with AF. PA patients with AF showed a higher frequency of cardiovascular events than those without AF (P < 0.001). Multivariate Cox analyses demonstrated AF in addition to older age, duration of hypertension, body mass index and chronic kidney disease as independent prognostic factors for cardiovascular events after PA treatment. Incidence of cardiovascular events were significantly lower in PA patients with AF than AF patients from the Fushimi registry during follow-up after adjusting age, sex and systolic blood pressure. Early diagnosis of PA may prevent AF and other cardiovascular events in PA patients by shortening the duration of hypertension and appropriate PA treatment.

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Longitudinal changes in pancreatic volume and pancreatic fat with weight gain in Japanese without diabetes: An analysis using health check-up data.

Sunouchi M, Inaishi J, Shimizu-Hirota R, Saisho Y, Hayashi K, Takaishi H, Itoh H

Metabolism open 19 100250 - 100250 2023年09月

AIMS/INTRODUCTION: There have been few reports about the longitudinal changes in pancreas volume (PV) or pancreatic steatosis (PS) in response to obesity. In this longitudinal analysis using health check-up data, we explored changes in PV, PS and glucose metabolic indices that occurred after weight gain in Japanese without diabetes. MATERIALS/METHODS: Clinical data on 37 Japanese subjects with a ≥1 kg/m2 increase in body mass index between two health check-ups and without diabetes were collected. PV, pancreas attenuation (PA) and splenic attenuation (SA) were evaluated using computed tomography (CT) images. The pancreas area was outlined by hand in multiple images with slice thickness of 2 mm, and the PV was computed by summing these areas. PS was defined as the difference between SA and PA (SA-PA). Medical records were collected, including findings on immunoreactive insulin (IRI), homeostasis model assessment of insulin resistance (HOMA-R) and beta cell function (HOMA-β). Paired t-test and Spearman's correlation coefficient were used in the analyses. RESULTS: The median follow-up period was 21.1 months and the mean BMI was increased from 25.5 ± 3.3 kg/m2 to 27.0 ± 3.3 kg/m2. PV (53.5 ± 15.9 cm3 vs. 56.2 ± 16.4 cm3) and SA-PA (8.7 ± 9.1 HU vs. 13.6 ± 10.9 HU) increased significantly after weight gain (both, P < 0.001). There were significant increases of IRI and HOMA-R with the weight gain (both, P < 0.05), whereas HOMA-β exhibited only a nonsignificant trend of increase (55.4％ (41.5-65.5) vs. 56.8％ (46.2-83.7), P = 0.07). CONCLUSIONS: Both PV and PS were increased longitudinally with weight gain in Japanese without diabetes.

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Characterizing non-Markovian Quantum Process by Fast Bayesian Tomography

R. Y. Su, J. Y. Huang, N. Dumoulin. Stuyck, M. K. Feng, W. Gilbert, T. J. Evans, W. H. Lim, F. E. Hudson, K. W. Chan, W. Huang, Kohei M. Itoh, R. Harper, S. D. Bartlett, C. H. Yang, A. Laucht, A. Saraiva, T. Tanttu, A. S. Dzurak

2023年07月

To push gate performance to levels beyond the thresholds for quantum error
correction, it is important to characterize the error sources occurring on
quantum gates. However, the characterization of non-Markovian error poses a
challenge to current quantum process tomography techniques. Fast Bayesian
Tomography (FBT) is a self-consistent gate set tomography protocol that can be
bootstrapped from earlier characterization knowledge and be updated in
real-time with arbitrary gate sequences. Here we demonstrate how FBT allows for
the characterization of key non-Markovian error processes. We introduce two
experimental protocols for FBT to diagnose the non-Markovian behavior of
two-qubit systems on silicon quantum dots. To increase the efficiency and
scalability of the experiment-analysis loop, we develop an online FBT software
stack. To reduce experiment cost and analysis time, we also introduce a native
readout method and warm boot strategy. Our results demonstrate that FBT is a
useful tool for probing non-Markovian errors that can be detrimental to the
ultimate realization of fault-tolerant operation on quantum computing.

Intermittent Fasting Sustainably Improves Glucose Tolerance in Normal Weight Male Mice Through Histone Hyperacetylation

Endo S., Uto A., Miyashita K., Sato M., Inoue H., Fujii K., Hagiwara A., Ryuzaki M., Oshida T., Kinouchi K., Itoh H.

Journal of the Endocrine Society 7 （ 7 ） bvad082 2023年07月

To explore the mechanism by which intermittent fasting (IF) exerts prolonged effects after discontinuation, we examined mice that had been subjected to 4 cycles of fasting for 72 hours and ad libitum feeding for 96 hours per week (72hIF), followed by 4 weeks of ad libitum feeding, focusing on expression of genes for lipid metabolism in the skeletal muscle and histone acetylation in the promoter region. The 72hIF regimen resulted in metabolic remodeling, characterized by enhanced lipid utilization and mitochondrial activation in the muscle. This longterm IF (72hIF) caused stronger metabolic effects than alternate day fasting (24hIF) wherein fasting and refeeding are repeated every 24 hours. Upregulation of lipid oxidation genes and an increase in oxygen utilization were sustained even at 4 weeks after discontinuation of 72hIF, associated with histone hyperacetylation of the promoter region of uncoupling protein 3 (Ucp3) and carnitine palmitoyl transferase 1b (Cpt1b) genes. An increase in leucine owing to fasting-induced muscle degradation was suggested to lead to the histone acetylation. These findings support the previously unappreciated notion that sustainable promotion of histone acetylation in lipid oxidation genes of the muscle and adipose tissues during and after IF may contribute to sustained metabolic effects of IF

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Impact of Prophylactic Corticosteroid Use on In-hospital Mortality and Respiratory Failure After Esophagectomy for Esophageal Cancer: Nationwide Inpatient Data Study in Japan.

Hirano Y, Konishi T, Kaneko H, Itoh H, Matsuda S, Kawakubo H, Uda K, Matsui H, Fushimi K, Daiko H, Itano O, Yasunaga H, Kitagawa Y

Annals of surgery 277 （ 6 ） e1247 - e1253 2023年06月

ISSN 0003-4932

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Mean annual intradialytic blood pressure decline and cardiovascular events in Japanese patients on maintenance hemodialysis

Takahashi R., Uchiyama K., Washida N., Shibagaki K., Yanai A., Nakayama T., Nagashima K., Sato Y., Kanda T., Itoh H.

Hypertension Research 46 （ 6 ） 1536 - 1546 2023年06月

ISSN 09169636

An intradialytic systolic blood pressure (SBP) decline, which defines intradialytic hypotension, may be associated with higher all-cause mortality. However, in Japanese patients on hemodialysis (HD), the association between intradialytic SBP decline and patient outcomes is unclear. This retrospective cohort study included 307 Japanese patients undergoing HD over 1 year in three dialysis clinics and evaluated the association between the mean annual intradialytic SBP decline (predialysis SBP-nadir intradialytic SBP) and clinical outcomes, including major adverse cardiovascular events (MACEs; cardiovascular death, nonfatal myocardial infarction or unstable angina, stroke, heart failure, and other severe cardiovascular events requiring hospitalization) by following up for 2 years. The mean annual intradialytic SBP decline was 24.2 (25–75th percentile, 18.3–35.0) mmHg. In the model fully adjusted for intradialytic SBP decline tertile group (T1, <20.4 mmHg; T2, 20.4 to <29.9 mmHg; T3, ≥29.9 mmHg), predialysis SBP, age, sex, HD vintage, Charlson comorbidity index, ultrafiltration rate, use of renin–angiotensin system inhibitors, corrected calcium, phosphorus, human atrial natriuretic peptide, geriatric nutritional risk index, normalized protein catabolism rate, C-reactive protein, hemoglobin, and use of pressor agents, Cox regression analyses showed that the hazard ratio (HR) was significantly higher for T3 than for T1 for MACEs (HR, 2.38; 95% confidence interval 1.12–5.09) and all-cause hospitalization (HR, 1.68; 95% confidence interval 1.03–2.74). Therefore, in Japanese patients on HD, a greater intradialytic SBP decline was associated with worse clinical outcomes. Further studies are warranted to investigate whether interventions to attenuate the intradialytic SBP decline will improve the prognosis of Japanese patients on HD. [Figure not available: see fulltext.]

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A systematic review and meta-analysis of the clinical impact of stopping renin–angiotensin system inhibitor in patients with chronic kidney disease

Nakayama T., Mitsuno R., Azegami T., Sato Y., Hayashi K., Itoh H.

Hypertension Research 46 （ 6 ） 1525 - 1535 2023年06月

ISSN 09169636

Although renin–angiotensin system (RAS) inhibitors reduce the risk of cardiovascular diseases and end-stage kidney disease (ESKD) in chronic kidney disease (CKD) patients, they are often discontinued in clinical practice due to drug-related adverse events. However, limited evidence is available about the clinical impact of RAS inhibitor discontinuation in CKD patients. A comprehensive search of publications investigating the effect of discontinuing RAS inhibitors on clinical outcomes in CKD patients in PubMed, the Cochrane Library, and Web of Science was conducted (inception to November 7, 2022), and potentially relevant studies were searched by hand (through November 30, 2022). Two reviewers independently extracted data according to the PRISMA and MOOSE guidelines and assessed the quality of each study with risk-of-bias tools, RoB2 and ROBINS-I. The pooled hazard ratio (HR) for each outcome was integrated with a random-effect model. A total of 1 randomized clinical trial and 6 observational studies involving 248,963 patients were included in the systematic review. The meta-analysis of observational studies showed that discontinuation of RAS inhibitors was associated with a higher risk of all-cause mortality (HR, 1.41 [95% CI, 1.23–1.62]; I2 = 97%), ESKD (1.32 [95% CI, 1.10–1.57]; I2 = 94%) and MACE (1.20 [95% CI 1.15–1.25]; I2 = 38%), but not with hyperkalemia (0.79 [95% CI 0.55–1.15]; I2 = 90%). Overall risk of bias was moderate-to-serious, and quality of evidence (GRADE system) was low-to-very low. The present study suggests that CKD patients would benefit from continuing RAS inhibitors. [Figure not available: see fulltext.]

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A higher resting heart rate is associated with cardiovascular event risk in patients with type 2 diabetes mellitus without known cardiovascular disease

Ikeda S., Shinohara K., Enzan N., Matsushima S., Tohyama T., Funakoshi K., Kishimoto J., Itoh H., Komuro I., Tsutsui H.

Hypertension Research 46 （ 5 ） 1090 - 1099 2023年05月

ISSN 09169636

A higher resting heart rate (RHR) is associated with an increased risk of cardiovascular events in patients with type 2 diabetes mellitus (T2DM) and cardiovascular diseases. The aim of this study was to investigate the association between RHR and cardiovascular events in T2DM patients with diabetic retinopathy and without known cardiovascular disease. We analyzed the association between RHR and cardiovascular events, including coronary, cerebral, renal and vascular events or cardiovascular death in T2DM patients with retinopathy and hyperlipidemia without prior cardiovascular events who were enrolled in the EMPATHY study. Data from 4746 patients were analyzed. The median RHR was 76 bpm. Patients were divided into four groups based on their baseline RHR (< 60, 60–69, 70–79, and ≥80 bpm). Patients with a higher RHR were more likely to be younger and had a higher body mass index, blood pressure value, HbA1c value, and estimated glomerular filtration rate and a lower B-type natriuretic peptide value; they also had a higher proportion of current smoking status, neuropathy, and nephropathy. After adjusting for confounders, including the aforementioned risk factors, a RHR of 70–79 bpm and a RHR ≥ 80 bpm were significantly associated with cardiovascular events (hazard ratio 1.50, 95% CI 1.03–2.20; and hazard ratio 1.62, 95% CI 1.11–2.36; respectively) compared to a RHR of 60–69 bpm. The analysis using restricted cubic splines indicated that the cardiovascular risk seemed to be similarly high when the RHR range was ≥70 bpm. In conclusion, in T2DM patients with diabetic retinopathy and without known cardiovascular disease, a high RHR, particularly ≥70 bpm, was associated with the risk of cardiovascular events compared to a RHR of 60–69 bpm. [Figure not available: see fulltext.].

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DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation

Nakamichi R., Hishikawa A., Chikuma S., Yoshimura A., Sasaki T., Hashiguchi A., Abe T., Tokuhara T., Yoshimoto N., Nishimura E.S., Hama E.Y., Azegami T., Nakayama T., Hayashi K., Itoh H.

Cell Reports 42 （ 4 ） 112302 - 112302 2023年04月

Recent epigenome-wide studies suggest an association between blood DNA methylation and kidney function. However, the pathological importance remains unclear. Here, we show that the homing endonuclease I-PpoI-induced DNA double-strand breaks in kidney glomerular podocytes cause proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis with DNA methylation changes in blood cells as well as in podocytes. Single-cell RNA-sequencing analysis reveals an increase in cytotoxic CD8+ T cells with the activating/costimulatory receptor NKG2D in the kidneys, which exhibit a memory precursor effector cell phenotype, and the CD44high memory CD8+ T cells are also increased in the peripheral circulation. NKG2D blockade attenuates the renal phenotype caused by podocyte DNA damage. Blood methylome shows increased DNA methylation in binding sites for STAT1, a transcription factor contributing to CD8+ T cell homeostasis. Collectively, podocyte DNA damage alters the blood methylome, leading to changes in CD8+ T cells, which contribute to sustained renal injury in chronic kidney disease.

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Impact of Body Mass Index on Major Complications, Multiple Complications, In-hospital Mortality, and Failure to Rescue After Esophagectomy for Esophageal Cancer: A Nationwide Inpatient Database Study in Japan.

Hirano Y, Kaneko H, Konishi T, Itoh H, Matsuda S, Kawakubo H, Uda K, Matsui H, Fushimi K, Itano O, Yasunaga H, Kitagawa Y

Annals of surgery 277 （ 4 ） e785 - e792 2023年04月

ISSN 0003-4932

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Canagliflozin protects the cardiovascular system through effects on the gut environment in non-diabetic nephrectomized rats

Matsui A., Yoshifuji A., Irie J., Tajima T., Uchiyama K., Itoh T., Wakino S., Itoh H.

Clinical and Experimental Nephrology 27 （ 4 ） 295 - 308 2023年04月

ISSN 13421751

Background: The gut produces toxins that contribute to the cardiovascular complications of chronic kidney disease. Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor that is used as an anti-diabetic drug, has a weak inhibitory effect against SGLT1 and may affect the gut glucose concentration and environment. Methods: Here, we determined the effect of canagliflozin on the gut microbiota and the serum gut-derived uremic toxin concentrations in 5/6th nephrectomized (Nx) rats. Results: Canagliflozin increased the colonic glucose concentration and restored the number of Lactobacillus bacteria, which was low in Nx rats. In addition, the expression of tight junction proteins in the ascending colon was low in Nx rats, and this was partially restored by canagliflozin. Furthermore, the serum concentrations of gut-derived uremic toxins were significantly increased by Nx and reduced by canagliflozin. Finally, the wall of the thoracic aorta was thicker and there was more cardiac interstitial fibrosis in Nx rats, and these defects were ameliorated by canagliflozin. Conclusions: The increases in colonic glucose concentration, Lactobacillus numbers and tight junction protein expression, and the decreases in serum uremic toxin concentrations and cardiac interstitial fibrosis may have been caused by the inhibition of SGLT1 by canagliflozin because similar effects were not identified in tofogliflozin-treated rats.

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Diagnosis of monoclonal immunotactoid glomerulopathy with positive λ chain by immunoelectron microscopy

Sugita E., Sonoda H., Ryuzaki M., Hashiguchi A., Tokuyama H., Wakino S., Kanda T., Itoh H.

CEN case reports 12 （ 1 ） 7 - 13 2023年02月

ISSN 2192-4449

We report the case of a 73-year-old-man who developed immunotactoid glomerulopathy (ITG). ITG is a rare disease characterized by proliferative glomerulonephritis and capillary wall deposits with a 10-60 nm diameter microtubular substructure. In monoclonal ITG, immunofluorescence analysis typically exhibits IgG with light chain restriction. Recent reviews recommend distinguishing monoclonal ITG from polyclonal ITG because monoclonal ITG is associated with a higher incidence of hematological disorders and better responsiveness to clone-directed therapy and renal prognosis. In our case, IgG, IgA, and IgM were negative by routine immunofluorescence; however, immunoelectron microscopy revealed positive λ chain. At 6 months after renal biopsy, the IgG λ chain was detected in the serum and urine, reflecting possible monoclonality. Therefore, it is useful to perform immunoelectron microscopy and follow-up with serum and urine protein electrophoresis and immunofixation to diagnose monoclonal ITG, even when routine immunofluorescence shows negative or nonspecific findings.

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Early postoperative non-steroidal anti-inflammatory drugs and anastomotic leakage after oesophagectomy

Hirano, Y; Konishi, T; Kaneko, H; Itoh, H; Matsuda, S; Kawakubo, H; Uda, K; Matsui, H; Fushimi, K; Daiko, H; Itano, O; Yasunaga, H; Kitagawa, Y

BJS-BRITISH JOURNAL OF SURGERY 110 （ 2 ） 260 - 266 2023年01月

ISSN 0007-1323

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Case report: Importance of early and continuous tocilizumab therapy in nephrotic syndrome associated with idiopathic multicentric Castleman disease: A case series

Kojima D., Yamaguchi S., Hashiguchi A., Hayashi K., Uchiyama K., Yoshimoto N., Adachi K., Nakayama T., Nishioka K., Tajima T., Morimoto K., Yoshino J., Yoshida T., Monkawa T., Kanda T., Itoh H.

Frontiers in Medicine 9 1037032 - 1037032 2023年01月

ISSN 2296-858X

Idiopathic multicentric Castleman disease (iMCD) is a systemic and polyclonal lymphoproliferative disease involving multiple organs, including the kidneys, due to the overproduction of interleukin-6 (IL-6). Recently, several reports have suggested that excessive IL-6 actions in iMCD could have a causal relationship with the development of diverse histopathological renal manifestations that cause nephrotic syndrome. However, the treatment for such cases remains unclear. We report a series of three cases of nephrotic syndrome due to iMCD that helps to delineate the importance of early and continuous therapy with the anti-interleukin-6 receptor antibody tocilizumab. First, treatment was suspended for infectious control, and the patient presented with nephrotic syndrome due to diffuse mesangial and endocapillary hypercellularity without immune deposits complicating acute kidney injury. Second, iMCD was treated with prednisolone alone. The patient suddenly developed nephrotic syndrome due to immune-complex glomerulonephritis, not otherwise specified, complicated with acute kidney injury. In the third case, nephrotic syndrome secondary to membranous glomerulonephritis was diagnosed, with a skin rash and IgE antibodies to tocilizumab, and was therefore treated with prednisolone alone. In contrast to the first two cases, the third progressed to end-stage renal disease on hemodialysis. Taken together, this series suggests that clinicians should maintain clinical vigilance for iMCD as a possible underlying component of nephrotic syndrome, since iMCD presents with a variety of renal pathologies. Prompt initiation and continuous administration of tocilizumab are likely key determinants of renal outcomes in such cases. In particular, when tocilizumab is suspended due to infection or in the perioperative period, consideration of its expeditious resumption should be made, taking into account both the withdrawal period and systemic conditions.

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MEAN ANNUAL INTRADIALYTIC BLOOD PRESSURE DECLINE AND CARDIOVASCULAR EVENTS IN JAPANESE MAINTENANCE HEMODIALYSIS PATIENTS

Takahashi, R; Uchiyama, K; Washida, N; Shibagaki, K; Yanai, A; Nakayama, T; Morimoto, K; Itoh, HI

JOURNAL OF HYPERTENSION 41 E387 - E387 2023年01月

ISSN 0263-6352

"MINERALOCORTICOID RECEPTOR (MR)ASSOCIATED HYPERTENSION" IN "GREEDY ORGAN HYPOTHESIS"

Itoh, H

JOURNAL OF HYPERTENSION 41 E143 - E143 2023年01月

ISSN 0263-6352

CONTINUOUS NON-MUTAGENIC DNA DAMAGE IN PODOCYTES ACTIVATES PATHOGENIC MEMORY T CELLS THROUGH ALTERED DNA METHYLATION

Nakamichi, R; Hayashi, K; Hishikawa, A; Chikuma, S; Yoshimoto, N; Sugita, E; Yoshida, E; Itoh, H

JOURNAL OF HYPERTENSION 41 E86 - E87 2023年01月

ISSN 0263-6352

CLINICAL AND BIOCHEMICAL OUTCOMES OF PATIENTS WITH ALDOSTERONE-PRODUCING ADENOMA AFTER RADIOFREQUENCY ABLATION THERAPY AT KEIO UNIVERSITY HOSPITAL: 2022 REPORT

Kozuma, T; Kobayashi, S; Nakamura, T; Kinouchi, K; Yokota, K; Miyashita, K; Kurihara, I; Takase, K; Nakatsuka, S; Itoh, H

JOURNAL OF HYPERTENSION 41 E314 - E314 2023年01月

ISSN 0263-6352

CHANGE OF PANCREAS VOLUME AND GLUCOSE METABOLIC INDEX WITH THE INCREASE OF WEIGHTS: ANALYSES OF COMPREHENSIVE HEALTH CHECKUP DATA

Sunouchi, M; Inaishi, J; Shimizu, R; Saisho, Y; Takaishi, H; Itoh, H

JOURNAL OF HYPERTENSION 41 E461 - E461 2023年01月

ISSN 0263-6352

CASE REPORT: A RARE CASE OF ALVEOLAR HEMORRHAGE AFTER COVID-19 VACCINATION IN A PATIENT WITH RENAL-LIMITED ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY-ASSOCIATED VASCULITIS

Nishioka, K; Yamaguchi, S; Yasuda, I; Yoshimoto, N; Kojima, D; Kaneko, K; Aso, M; Nagasaka, T; Yoshida, E; Uchiyama, K; Tajima, T; Yoshino, J; Yoshida, T; Kanda, T; Itoh, H

JOURNAL OF HYPERTENSION 41 E443 - E443 2023年01月

ISSN 0263-6352

BODY MASS INDEX TRAJECTORY AND TECHNIQUE FAILURE OR DEATH IN PATIENTS INITIATING PERITONEAL DIALYSIS

Kojima, D; Uchiyama, K; Hama, EY; Nagasaka, T; Kusahana, E; Nakayama, T; Morimoto, K; Kanda, T; Washida, N; Itoh, H

JOURNAL OF HYPERTENSION 41 E385 - E385 2023年01月

ISSN 0263-6352

BILATERAL ADRENAL TUMORS IN A PATIENT WITH PRIMARY ALDOSTERONISM CONCURRENT WITH CUSHING'S SYNDROME: A CASE REPORT.

Otomo, Y; Irie, J; Miyashita, K; Kobayashi, S; Kinouchi, K; Nakamura, T; Kubota, Y; Nishimura, T; Itoh, H

JOURNAL OF HYPERTENSION 41 E510 - E510 2023年01月

ISSN 0263-6352

ASSOCIATION BETWEEN DNA METHYLATION AGE OR DNA DAMAGE IN URINARY SHEDDING CELLS AND EARLY CKD

Hishikawa, A; Hayashi, K; Sugita, E; Yoshimoto, N; Nakamichi, R; Yoshida, E; Shimizu, R; Takaishi, H; Itoh, H

JOURNAL OF HYPERTENSION 41 E85 - E86 2023年01月

ISSN 0263-6352

Antineutrophil cytoplasmic antibody-associated vasculitis predominantly manifesting tubulointerstitial nephritis: A case report

Nishioka K., Yamaguchi S., Hashiguchi A., Yoshimoto N., Tajima T., Yasuda I., Uchiyama K., Kaneko K., Aso M., Yoshino J., Monkawa T., Kanda T., Hayashi K., Itoh H.

SAGE Open Medical Case Reports 11 2050313X231197324 2023年01月

ISSN 2050-313X

The common histopathology of antineutrophil cytoplasmic antibody-associated vasculitis comprises pauci-immune crescentic glomerulonephritis with concomitant tubulointerstitial nephritis. Tubulointerstitial nephritis in the absence of glomerular involvement in patients with antineutrophil cytoplasmic antibody-associated vasculitis is uncommon. We report a case of antineutrophil cytoplasmic antibody-associated vasculitis-associated acute kidney injury manifesting as tubulointerstitial nephritis without glomerulonephritis. A 75-year-old woman with fever, cough, and myalgia developed kidney dysfunction with inflammatory reactions and tubular-type proteinuria, without glomerular hematuria. A kidney biopsy revealed tubulointerstitial nephritis with arteritis. We ruled out important underlying etiologies of tubulointerstitial nephritis, including infection, drug reactions, and autoimmune diseases. Since chest high-resolution computed tomography demonstrated mild interstitial pneumonia in bilateral lower lung fields, myeloperoxidase antineutrophil cytoplasmic antibody was measured and found to be positive. Therefore, we diagnosed the patient with antineutrophil cytoplasmic antibody-associated vasculitis-associated tubulointerstitial nephritis but not glomerulonephritis, and interstitial pneumonia. The patient’s kidney function and symptoms markedly improved with prednisolone treatment. Clinicians should maintain high-level vigilance for antineutrophil cytoplasmic antibody-associated vasculitis as a possible underlying component of tubulointerstitial nephritis, particularly when kidney function deteriorates with tubulointerstitial injuries without glomerular features.

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ADENINE NEPHROPATHY IS ALLEVIATED BY ANTI-INFLAMMATORY PROPERTY OF SODIUM BENZOATE

Oshima, Y; Wakino, S; Kanda, T; Tajima, T; Itoh, T; Uchiyama, K; Yoshimoto, K; Sasabe, J; Itoh, H

JOURNAL OF HYPERTENSION 41 E367 - E368 2023年01月

ISSN 0263-6352

A CASE OF RESISTANT HYPERTENSION

Nakajima, Y; Irie, J; Nakamura, T; Kawano, Y; Ito, A; Kinouchi, K; Kobayashi, S; Meguro, S; Itoh, H

JOURNAL OF HYPERTENSION 41 E440 - E440 2023年01月

ISSN 0263-6352

A CASE OF PRIMARY ALDOSTERONISM WITH DECLINED GLOMERULAR FILTRATION RATE AFTER ADRENALECTOMY

Kohmoto, H; Kobayashi, S; Miyashita, K; Kinouchi, K; Nakamura, T; Mizutani, Y; Takeda, T; Oya, M; Tamura, M; Nakatsuka, S; Itoh, H

JOURNAL OF HYPERTENSION 41 E511 - E511 2023年01月

ISSN 0263-6352

A CASE OF PATIENT WITH END-STAGE KIDNEY DISEASE INTRODUCED HEMODIALYSIS AFTER CEREBRAL HEMORRHAGE.

Aso, M; Yamaguchi, S; Yasuda, I; Nishioka, K; Kaneko, K; Kanda, T; Itoh, H

JOURNAL OF HYPERTENSION 41 E508 - E508 2023年01月

ISSN 0263-6352

A CASE OF ALDOSTERONE-PRODUCING ADENOMA DIAGNOSED BY ADRENAL ARTERIOGRAPHY AND BRANCH SELECTIVE ADRENAL VENOUS SAMPLING

Nishikawa, M; Kinouchi, K; Kobayashi, S; Miyashita, K; Takeda, T; Tamura, M; Nakatsuka, S; Mizutani, Y; Otomo, Y; Aoyama, K; Yokota, K; Kurihara, I; Itoh, H

JOURNAL OF HYPERTENSION 41 E345 - E346 2023年01月

ISSN 0263-6352

DISSOCIATION OF SERUM ALDOSTERONE CONCENTRATIONS BETWEEN THE MEASUREMENT METHODS: A CASE REPORT.

Torimitsu, T; Kinouchi, K; Kato, K; Iwahara, A; Kozuma, T; Nakamura, T; Kobayashi, S; Miyashita, K; Itoh, H

JOURNAL OF HYPERTENSION 41 E345 - E345 2023年01月

ISSN 0263-6352

Mechanisms of mineralocorticoid receptor-associated hypertension in diabetes mellitus: the role of O-GlcNAc modification

Jo R., Shibata H., Kurihara I., Yokota K., Kobayashi S., Murai-Takeda A., Mitsuishi Y., Hayashi T., Nakamura T., Itoh H.

Hypertension Research 46 （ 1 ） 19 - 31 2023年01月

ISSN 09169636

This study investigated the mechanism underlying the beneficial effects of mineralocorticoid receptor (MR) antagonists in patients with resistant hypertension and diabetic nephropathy by examining post-translational modification of the MR by O-linked-N-acetylglucosamine (O-GlcNAc), which is strongly associated with type 2 diabetes. Coimmunoprecipitation assays in HEK293T cells showed that MR is a target of O-GlcNAc modification (O-GlcNAcylation). The expression levels and transcriptional activities of the receptor increased in parallel with its O-GlcNAcylation under high-glucose conditions. Liquid chromatography–tandem mass spectrometry revealed O-GlcNAcylation of the MR at amino acids 295–307. Point mutations in those residues decreased O-GlcNAcylation, and both the protein levels and transcriptional activities of MR. In db/db mouse kidneys, MR protein levels increased in parallel with overall O-GlcNAc levels of the tissue, accompanied by increased SGK1 mRNA levels. The administration of 6-diazo-5-oxo-L-norleucin, an inhibitor of O-GlcNAcylation, reduced tissue O-GlcNAc levels and MR protein levels in db/db mice. Thus, our study showed that O-GlcNAcylation of the MR directly increases protein levels and transcriptional activities of the receptor under high-glucose conditions in vitro and in vivo. These findings provide a novel mechanism of MR as a target for prevention of complications associated with diabetes mellitus.

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MECHANISMS OF MINERALOCORTICOID RECEPTOR-ASSOCIATED HYPERTENSION IN DIABETES MELLITUS: ROLE OF O-GLCNAC MODIFICATION

Jo, R; Shibata, H; Kurihara, I; Yokota, K; Kobayashi, S; Murai-Takeda, A; Mitsuishi, Y; Hayashi, T; Nakamura, T; Itoh, H

JOURNAL OF HYPERTENSION 41 E285 - E286 2023年01月

ISSN 0263-6352

ISH2022KYOTO Hypertension Zero Declaration

Tomaszewski, M; Itoh, H

HYPERTENSION RESEARCH 46 （ 1 ） 1 - 2 2023年01月

ISSN 0916-9636

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RENIN-ANGIOTENSIN SYSTEM INHIBITORS IN PATIENTS WITH ADVANCED CHRONIC KIDNEY DISEASE ASSOCIATED WITH A LOWER RISK OF UNPLANNED DIALYSIS INITIATION

Nakayama, T; Morimoto, K; Uchiyama, K; Kusahana, E; Washida, N; Azegami, T; Kanda, T; Yoshida, T; Itoh, H

JOURNAL OF HYPERTENSION 41 E385 - E385 2023年01月

ISSN 0263-6352

RENOVASCULAR HYPERTENSION FROM FIBROMUSCULAR DYSPLASIA WITHOUT ABNORMALITIES IN RENAL DOPPLER ULTRASOUND: A CASE REPORT.

Kato, K; Mizutani, Y; Nakamura, T; Kinouchi, K; Kobayashi, S; Miyashita, K; Itoh, H

JOURNAL OF HYPERTENSION 41 E350 - E350 2023年01月

ISSN 0263-6352

INTERMITTENTLY SCANNED CONTINUOUS GLUCOSE MONITORING IN A DIFFICULT PATIENT WITH GESTATIONAL DIABETES MELLITUS AND SUBCLINICAL CUSHING'S SYNDROME: A CASE REPORT.

Iwahara, A; Sugiyama, K; Tsuchiya, T; Itoh, A; Nakajima, Y; Saisho, Y; Kinouchi, K; Kobayashi, S; Miyashita, K; Irie, J; Meguro, S; Ikenoue, S; Tanaka, M; Itoh, H

JOURNAL OF HYPERTENSION 41 E437 - E437 2023年01月

ISSN 0263-6352

HYPOBILIRUBINEMIA AND HYPERTENSION AS RISK FACTORS FOR DIABETIC RETINOPATHY OF TYPE 1 AND TYPE 2 DIABETES MELLITUS

Tanaka, M; Nishimura, T; Itoh, H

JOURNAL OF HYPERTENSION 41 E382 - E382 2023年01月

ISSN 0263-6352

HIGH BODY MASS INDEX IS A RISK FACTOR FOR TRANSITION TO HEMODIALYSIS OR HYBRID THERAPY AND PERITONEAL DIALYSIS-RELATED INFECTION

Hama, EY; Uchiyama, K; Nagasaka, T; Kusahana, E; Nakayama, T; Yasuda, I; Morimoto, K; Washida, N; Hayashi, K; Itoh, H

JOURNAL OF HYPERTENSION 41 E385 - E386 2023年01月

ISSN 0263-6352

GLUCAGON-LIKE PEPTIDE-1 SUPPRESSES ACTIVATED EFFECTOR MEMORY T CELL SUBSETS IN THE FATTY LIVER INDUCED BY ANTI-CD3-ADNTIBODY ADMINISTRATION IN LEAN MICE

Itoh, A; Yuki, K; Irie, J; Itoh, H

JOURNAL OF HYPERTENSION 41 E369 - E369 2023年01月

ISSN 0263-6352

EVALUATION OF HYPERTENSION COMPLICATIONS AFTER THE START OF WEIGHT MANAGEMENT THERAPY IN OBESITY

Goto, N; Kita, M; Irie, J; Itoh, H

JOURNAL OF HYPERTENSION 41 E461 - E461 2023年01月

ISSN 0263-6352

ENDOTHELIAL GHRELIN RECEPTOR INCREASE WHITE FAT WEIGHT THROUGH ACTIVATION OF MTOR-PPARGAMMA PATHWAY

Kanda, T; Urai, H; Azegami, A; Takahashi, R; Itoh, H

JOURNAL OF HYPERTENSION 41 E450 - E450 2023年01月

ISSN 0263-6352

EFFECTIVENESS OF STATIN INTENSIVE THERAPY IN TYPE 2 DIABETES WITH HIGH VISIT-TO-VISIT BLOOD PRESSURE VARIABILITY

Ikeda, S; Shinohara, K; Enzan, N; Matsushima, S; Tohyama, T; Funakoshi, K; Kishimoto, J; Itoh, H; Komuro, I; Tsutsui, H

JOURNAL OF HYPERTENSION 41 E44 - E45 2023年01月

ISSN 0263-6352

EFFECT OF ESAXERENONE ON NOCTURNAL BLOOD PRESSURE COMBINED WITH RENIN-ANGIOTENSIN SYSTEM INHIBITOR OR CALCIUM CHANNEL BLOCKER IN UNCONTROLLED HYPERTENSION

Kario, K; Ito, S; Itoh, H; Rakugi, H; Okuda, Y; Yamakawa, S

JOURNAL OF HYPERTENSION 41 E65 - E65 2023年01月

ISSN 0263-6352

DNA DAMAGE REPAIR AND DNA METHYLATION IN THE KIDNEY AND CKD

Hayashi, K; Itoh, H

JOURNAL OF HYPERTENSION 41 E87 - E87 2023年01月

ISSN 0263-6352

ONE-YEAR TIME-SERIES OBSERVATIONS OF VARIABLE COMPONENTS OF URINE PROTEIN AND EGFR PREDICT WORSENING RENAL FUNCTION IN TYPE 2 DIABETES

Watanabe, M; Meguro, S; Kimura, K; Furukoshi, M; Masuda, T; Enomoto, M; Itoh, H

JOURNAL OF HYPERTENSION 41 E381 - E381 2023年01月

ISSN 0263-6352

RENAL FUNCTION AND URINARY PROTEIN 1 YEAR AFTER INITIATION OF ESAXERENONE

Aoyama, K; Nakajima, Y; Meguro, S; Itoh, H

JOURNAL OF HYPERTENSION 41 E403 - E403 2023年01月

ISSN 0263-6352

RECURRENCE OF RENAL ARTERY STENOSIS BY PONATINIB, A MULTI-TARGETED TYROSINEKINASE INHIBITOR

Kusahana, E; Wakino, S; Kanda, T; Itoh, H

JOURNAL OF HYPERTENSION 41 E351 - E351 2023年01月

ISSN 0263-6352

PERFORMANCE OF PREDICTION ALGORITHM FOR THE SUBTYPE DIAGNOSIS OF PRIMARY ALDOSTERONISM WHICH WAS ADVOCATED IN THE JAPAN PRIMARY ALDOSTERONISM STUDY

Kobayashi, S; Kurihara, I; Yokota, K; Kinouchi, K; Nakamura, T; Miyashita, K; Itoh, H

JOURNAL OF HYPERTENSION 41 E402 - E402 2023年01月

ISSN 0263-6352

PEDIATRIC BLOOD PRESSURE CATEGORY PREDICTS LONGITUDINAL VARIABILITY IN BLOOD PRESSURE IN YOUTH

Azegami, T; Uchida, K; Sato, Y; Takeda, A; Inokuchi, M; Itoh, H; Mori, M

JOURNAL OF HYPERTENSION 41 E321 - E321 2023年01月

ISSN 0263-6352

PARTIAL ADRENALECTOMY IN A PATIENT WITH ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA: A CASE REPORT.

Takebayashi, S; Irie, J; Kurihara, I; Kobayashi, S; Miyashita, K; Kinouchi, K; Nakamura, T; Itoh, H

JOURNAL OF HYPERTENSION 41 E438 - E438 2023年01月

ISSN 0263-6352

Compared effectiveness of sodium zirconium cyclosilicate and calcium polystyrene sulfonate on hyperkalemia in patients with chronic kidney disease

Nakayama T., Yamaguchi S., Hayashi K., Uchiyama K., Tajima T., Azegami T., Morimoto K., Yoshida T., Yoshino J., Monkawa T., Kanda T., Itoh H.

Frontiers in Medicine 10 1137981 - 1137981 2023年

ISSN 2296-858X

Hyperkalemia is a well-recognized electrolyte abnormality in patients with chronic kidney disease (CKD). Potassium binders are often used to prevent and treat hyperkalemia. However, few studies have evaluated the difference in serum potassium (K+) level-lowering effect during the post-acute phase between the novel potassium binder, sodium zirconium cyclosilicate (ZSC), and conventional agents. This retrospective study included patients who received potassium binders (either ZSC or calcium polystyrene sulfonate [CPS]) in our hospital between May 2020 and July 2022. The patients were divided into the ZSC and CPS groups. After propensity score matching, we compared changes from baseline to the first follow-up point, at least 4 weeks after initiating potassium binders, in electrolytes including K+ level between the two groups. Of the 132 patients, ZSC and CPS were administered in 48 and 84 patients, respectively. After matching, 38 patients were allocated to each group. The ZSC group showed greater reduction in K+ levels than did the CPS group (P < 0.05). Moreover, a significant increase in serum sodium minus chloride levels, a surrogate marker for metabolic acidosis, was observed in the ZSC group (P < 0.05). Our results demonstrated that ZSC could potentially improve hyperkalemia and metabolic acidosis in patients with CKD.

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Correlation between acylcarnitine/free carnitine ratio and cardiopulmonary exercise test parameters in patients with incident dialysis

Ito W., Uchiyama K., Mitsuno R., Sugita E., Nakayama T., Ryuzaki T., Takahashi R., Katsumata Y., Hayashi K., Kanda T., Washida N., Sato K., Itoh H.

Frontiers in Physiology 14 1155281 - 1155281 2023年

ISSN 1664-042X

Objective: Diminished physical capacity is common and progressive in patients undergoing dialysis, who are also prone to deficiency in carnitine, which plays a pivotal role in maintaining skeletal muscle and cardiac function. The present study aimed to evaluate the association of carnitine profile with exercise parameters in patients with incident dialysis. Design and Methods: This was a single-center cross-sectional study including 87 consecutive patients aged 20–90 years who were initiated on dialysis in Keio University Hospital between December 2019 and December 2022 and fulfilled the eligibility criteria. Exercise parameters were evaluated via cardiopulmonary testing (CPX) using the electronically braked STRENGTH ERGO 8 ergometer, whereas the carnitine profile was assessed by determining serum free carnitine (FC), acylcarnitine (AC) levels and AC/FC ratio. Results: The mean cohort age was 62.1 ± 15.2 years, with male and hemodialysis predominance (70% and 73%, respectively). AC/FC was 0.46 ± 0.15, and CPX revealed peak oxygen consumption (VO2) of 13.9 ± 3.7 (mL/kg/min) with percent-predicted peak VO2 of 53.6% ± 14.7% and minute ventilation (VE)/carbon dioxide output (VCO2) slope of 35.1 ± 8.0. Fully-adjusted multivariate linear regression analysis showed that AC/FC was significantly associated with decreased peak VO2 (β, −5.43 [95% confidence interval (CI), −10.15 to −0.70]) and percent-predicted peak VO2 (β, −19.98 [95% CI, −38.43 to −1.52]) and with increased VE/VCO2 slope (β, 13.76 [95% CI, 3.78–23.75]); FC and AC did not exhibit similar associations with these parameters. Moreover, only AC/FC was associated with a decreased peak work rate (WR), percent-predicted WR, anaerobic threshold, delta VO2/delta WR, and chronotropic index. Conclusion: In patients on incident dialysis, exercise parameters, including those related to both skeletal muscle and cardiac function, were strongly associated with AC/FC, a marker of carnitine deficiency indicating altered fatty acid metabolism. Further studies are warranted to determine whether carnitine supplementation can improve exercise capacity in patients on incident dialysis.

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Host metabolic benefits of prebiotic exopolysaccharides produced by Leuconostoc mesenteroides

Miyamoto J., Shimizu H., Hisa K., Matsuzaki C., Inuki S., Ando Y., Nishida A., Izumi A., Yamano M., Ushiroda C., Irie J., Katayama T., Ohno H., Itoh H., Yamamoto K., Kimura I.

Gut Microbes （Taylor & Francis） 15 （ 1 ） 2161271 - 2161271 2023年

ISSN 19490976

Fermented foods demonstrate remarkable health benefits owing to probiotic bacteria or microproducts produced via bacterial fermentation. Fermented foods are produced by the fermentative action of several lactic acid bacteria, including Leuconostoc mesenteroides; however, the exact mechanism of action of these foods remains unclear. Here, we observed that prebiotics associated with L. mesenteroides-produced exopolysaccharides (EPS) demonstrate substantial host metabolic benefits. L. mesenteroides-produced EPS is an indigestible α-glucan, and intake of the purified form of EPS improved glucose metabolism and energy homeostasis through EPS-derived gut microbial short-chain fatty acids, and changed gut microbial composition. Our findings reveal an important mechanism that accounts for the effects of diet, prebiotics, and probiotics on energy homeostasis and suggests an approach for preventing lifestyle-related diseases by targeting bacterial EPS.

Risk factors of neonatal hypoglycemia in neonates born to mothers with gestational diabetes

Arimitsu T., Kasuga Y., Ikenoue S., Saisho Y., Hida M., Yoshino J., Itoh H., Tanaka M., Ochiai D.

Endocrine Journal （一般社団法人日本内分泌学会） 70 （ 5 ） 511 - 517 2023年

ISSN 09188959

Hypoglycemia is one of the most significant problems in neonates born to mothers with gestational diabetes (GDM). This study aimed to identify novel predictors of hypoglycemia in neonates born to mothers with GDM. A total of 443 term singleton infants from mothers diagnosed with GDM and cared for at Keio University Hospital between January 2013 and December 2019 were included in this study. Neonatal hypoglycemia was defined as hypoglycemia of less than 47 mg/dL at 1 or 2 or 4 h after birth, according to previous studies. Among 443 full-term singleton neonates born to mothers with GDM, 200 developed hypoglycemia (45%). Gestational weight gain (GWG), HbA1c at 1st trimester, HbA1c at GDM diagnosis, and the incidence of insulin therapy in the neonatal hypoglycemia group were significantly higher than those in the non-neonatal hypoglycemia group (p = 0.016, p = 0.032, p = 0.011, and p = 0.017, respectively). Regarding the multiple regression analysis adjusted for nulliparity, GWG, and gestational weeks at delivery, the odds ratio for maternal HbA1c ≥5.2% at 1st trimester was 1.63 (p = 0.034), and maternal insulin therapy during pregnancy was 1.72 (p = 0.015). In conclusion, HbA1c in the 1st trimester and insulin therapy during pregnancy were good predictors of hypoglycemia in neonates born to GDM mothers, especially when their HbA1c was 5.2% or more. Further research will be necessary to improve the perinatal management of hypoglycemia.

Impact of coronavirus disease 2019 in seasonal variation of hemoglobin A1c in adults with type 1 diabetes and the effect of the mode of treatment: a single-center retrospective study for 2019 and 2021 and analysis by the mode of treatment

Tanaka K., Meguro S., Itoh A., Kodani N., Itoh H.

Endocrine Journal （一般社団法人日本内分泌学会） 70 （ 8 ） 787 - 795 2023年

ISSN 09188959

The study was aimed to investigate the seasonal variation of hemoglobin A1c (HbA1c) in adults with type 1 diabetes (T1D) and the impact of coronavirus disease 2019 (COVID-19) by comparing 2019 and 2021 data and differences in treatment modes. This was a single-center retrospective observational study including 52 adult patients with T1D who regularly visited hospital in 2019 and 2021. Twenty-five patients used multiple daily injections (MDI)/self-measurement of blood glucose (SMBG), 16 used MDI/intermittently scanned continuous glucose monitoring (isCGM), 9 used sensor-augmented pump (SAP), and 2 used continuous subcutaneous insulin infusion (CSII)/isCGM. The mean HbA1c level was calculated for each month. The correlation between monthly means of temperature and HbA1c was investigated. Similar analyses were performed for the MDI/SMBG, MDI/isCGM, and SAP + CSII/isCGM groups. HbA1c levels in 2019 decreased in summer and increased in winter and showed a significant negative correlation with temperature (r = –0.652, p = 0.022). However, HbA1c in 2021 showed no seasonal variation and no correlation with temperature (r = –0.134, p = 0.678) and tended to decline after the three emergency declarations. HbA1c in the MDI/SMBG group showed the same trend as the whole group in 2019 and 2021. However, the effect of seasonal variation in HbA1c was lower in the MDI/isCGM group and the lowest in the SAP + CSII/isCGM group in 2019. The impact of emergency declaration on HbA1c level was small for the MDI/isCGM group and smaller for the SAP + CSII/isCGM group in 2021. The COVID-19 pandemic has affected the seasonal variation of HbA1c levels in T1D; the variation differed according to the treatment mode.

ASO Author Reflections: Epidural Analgesia Decreases In-Hospital Mortality, Respiratory Complications, and Anastomotic Leakage After Minimally Invasive Esophagectomy for Esophageal Cancer

Hirano, Y; Kaneko, H; Konishi, T; Itoh, H; Matsuda, S; Kawakubo, H; Daiko, H; Itano, O; Yasunaga, H; Kitagawa, Y

ANNALS OF SURGICAL ONCOLOGY 29 （ 13 ） 8235 - 8236 2022年12月

ISSN 1068-9265

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Changes in glycemic variability, gastric emptying and vascular endothelial function after switching from twice-daily to once-weekly exenatide in patients with type 2 diabetes: a subpopulation analysis of the twin-exenatide study

Inaishi J., Saisho Y., Watanabe Y., Tsuchiya T., Sasaki H., Masaoka T., Itoh H.

BMC Endocrine Disorders 22 （ 1 ） 20 - 20 2022年12月

Background: We investigated the changes in blood glucose fluctuation, gastric emptying, and vascular endothelial function by switching from an exenatide twice-daily formulation (BID) to a once-weekly formulation (QW) since the evaluation of postprandial glucose excursion and glycemic variability (GV) by continuous glucose monitoring (CGM) after switching was lacking. Methods: Twenty-nine patients with type 2 diabetes treated with exenatide BID were included in this study and switched to exenatide QW for 24 weeks. GV assessed by CGM, gastric emptying (by 13 C-acetate breath test) and vascular endothelial function (by reactive hyperemia - peripheral arterial tonometry) were evaluated at baseline and 24 weeks after switching. Results: HbA1c decreased significantly from the baseline to week 24, while postprandial glucose levels after breakfast and dinner significantly increased (both P <0.05). However, the increases in GV indices were modest and not statistically significant at week 24. Vascular endothelial function was also not significantly changed after switching (P >0.05). Gastric emptying was significantly accelerated at week 24 (Tmax 83.4 ± 12.1 min vs. 58.2 ± 16.4 min) (P <0.001) and correlated with increased postprandial glucose levels after breakfast and dinner (both P <0.05). Conclusions: Despite the increase in postprandial glucose associated with accelerated gastric emptying after switching from exenatide BID to QW, change in GV was modest and no significant deterioration in vascular endothelial function was observed after switching. These results support the superiority of treatment with exenatide QW over exenatide BID in clinical practice; however, attention should be paid to the monitoring and management of postprandial glucose levels when selecting exenatide QW. Trial registration: Clinical trial registry number; UMIN000016390 and jRCTs031180320. Approval date of Registry and the Registration: December 12, 2014.

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ASO Visual Abstract: Short-Term Outcomes of Epidural Analgesia in Minimally Invasive Esophagectomy for Esophageal Cancer: Nationwide Inpatient Data Study in Japan

Hirano, Y; Kaneko, H; Konishi, T; Itoh, H; Matsuda, S; Kawakubo, H; Uda, K; Matsui, H; Fushimi, K; Daiko, H; Itano, O; Yasunaga, H; Kitagawa, Y

ANNALS OF SURGICAL ONCOLOGY 29 （ 13 ） 8237 - 8238 2022年12月

ISSN 1068-9265

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Effect of Tolvaptan in Patients with Chronic Kidney Disease Stage G5, and Impact of Concomitant Use of Thiazide Diuretics: A Retrospective Cohort Study

Uchiyama K., Kojima D., Hama E.Y., Nagasaka T., Nakayama T., Takahashi R., Tajima T., Morimoto K., Washida N., Itoh H.

Drugs - Real World Outcomes 9 （ 4 ） 649 - 657 2022年12月

ISSN 21991154

Background: The diuretic effect of tolvaptan, a vasopressin V2 receptor antagonist, in patients with severe renal dysfunction remains poorly characterized. Thiazide diuretics reduce urinary volume (UV) in patients with nephrogenic diabetes insipidus, which lacks V2 receptor function. Objective: This retrospective study investigated the acute urinary effects of tolvaptan in patients with stage G5 chronic kidney disease and congestive heart failure (CHF), and the impact of thiazide diuretics on the urinary effects of tolvaptan. Methods: UVs 24 h before and after tolvaptan administration and 30-day dialysis initiation rate were compared between patients with and without thiazide diuretic administration. Results: Thiazide diuretics were used in 26 of the 106 recruited patients (age 73.4 ± 13.0 years; estimated glomerular filtration rate 8.07 ± 3.13 mL/min/1.73 m2). The pre- and post-tolvaptan 24-h UVs were significantly higher in patients not administered thiazide diuretics (1043.4 ± 645.6 vs. 1422.2 ± 774.0 mL/day; p < 0.001) than in those administered thiazide diuretics (1177.3 ± 686.5 vs. 1173.1 ± 629.1 mL/day; p = 0.93). In a multivariate regression model, thiazide diuretic use was significantly associated with decreased 24-h UV (β coefficient − 486.7, 95% confidence interval [CI] − 674.5 to − 298.8); increased urine osmolality (β coefficient 37.7, 95% CI 17.1–58.4); increased body weight (β coefficient 0.62, 95% CI 0.31–0.92); and increased 30-day dialysis initiation rate (odds ratio 3.40, 95% CI 1.18–9.82) after tolvaptan administration. Conclusions: Tolvaptan exhibited significant diuretic effects in patients with CHF, including those with severe renal dysfunction, which were diminished with concomitant thiazide diuretic use.

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Iliopsoas abscess in patients receiving hemodialysis: a case series and a literature survey

Oshida T., Yoshida T., Itoh H., Oya M.

Renal Replacement Therapy 8 （ 1 ） 2022年12月

Background: Iliopsoas abscess is a relatively rare but serious infectious disease. Infectious disease is one of the major causes of death among patients receiving hemodialysis for end-stage renal disease (ESRD). Case presentation: We experienced three cases of iliopsoas abscess in patients receiving hemodialysis. The infection route was distinct in each case. A 79-year-old woman with ESRD due to autosomal dominant polycystic kidney disease exhibited bilateral iliopsoas abscesses caused by bacterial contamination during a lumbar epidural block procedure. A 60-year-old woman with ESRD due to diabetic nephropathy was diagnosed as having an iliopsoas abscess, caused by the direct invasion of bacteria from a renal abscess. A 78-year-old woman who started hemodialysis because of nephrosclerosis developed an iliopsoas abscess caused by the hematogenous spread of bacteria from emphysematous cystitis. All three cases were treated with antibiotics and/or percutaneous drainage. A survey of published reports suggested that iliopsoas abscess can be caused by infection through a variety of routes in hemodialysis patients. Conclusion: Because hemodialysis patients are at a high risk of infection because of their immunocompromised state, physicians should pay close attention to infection prevention. If iliopsoas abscess is suspected, examinations such as computed tomography, magnetic resonance imaging, and blood culture sampling should be conducted promptly, followed by appropriate treatment with antibiotics and/or drainage.

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High body mass index is a risk factor for transition to hemodialysis or hybrid therapy and peritoneal dialysis-related infection in Japanese patients undergoing peritoneal dialysis

Hama E.Y., Uchiyama K., Nagasaka T., Kusahana E., Nakayama T., Yasuda I., Morimoto K., Washida N., Itoh H.

International Urology and Nephrology 54 （ 12 ） 3193 - 3202 2022年12月

ISSN 03011623

Purpose: Obesity may negatively impact the clinical outcomes of patients undergoing peritoneal dialysis (PD). However, the impact of obesity on PD-related outcomes remains unclear. We herein examined the association of high body mass index (BMI) with complete hemodialysis (HD) transfer, transition to HD and PD/HD hybrid therapy, peritonitis, catheter exit-site and tunnel infection (ESI/TI), and heart failure-related hospitalization. Methods: This retrospective cohort study included 120 patients who underwent PD-catheter insertion between January 2008 and June 2018. BMI ≥ 25 kg/m2 at the time of PD-catheter insertion was defined as high BMI, and its association with outcomes was analyzed using the log-rank test and Cox proportional hazards models. Results: The follow-up duration was 46.2 (23.3–75.3) months. The time until transfer to HD and hybrid therapy was significantly shorter in the high BMI group than that in the low BMI group, whereas the time until HD transfer was not significantly different between the two groups (P < 0.001 and 0.18, respectively). Peritonitis-free and ESI/TI-free survivals were significantly shorter in the high BMI group than those in the low BMI group (P = 0.006 and 0.03, respectively). After adjusting for age, sex, diabetes mellitus, and estimated glomerular filtration rate, high BMI remained a significant risk factor for transferring to HD and hybrid therapy, peritonitis, and ESI/TI (hazard ratio [HR] 2.60, P < 0.001; HR 2.08, P = 0.01; HR 2.64, P = 0.02, respectively). Conclusion: BMI ≥ 25 kg/m2 is a risk factor for transition to HD and hybrid therapy, peritonitis, and ESI/TI, but not for complete HD transfer in Japanese patients with PD.

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Effects of a remote patient monitoring system for patients on automated peritoneal dialysis: a randomized crossover controlled trial

Uchiyama K., Morimoto K., Washida N., Kusahana E., Nakayama T., Itoh T., Kasai T., Wakino S., Itoh H.

International Urology and Nephrology 54 （ 10 ） 2673 - 2681 2022年10月

ISSN 03011623

Purpose: Remote patient monitoring (RPM) has contributed to improved patient-centered outcomes and prognosis in patients with end-stage renal disease on automated peritoneal dialysis (APD). However, evidence from prospective trials is lacking. Methods: The participants (n = 15; median age: 65 years; males: 10; peritoneal dialysis vintage: 6.4 ± 3.5 years) randomly received APD therapy using the Kaguya® APD system either with or without the connective use of the cloud-based RPM software Sharesource® for 12 weeks. The primary outcome was patient satisfaction assessed using a modified nine-item Treatment Satisfaction Questionnaire for Medication (TSQM-9) questionnaire. The secondary outcomes were healthcare resource consumption, the health-related quality of life (HRQOL) subscales assessed with the Kidney Disease Quality of Life-Short Form questionnaire, and clinical laboratory parameters. Results: Significant improvements were observed in the TSQM-9 subscales of Effectiveness (64.4 ± 18.8 vs. 57.8 ± 18.8; P = 0.006) and Convenience (76.3 ± 15.4 vs. 63.3 ± 17.3; P < 0.001) in patients on Sharesource®. Moreover, Sharesource® reduced the total amount of healthcare resource consumption (0.80 ± 1.32 vs. 1.87 ± 2.39 times/12 weeks; P = 0.02) and consultation time during regular monthly visits (813 ± 269 vs. 1024 ± 292 s; P < 0.001). A significant increase in ultrafiltration volume was found associated with more frequent modification of APD prescription in patients with Sharesource®. Sharesource® also improved the HRQOL subscale of General Health and Vitality. Conclusion: Sharesource® can improve patient-centered outcomes in patients on APD while reducing the treatment burden for both patients and medical staff. Trial registration: The study was registered in the Japan Registry of Clinical Trials (jRCT Number: jRCTs032190005).

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Proximal-tubule molecular relay from early Protein diaphanous homolog 1 to late Rho-associated protein kinase 1 regulates kidney function in obesity-induced kidney damage

Ida-Naitoh M., Tokuyama H., Futatsugi K., Yasuda M., Adachi K., Kanda T., Tanabe Y., Wakino S., Itoh H.

Kidney International 102 （ 4 ） 798 - 814 2022年10月

ISSN 00852538

The small GTPase protein RhoA has two effectors, ROCK (Rho-associated protein kinase 1) and mDIA1 (protein diaphanous homolog 1), which cooperate reciprocally. However, temporal regulation of RhoA and its effectors in obesity-induced kidney damage remains unclear. Here, we investigated the role of RhoA activation in the proximal tubules at the early and late stages of obesity-induced kidney damage. In mice, a three-week high-fat–diet induced proximal tubule hypertrophy and damage without increased albuminuria, and RhoA/mDIA1 activation without ROCK activation. Conversely, a 12-week high-fat diet induced proximal tubule hypertrophy, proximal tubule damage, increased albuminuria, and RhoA/ROCK activation without mDIA1 elevation. Proximal tubule hypertrophy resulting from cell cycle arrest accompanied by downregulation of the multifunctional cyclin-dependent kinase inhibitor p27Kip1 was elicited by RhoA activation. Mice overexpressing proximal tubule-specific and dominant-negative RHOA display amelioration of high-fat diet-induced kidney hypertrophy, cell cycle abnormalities, inflammation, and renal impairment. In human proximal tubule cells, mechanical stretch mimicking hypertrophy activated ROCK, which triggered inflammation. In human kidney samples from normal individuals with a body mass index of about 25, proximal tubule cell size correlated with body mass index, proximal tubule cell damages, and mDIA1 expression. Thus, RhoA activation in proximal tubules is critical for the initiation and progression of obesity-induced kidney damage. Hence, the switch in the downstream RhoA effector in proximal tubule represents a transition from normal to pathogenic kidney adaptation and to body weight gain, leading to obesity-induced kidney damage.

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Association of cardiovascular disease risk and changes in renin levels by mineralocorticoid receptor antagonists in patients with primary aldosteronism

Nomura M., Kurihara I., Itoh H., Ichijo T., Katabami T., Tsuiki M., Wada N., Yoneda T., Sone M., Oki K., Yamada T., Kobayashi H., Tamura K., Ogawa Y., Inagaki N., Yamamoto K., Otsuki M., Yabe D., Izawa S., Takahashi Y., Suzuki T., Yasoda A., Tanabe A., Naruse M., Fukuda H., Tanaka Y., Takeda Y., Umakoshi H., Shibayama Y., Yoshimoto T., Kawashima J., Takahashi K., Fujita M., Watanabe M., Matsuda Y., Shibata H., Kamemura K., Fujii Y., Rakugi H., Ogo A., Okamura S., Miyauchi S., Yanase T., Kawamura T., Fukuoka T., Kai T., Yoshikawa Y., Hashimoto S., Yamada M., Sakamoto R., Yoshiro C.

Hypertension Research 45 （ 9 ） 1476 - 1485 2022年09月

ISSN 09169636

A recent report stated that patients with primary aldosteronism who remain renin suppressed during mineralocorticoid receptor antagonist treatment might have a higher risk of developing cardiovascular disease than those with unsuppressed renin activity. We retrospectively investigated the incidence of composite cardiovascular disease and risk factors for cardiovascular disease in 1115 Japanese patients with primary aldosteronism treated with mineralocorticoid receptor antagonists. The median follow-up period was 3.0 years, and the incidence of cardiovascular events was very low (2.1%) throughout 5 years of follow-up. Changes in plasma renin activity from before to after mineralocorticoid receptor antagonist treatment were divided into three groups based on tertile, low, intermediate, and high plasma renin activity change groups, with incidences of cardiovascular disease events of 2.1%, 0.5%, and 3.7%, respectively. Multivariate Cox regression analysis revealed age (adjusted hazard ratio, 1.07; 95% confidence interval, [1.02–1.12]) and body mass index (adjusted hazard ratio, 1.13 [1.04–1.23]) as independent risk factors for cardiovascular disease. The high plasma renin activity change group had significantly higher cardiovascular disease risk with mineralocorticoid receptor antagonist treatment than the intermediate plasma renin activity change group (adjusted hazard ratio, 5.71 [1.28–25.5]). These data suggest that a high change in renin level after mineralocorticoid receptor antagonist treatment may not necessarily predict a better prognosis of cardiovascular disease in patients with primary aldosteronism.

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Late Dialysis Modality Education Could Negatively Predict Peritoneal Dialysis Selection

Nakayama T., Nishioka K., Uchiyama K., Morimoto K., Kusahana E., Washida N., Yamaguchi S., Azegami T., Yoshida T., Itoh H.

Journal of Clinical Medicine 11 （ 14 ） 2022年07月

ISSN 2077-0383

Patients with end-stage renal disease are less likely to choose peritoneal dialysis (PD) as renal replacement therapy (RRT). The reasons for this biased selection are still poorly understood. In this study, we evaluated the effect of the timing of RRT education on PD selection. This single-center retrospective observational study included patients who initiated maintenance dialysis at our hospital between April 2014 and July 2021. A logistic regression analysis was performed to investigate the association of RRT education timing with PD selection. Among the 355 participants (median age [IQR] 70 (59–79) years; 28.7% female), 53 patients (14.9%) and 302 patients (85.1%) selected PD and hemodialysis, respectively. Multivariate analysis demonstrated that high estimated glomerular filtration (eGFR) at RRT education positively predicted PD selection (p < 0.05), whereas old age (p < 0.01) and high Charlson comorbidity index (p < 0.05) were negative predictors of PD selection. Female sex (p = 0.44), welfare public assistance (p = 0.78), living alone (p = 0.25), high geriatric nutritional risk index (p = 0.10) and high eGFR at first visit to the nephrology department (p = 0.83) were not significantly associated with PD selection. Late RRT education could increase the biased selection of dialysis modality.

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Prevalence of hypertensive diseases and treated hypertensive patients in Japan: A nationwide administrative claims database study

Waki T., Miura K., Tanaka-Mizuno S., Ohya Y., Node K., Itoh H., Rakugi H., Sato J., Goda K., Kitsuregawa M., Ishikawa T., Mitsutake N.

Hypertension Research 45 （ 7 ） 1123 - 1133 2022年07月

ISSN 09169636

We investigated the prevalence of hypertensive patients and treated hypertensive patients using a Japanese nationwide administrative claims database. We analyzed national database data from 2014, including all claims data, provided by the Ministry of Health, Labour and Welfare of Japan. Hypertensive diseases were identified using Japanese standardized disease codes. Among hypertensive patients, treated hypertensive patients were defined by the prescription of any antihypertensive medication, identified using national health insurance price listing codes. We calculated and compared the number and age-adjusted prevalence of hypertensive patients and treated hypertensive patients by prefecture and the proportion of these patients by the size of medical facilities. In 2014, approximately 27 million Japanese people were identified as hypertensive, among which 89.6% were treated. The age-adjusted prevalence of hypertensive patients (per 100,000 persons) among women and men was 21,414 and 21,084, respectively. The age-adjusted prevalence of treated hypertensive patients (per 100,000 persons) among women and men was 19,118 and 18,974, respectively. While the prevalence of hypertensive and treated hypertensive patients varied geographically, the prevalence remained similar between the sexes. Approximately 59% of hypertensive patients visited clinics (0 to 19 beds) in Japan. In Japan, 27 million people were diagnosed with hypertensive diseases, and approximately 90% of these patients were treated with any antihypertensive medication in 2014. The distribution of hypertensive patients varied geographically throughout Japan.

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Effects of renin-angiotensin system inhibitors on the incidence of unplanned dialysis

Nakayama T., Morimoto K., Uchiyama K., Kusahana E., Washida N., Azegami T., Kanda T., Yoshida T., Itoh H.

Hypertension Research 45 （ 6 ） 1018 - 1027 2022年06月

ISSN 09169636

Unplanned dialysis initiation is associated with poor outcomes. It is controversial whether patients with advanced chronic kidney disease (CKD) should receive renin-angiotensin system (RAS) inhibitor therapy. The aim of this study was to evaluate the effect of RAS inhibitor therapy in patients with advanced CKD on the incidence of unplanned dialysis initiation. This single-center, retrospective study included patients who started maintenance dialysis at our hospital between April 2014 and March 2021. Patients who initiated dialysis within 6 months of nephrology referral or after kidney transplant were excluded. Among 334 patients (aged 70.0 [59.0–79.0] years; 28.4% women), 186 (55.7%) and 148 (44.3%) had planned and unplanned dialysis initiation, respectively. Multivariate logistic regression analysis revealed that the use of RAS inhibitors was significantly associated with a lower incidence of unplanned dialysis initiation (odds ratio [OR], 0.36; P < 0.01). Female sex (OR, 0.41; P < 0.05), use of potassium binders (OR, 0.28; P < 0.001), earlier referral to nephrology (OR, 0.39; P < 0.01), and earlier discussion of renal replacement therapy (OR, 0.33; P < 0.001) were also significantly associated with a lower incidence, whereas older age (OR, 1.28; P < 0.05), higher Charlson Comorbidity Index (OR, 1.24; P < 0.05), and faster decline in kidney function (OR, 1.29; P < 0.01) were associated with a higher risk of unplanned dialysis initiation. RAS inhibitor therapy in patients with advanced CKD is associated with a lower risk of unplanned dialysis initiation.

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Nagasaka T., Washida N., Uchiyama K., Hama E.Y., Kusahana E., Nakayama T., Yasuda I., Morimoto K., Itoh H.

Healthcare (Switzerland) 10 （ 6 ） 2022年06月

ISSN 2227-9032

Despite the superiority of peritoneal dialysis (PD) over hemodialysis (HD) regarding health-related quality of life (HRQOL), the specific HRQOL domain(s) that predict unplanned HD transfer remains uncertain. In this cohort study, we assessed the HRQOL of 50 outpatients undergoing PD using the Japanese version 1.3 Kidney Disease Quality of Life-Short Form from March 2017 to March 2018 and prospectively analyzed the association of each HRQOL component with HD transfer until June 2021. During the follow-up (41.5 (13.0–50.1) months), 21 patients were transferred to HD. In a multivariate Cox proportional hazards model adjusted for age, sex, PD vintage, urine output, Charlson comorbidity index, and incremental shuttle walking test, a higher sleep score was significantly associated with lower HD transfer rates (HR 0.70 per 10, p = 0.01). An adjusted subdistribution hazard model where elected transition to HD, death, and transplantation were considered competing events of unintended HD transfer that showed sleep score as an exclusive predictor of HD transfer (HR 0.70 per 10, p = 0.002). Our results suggest that sleep score among the HRQOL subscales is instrumental in predicting HD transfer in patients undergoing PD.

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Newly developed type 1 diabetes after coronavirus disease 2019 vaccination: A case report

Sasaki H., Itoh A., Watanabe Y., Nakajima Y., Saisho Y., Irie J., Meguro S., Itoh H.

Journal of Diabetes Investigation 13 （ 6 ） 1105 - 1108 2022年06月

ISSN 20401116

The vaccine for the coronavirus disease 2019 (COVID-19) has been reported to potentially cause or worsen diabetes. A 73-year-old Japanese woman received two doses of Moderna COVID-19 vaccine. Four weeks after the second vaccination, her glycemic control began to deteriorate, and 8 weeks after the second vaccination, the patient was diagnosed with new-onset type 1 diabetes that was strongly positive for autoantibodies and showed a disease-susceptible human leukocyte antigen haplotype, DRB1*04:05:01-DQB1*04:01:01. The glucagon stimulation test suggested an insulin-dependent state, and induction of intensive insulin therapy brought about fair glycemic control. The time period from the COVID-19 vaccination to the development of type 1 diabetes was relatively longer than to the onset or exacerbation of type 2 diabetes, as previously reported, suggesting the complicated immunological mechanisms for the destruction of β-cells associated with the vaccination. In recipients with the disease-susceptible haplotypes, one should be cautious about autoimmune responses for several months after the vaccination.

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Development of Alveolar Hemorrhage After Pfizer-BioNTech COVID-19 mRNA Vaccination in a Patient With Renal-Limited Anti-neutrophil Cytoplasmic Antibody-Associated Vasculitis: A Case Report

Nishioka K., Yamaguchi S., Yasuda I., Yoshimoto N., Kojima D., Kaneko K., Aso M., Nagasaka T., Yoshida E., Uchiyama K., Tajima T., Yoshino J., Yoshida T., Kanda T., Itoh H.

Frontiers in Medicine 9 874831 - 874831 2022年04月

ISSN 2296-858X

Since the coronavirus disease 2019 (COVID-19) pandemic continues and a new variant of the virus has emerged, the COVID-19 vaccination campaign has progressed. Rare but severe adverse outcomes of COVID-19 vaccination such as anaphylaxis and myocarditis have begun to be noticed. Of note, several cases of new-onset antineutrophil cytoplasmic antibody-associated vasculitis (AAV) after COVID-19 mRNA vaccination have been reported. However, relapse of AAV in remission has not been recognized enough as an adverse outcome of COVID-19 vaccination. We report, to our knowledge, a first case of renal-limited AAV in remission using every 6-month rituximab administration that relapsed with pulmonary hemorrhage, but not glomerulonephritis, following the first dose of the Pfizer-BioNTech COVID-19 vaccine. The patient received the COVID-19 vaccine more than 6 months after the last dose of rituximab according to the recommendations. However, his CD19+ B cell counts were found to be increased after admission, indicating that our case might have been prone to relapse after COVID-19 vaccination. Although our case cannot establish causality between AAV relapse and COVID-19 mRNA vaccination, a high level of clinical vigilance for relapse of AAV especially in patients undergoing rituximab maintenance therapy following COVID-19 vaccination should be maintained. Furthermore, elapsed time between rituximab administration and COVID-19 mRNA vaccination should be carefully adjusted based on AAV disease-activity.

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Eosinophilic Reaction at the Time of Catheter Insertion Predicts Survival in Patients Initiating Peritoneal Dialysis

Uchiyama K., Washida N., Kusahana E., Nakayama T., Morimoto K., Itoh H.

Blood Purification 51 （ 4 ） 355 - 364 2022年04月

ISSN 02535068

Introduction: Despite excellent biocompatibility, insertion of silicone peritoneal dialysis (PD) catheters can induce minor foreign body reaction, affecting long-term patient outcomes. We evaluated the effect of eosinophilic reaction associated with PD catheter insertion on outcomes of patients initiating PD. Methods: Eosinophilic reaction to PD catheter insertion was defined as the ratio of peripheral blood eosinophil count at 1 week after insertion (E1W) to pre-insertion eosinophil count (E0), and the association of E1W/E0 with technique survival, peritonitis-free survival, and heart failure (HF)-related hospitalization-free survival was analyzed. Results: This retrospective cohort study included 116 patients (89 male patients) who underwent PD catheter insertion between January 2008 and June 2018 (61.3 ± 12.9 years). The follow-up duration was 46.2 (23.8-75.3) months. E1W was significantly higher than E0 (median, 333 vs. 234/μL, p < 0.001), with a median E1W/E0 of 1.54. The log-rank test showed that technique survival, peritonitis-free survival, and HF-related hospitalization-free survival were significantly better in patients with E1W/E0 < 1.54 than in those with E1W/E0 ≥ 1.54 (p = 0.002, <0.001, and <0.001, respectively). By the Cox regression analysis adjusted for age, sex, the Charlson comorbidity index, the estimated glomerular filtration rate, and the geriatric nutritional risk index, E1W/E0 remained a significant risk factor for technique failure, peritonitis, and hospitalization for HF (hazard ratio (HR) 1.68, p = 0.01; HR 2.19, p < 0.001; HR 2.15, p < 0.001, respectively). Conclusion: Eosinophilic reaction at the time of PD catheter insertion is a novel marker that may predict outcomes in patients initiating PD.

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Intestinal Epithelial NAD+Biosynthesis Regulates GLP-1 Production and Postprandial Glucose Metabolism in Mice

Nagahisa T., Yamaguchi S., Kosugi S., Homma K., Miyashita K., Irie J., Yoshino J., Itoh H.

Endocrinology (United States) （Endocrinology (United States)） 163 （ 4 ） 2022年04月

ISSN 00137227

Obesity is associated with perturbations in incretin production and whole-body glucose metabolism, but the precise underlying mechanism remains unclear. Here, we tested the hypothesis that nicotinamide phosphoribosyltransferase (NAMPT), which mediates the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a key regulator of cellular energy metabolism, plays a critical role in obesity-associated intestinal pathophysiology and systemic metabolic complications. To this end, we generated a novel mouse model, namely intestinal epithelial cell-specific Nampt knockout (INKO) mice. INKO mice displayed diminished glucagon-like peptide-1 (GLP-1) production, at least partly contributing to reduced early-phase insulin secretion and postprandial hyperglycemia. Mechanistically, loss of NAMPT attenuated the Wnt signaling pathway, resulting in insufficient GLP-1 production. We also found that diet-induced obese mice had compromised intestinal NAMPT-mediated NAD+ biosynthesis and Wnt signaling pathway, associated with impaired GLP-1 production and whole-body glucose metabolism, resembling the INKO mice. Finally, administration of a key NAD+ intermediate, nicotinamide mononucleotide (NMN), restored intestinal NAD+ levels and obesity-associated metabolic derangements, manifested by a decrease in ileal Proglucagon expression and GLP-1 production as well as postprandial hyperglycemia in INKO and diet-induced obese mice. Collectively, our study provides mechanistic and therapeutic insights into intestinal NAD+ biology related to obesity-associated dysregulation of GLP-1 production and postprandial hyperglycemia.

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Home-Based Exercise Program Ameliorates Renal Function Decline in Patients With CKD Stage 4

Adachi K., Uchiyama K., Muraoka K., Nakayama T., Yasuda M., Miyashita K., Tokuyama H., Wakino S., Itoh H.

Kidney International Reports 7 （ 4 ） 899 - 903 2022年04月

ISSN 24680249

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Lysine-specific demethylase 1 as a corepressor of mineralocorticoid receptor

Kohata N., Kurihara I., Yokota K., Kobayashi S., Murai-Takeda A., Mitsuishi Y., Nakamura T., Morisaki M., Kozuma T., Torimitsu T., Kawai M., Itoh H.

Hypertension Research 45 （ 4 ） 641 - 649 2022年04月

ISSN 09169636

Mineralocorticoid receptor (MR) and its ligand aldosterone play a central role in controlling blood pressure by promoting sodium reabsorption in the kidney. Coregulators are recruited to regulate the activation of steroid hormone receptors. In our previous study, we identified several new candidates for MR coregulators through liquid chromatography-tandem mass spectrometry analysis using a biochemical approach. Lysine-specific demethylase 1 (LSD1) was identified as a candidate. The relationship between LSD1 and salt-sensitive hypertension has been reported; however, the role of MR in this condition is largely unknown. Here, we investigated the functions of LSD1 as a coregulator of MR. First, a coimmunoprecipitation assay using HEK293F cells showed specific interactions between MR and LSD1. A chromatin immunoprecipitation study demonstrated LSD1 recruitment to the gene promoter of epithelial Na+ channel (ENaC), a target gene of MR. Reduced LSD1 expression by treatment with shRNA potentiated the hormonal activation of ENaC and serum/glucocorticoid-regulated kinase 1, another target gene of MR, indicating that LSD1 is a corepressor of MR. In an animal study, mice with kidney-specific LSD1 knockout (LSD1flox/floxKSP-Cre mice) developed hypertension after a high-salt diet without elevation of aldosterone levels, which was counteracted by cotreatment with spironolactone, an MR antagonist. In conclusion, our in vitro and in vivo studies demonstrated that LSD1 is a newly identified corepressor of MR.

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"Greedy Organs Hypothesis" for sugar and salt in the pathophysiology of non-communicable diseases in relation to sodium-glucose co-transporters in the intestines and the kidney

Itoh, H; Tanaka, M

METABOLISM OPEN 13 100169 - 100169 2022年03月

Deposition of visceral fat and insulin resistance play central role in the development of non-communicable diseases (NCDs) including obesity, hypertension and type 2 diabetes. However, we shed more light upon the intestines and the kidney as a strong driver of NCDs. Based upon unexpected outcomes of clinical trials using sodium-glucose cotransporter (SGLT) 2 inhibitors to demonstrate their actions for not only body weight reduction and blood glucose fall but also remarkable cardiorenal protection, we speculate that hyperfunction of the intestines and the kidney is one of critical contributing factors for initiation of NCDs. By detecting high amount of glucose and sodium chloride around them by sweet/salt taste sensors, the intestines and the kidney are designed to (re)absorb these nutrients by up-regulating SGLT1 or SGLT2. We designate these hyperfunctioning organs for nutrient uptake as "greedy organs". The greedy organs can induce NCDs ("greedy organ hypothesis"). SGLTs are regulated by glucose and sodium chloride, and SGLTs or other genes can be "greedy genes." Regulating factors for greedy organs are renin-angiotensin system, renal sympathetic nervous activity, gut inflammation/microbiota or oxidative stress. Mitigation of organ greediness by SGLT2 inhibitors, ketone bodies, bariatric surgery, and regular lifestyle to keep rhythmicity of biological clock are promising.

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Analysis of the IW And star ASAS J071404+7004.3

Taichi Kato, Kiyoshi Kasai, Elena P. Pavlenko, Nikolaj V. Pit, Aleksei A. Sosnovskij, Hiroshi Itoh, Hidehiko Akazawa, Stephen M. Brincat, Leonid E. Keir, Sergei N. Udovichenko, Yusuke Tampo, Naoto Kojiguchi, Masaaki Shibata, Yasuyuki Wakamatsu, Tamas Tordai, Tonny Vanmunster, Charles Galdies

2022年02月

We made a time-resolved photometric campaign of the bright cataclysmic
variable ASAS J071404+7004.3 in 2020. Inight et al. (2022, arXiv/2109.14514)
recently published time-resolved optical spectroscopy, X-ray observations and
long- and short-term optical variations. Although their results were correct in
many parts, they classified ASAS J071404+7004.3 as a VY Scl-type novalike
object. By comparing the ASAS-SN data of this object and the IW And-type object
HO Pup, we showed that their type classification was incorrect. ASAS
J071404+7004.3 showed outbursts from a standstill followed by shallow dips,
which is the defining characteristic of an IW And star. This object
predominantly showed states with low-amplitude dwarf nova-type oscillations,
some of which could be identified as the "heartbeat"-type state as a variety of
the IW And-type phenomenon. The low state described by Inight et al. (2022) was
not a true low state of a VY Scl star, but a dwarf nova-type state with
increased outburst amplitudes. Both ground-based (our campaign) and TESS
observations detected orbital variations whose periods [0.136589(5) d by the
ground-based campaign and 0.1366476(3) d by the TESS data] are in very good
agreement with the one obtained by radial-velocity studies by Inight et al.
(2022). The standstill in 2019-2020 in ASAS J071404+7004.3 was not brighter
than its dwarf nova-type states. The brightest moment of this object occurred
when the amplitudes of dwarf nova-type variations were large, which challenges
the widely accepted interpretation that standstills in Z Cam stars occur when
the mass-transfer rates are high.

Amiodarone-induced multiple organ damage in an Alström syndrome patient with end-stage renal disease and hepatic cirrhosis

Torimitsu T., Yoshida T., Makiuchi S., Itoh H., Oya M.

CEN case reports 11 （ 1 ） 11 - 16 2022年02月

ISSN 2192-4449

Alström syndrome (AS) is an extremely rare disease accompanied by blindness, hearing loss, obesity, type 2 diabetes, dilated cardiomyopathy, and progressive hepatic and renal dysfunction. The life span of AS patients rarely exceeds 50 years, and thus there are very few reports describing the implementation of renal replacement therapy for these patients. We here report a case of AS patient who exhibited dilated cardiomyopathy, end-stage renal disease, and hepatic cirrhosis. He underwent hemodialysis therapy more than 3 years. Although he eventually died of amiodarone-induced multiple organ damage in the lungs and liver, the present case suggests that hemodialysis therapy can be a choice of renal replacement therapy for AS patients with end-stage renal disease.

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Fabry disease associated with multiple myeloma: a case report

Adachi K., Tokuyama H., Oshima Y., Itoh T., Hashiguchi A., Yamakawa H., Togawa T., Sakuraba H., Wakino S., Itoh H.

CEN case reports 11 （ 1 ） 146 - 153 2022年02月

ISSN 2192-4449

Fabry disease (FD) is an X-linked genetic lysosomal disorder caused by alpha-galactosidase A (GLA) deficiency. Multiple myeloma (MM) predominately affects older adults, which ranks as the second commonest hematological malignancy. Their overlap has rarely been reported. We present a case of the coexistence of FD and MM in a patient. We report the case of a 68-year-old woman who was referred to our hospital for the evaluation of thoracic spine tumor with bone destruction. On admission, her serum creatinine (Cr) level was elevated to 12.70 mg/dL from the baseline value of 0.91 mg/dL. Bone marrow aspiration revealed MM. Renal biopsy showed myeloma cast nephropathy, which was the primary cause of acute kidney injury. Renal pathology also showed podocyte swelling and tubule myeloid bodies in a mosaic pattern compatible with female FD. Consequently, the patient was diagnosed as FD based on the germ line mutation in GLA. The patient was treated with bortezomib and dexamethasone therapy, which significantly improved the renal function. This is the second case demonstrating a potential pathogenic relationship between FD and MM. Since FD is one of the few genetic diseases for which there are therapeutic agents with fewer side effects, diagnostic value of FD is high. If an MM patient has multiple organ abnormalities or any familial history, the physician should suspect FD.

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Activation of the intestinal tissue renin-angiotensin systemby transient sodium loading in saltsensitive rats

Ryuzaki M., Miyashita K., Sato M., Inoue H., Fujii K., Hagiwara A., Uto A., Endo S., Oshida T., Kinouchi K., Itoh H.

Journal of Hypertension 40 （ 1 ） 33 - 45 2022年01月

ISSN 02636352

Background: The renal tissue renin-angiotensin system is known to be activated by salt loading in salt-sensitive rats; however, the response in other organs remains unclear. Method: Spontaneously hypertensive rats were subjected to normal tap water or transient high-salt-concentration water from 6 to 14 weeks of age and were thereafter given normal tap water. From 18 to 20 weeks of age, rats given water with a high salt concentration were treated with an angiotensin II type 1 receptor blocker, valsartan. Results: Sustained blood pressure elevation by transient salt loading coincided with a persistent decrease in the fecal sodium content and sustained excess of the circulating volume in spontaneously hypertensive rats. Administration of valsartan sustainably reduced the blood pressure and normalized the fecal sodium levels. Notably, transient salt loading persistently induced the intestinal tissue renin-angiotensin system and enhanced sodium transporter expression exclusively in the small intestine of salt-sensitive rats, suggesting the potential connection of intestinal sodium absorption to salt sensitivity. Conclusion: These results reveal the previously unappreciated contribution of the intestinal tissue reninangiotensin system to sodium homeostasis and blood pressure regulation in the pathophysiology of salt-sensitive hypertension.

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Effect of esaxerenone on nocturnal blood pressure and natriuretic peptide in different dipping phenotypes

Kario K., Ito S., Itoh H., Rakugi H., Okuda Y., Yamakawa S.

Hypertension Research 45 （ 1 ） 97 - 105 2022年01月

ISSN 09169636

There are limited data on the nighttime blood pressure (BP)-lowering effect of esaxerenone and its effect on N-terminal pro b-type natriuretic peptide (NT-proBNP), a predictor of cardiovascular risk, according to different dipping patterns of nocturnal BP. This was a post hoc analysis of a multicenter, open-label, long-term phase 3 study of esaxerenone, a new highly selective mineralocorticoid receptor blocker, in patients with essential hypertension. Patients were classified by dipping pattern (extreme dippers, dippers, non-dippers, risers). Mean changes in BP, changes in dipping pattern, mean NT-proBNP levels, and percentage of patients with normal NT-proBNP levels (<55 pg/mL) at baseline and Weeks 12 and 28 were evaluated. Nighttime systolic BP decreased in all dipping pattern groups at Week 28, with the riser group showing the greatest change (−25.5 mmHg). A significant shift in dipping pattern and riser/non-dipper pattern changes to dipper/extreme dipper pattern were found from baseline to Week 28 (p < 0.0001). The prevalence of the riser pattern decreased from 14.4% to 9.8%, and that of the non-dipper pattern from 44.7% to 39.2%. The decrease in NT-proBNP from baseline to Week 28 was statistically significant in risers, non-dippers, dippers, and extreme dippers (p < 0.001, respectively). At baseline, the proportion of patients with NT-proBNP <55 pg/mL was lowest in risers versus the other dipping pattern types, but after reductions in NT-proBNP in all groups to Week 28, these differences disappeared. Long-term administration of esaxerenone may be a useful treatment option for nocturnal hypertension, especially in patients with a riser pattern.

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Efficacy of dexmedetomidine on peritoneal dialysis catheter insertion

Nakayama T., Uchiyama K., Morimoto K., Washida N., Kasai T., Nakamichi R., Kusahana E., Wakino S., Itoh H.

International Urology and Nephrology 54 （ 1 ） 209 - 215 2022年01月

ISSN 03011623

Purpose: Dexmedetomidine (DEX) is a sedative agent with minimal respiratory and hemodynamic effects. The present study aimed to evaluate its effectiveness in peritoneal dialysis (PD) catheter insertion. Methods: This single-center retrospective study included patients who underwent PD catheter insertion under spinal anesthesia in our hospital between January 2016 and December 2020. Patients were divided into the DEX and non-DEX groups according the use of DEX. After 1:1 propensity score matching to adjust for age, sex, body mass index, mean blood pressure (BP), and Charlson comorbidity index, we compared operation-related outcomes, including peak numerical rating scale (NRS), occurrence of nausea, vital signs, or operative time between the two groups. Results: Of a total of 44 patients, 9 patients received DEX, and 35 did not. After propensity score matching, each group consisted of 8 patients. Peak NRS was significantly lower (P = 0.003) in the DEX group compared with the non-DEX group. Maximum mean BP during the operation was also significantly lower in the DEX group compared with the non-DEX group (P = 0.020), with no significant differences in minimum mean BP between the two groups (P = 0.831). The DEX group showed a trend of shortened operative time (P = 0.068). There were no significant differences in the occurrence of nausea (P = 1.000). Moreover, there was no clinically important adverse event associated with use of DEX. Conclusion: The use of DEX in PD catheter insertion under spinal anesthesia could safely improve operative analgesia.

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Comparison and commutability study between standardized liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) and chemiluminescent enzyme immunoassay for aldosterone measurement in blood

Nishikawa T., Satoh F., Takashi Y., Yanase T., Itoh H., Kurihara I., Shibata H., Oki Y., Naruse M., Sasamoto H., Kuwa K.

Endocrine Journal （一般社団法人日本内分泌学会） 69 （ 1 ） 45 - 54 2022年

ISSN 09188959

A commutability confirmation test for the blood aldosterone measurement was performed on liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) as a designated comparison method (DCM) and four chemiluminescent enzyme immunoassay (CLEIA) measurement procedures based on metrological traceability. A conventional radioimmunoassay (RIA) and two measurement procedures of CLEIA which obtains RIA equivalent values were also compared. The relationship between the DCM value and the CLEIA value with respect to 120 pg/mL of the RIA value, which is the screening criterion of primary aldosteronism (PA) was clarified. For the correlation test, 75 samples of patient serum and plasma were used. Regression analysis revealed that the standardized LC-MS/MS and four CLEIA measurement procedures were in good agreement. This is the effect of measurement specificity and calibration using by certified reference material (CRM). The median of the LC-MS/MS corresponding to 120 pg/mL of RIA was 48.5 pg/mL. In the mean of standardized four CLEIA values corresponding to the 48.5 pg/mL of LC-MS/MS value was 47.51 pg/mL and the standard deviation (SD) was 2.93 pg/mL. However, the correlation between the RIA value and the RIA equivalent of the two measurement procedures by CLEIA differed depending on the measurement procedure. This is due to the influence of RIA measurement performance. Standardized CLEIA measurements are suitable for routine measurement procedure. When converting the LC-MS/MS equivalent value by the standardized CLEIA to the conventional RIA value, it is necessary to use the conversion formula.

Fibronectin Glomerulopathy Confused with Glomerular Endothelial Injury in a Patient with Takotsubo Cardiomyopathy

Azegami T., Hashiguchi A., Nakayama T., Hayashi K., Kanda T., Itoh H.

Internal Medicine （一般社団法人日本内科学会） 61 （ 13 ） 2027 - 2032 2022年

ISSN 09182918

A 46-year-old woman developed takotsubo cardiomyopathy and nephrotic syndrome. The first kidney biopsy suggested non-immune-complex-mediated membranoproliferative glomerulonephritis (MPGN), and she was diagnosed with glomerular endothelial injury associated with takotsubo cardiomyopathy. A second biopsy was performed two years later because of persistent proteinuria despite renin-angiotensin system inhibition. This biopsy indicated non-immune-complex-mediated MPGN, but a mesangial and subendothelial substance of a higher electron density than that in the first biopsy was detected, suggesting the possibility of glomerular disease with non-immune deposits rather than endothelial injury. Finally, she was diagnosed with fibronectin nephropathy. Although rare, fibronectin glomerulopathy should be considered in non-immune-complex-mediated MPGN.

Increased alpha cell to beta cell ratio in patients with pancreatic cancer

Tsuchiya T., Saisho Y., Inaishi J., Sasaki H., Sato M., Nishikawa M., Masugi Y., Yamada T., Itoh H.

Endocrine Journal （一般社団法人日本内分泌学会） 69 （ 12 ） 1407 - 1414 2022年

ISSN 09188959

The development of pancreatic cancer (PC) is associated with worsening of glucose tolerance. However, there is limited information about the effects of PC on islet morphology. The aim of this study was to elucidate changes in alpha and beta cell mass in patients with PC. We enrolled 30 autopsy cases with death due to PC (9 with diabetes; DM) and 31 age-and BMI-matched autopsy cases without PC (controls, 12 with DM). Tumor-free pancreatic sections were stained for insulin and glucagon, and fractional beta cell (BCA) and alpha cell area (ACA) were quantified. In addition, expression of de-differentiation markers, i.e., ALDH1A3 and UCN3, was qualitatively evaluated. The pancreas of subjects with PC showed atrophic and fibrotic changes. There was no significant difference in BCA in subjects with PC compared to controls (1.53 ± 1.26% vs. 0.95 ± 0.42%, p = 0.07). However, ACA and ACA to BCA ratio were significantly higher in subjects with PC compared to controls (2.48 ± 2.39% vs. 0.53 ± 0.26% and 1.94 ± 1.93 vs. 0.59 ± 0.26, respectively, both p < 0.001). Increased ACA to BCA ratio was observed in subjects with PC irrespective of the presence of DM. Qualitative evaluation of ALDH1A3 and UCN3 expression showed no significant difference between the groups. In conclusion, in subjects with PC, alpha to beta cell mass ratio is increased, which may contribute to the increased risk of worsening glucose metabolism. Further studies are warranted to elucidate the mechanisms of increased alpha to beta cell mass in patients with PC.

Remission of Angiographically Confirmed Minocycline-induced Renal Polyarteritis Nodosa: A Case Report and Literature Review

Yokota K., Kurihara I., Nakamura T., Nakatsuka S., Miyashita K., Kobayashi S., Murai-Takeda A., Sone M., Itoh H.

Internal Medicine （一般社団法人日本内科学会） 61 （ 1 ） 103 - 110 2022年

ISSN 09182918

A 23-year-old man presented with severe hypertension. Based on his history of minocycline treatment for over three years and clinical symptoms, such as myalgias and renovascular hypertension with multiple intrarenal aneurysms, he was diagnosed with minocycline-induced renal polyarteritis nodosa (PAN). After minocycline treatment cessation and management of the hypertension, his blood pressure, renin-aldosterone levels, and urinary protein levels gradually improved. Seven and a half years later, repeated angiography found that the aneurysms had resolved. This is the first report in English describing a case of minocycline-induced renal PAN that was reversed functionally and morphologically without steroids or immunosuppressive drugs.

DNA repair factor KAT5 prevents ischemic acute kidney injury through glomerular filtration regulation

Hishikawa A., Hayashi K., Kubo A., Miyashita K., Hashiguchi A., Kinouchi K., Yoshimoto N., Nakamichi R., Akashio R., Sugita E., Azegami T., Monkawa T., Suematsu M., Itoh H.

iScience 24 （ 12 ） 103436 - 103436 2021年12月

The “preconditioning effect” in AKI is a phenomenon in which an episode of ischemia-reperfusion results in tolerance to subsequent ischemia-reperfusion injury. However, its relationship between DNA damage repair has not been elucidated. Here, we show the role of KAT5 in the preconditioning effect. Preconditioning attenuated DNA damage in proximal tubular cells with elevated KAT5 expression. Ischemia-reperfusion (IR) injuries were exacerbated, and preconditioning effect vanished in proximal tubular-cell-specific KAT5 knockout mice. Investigation of tubuloglomerular feedback (TGF) by MALDI-IMS and urinary adenosine revealed that preconditioning caused attenuated TGF at least in part via KAT5. In addition, K-Cl cotransporter 3 (KCC3) expression decreased in damaged proximal tubular cells, which may be involved in accelerated TGF following IR. Furthermore, KAT5 induced KCC3 expression by maintaining chromatin accessibility and binding to the KCC3 promoter. These results suggest a novel mechanism of the preconditioning effect mediated by the promotion of DNA repair and attenuation of TGF through KAT5.

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Age-stratified comparison of clinical outcomes between medical and surgical treatments in patients with unilateral primary aldosteronism

Nakamaru R., Yamamoto K., Akasaka H., Rakugi H., Kurihara I., Yoneda T., Ichijo T., Katabami T., Tsuiki M., Wada N., Yamada T., Kobayashi H., Tamura K., Ogawa Y., Kawashima J., Inagaki N., Fujita M., Watanabe M., Kamemura K., Okamura S., Tanabe A., Naruse M., Itoh H., Fukuda H., Umakoshi H., Shibayama Y., Murakami M., Yoshimoto T., Haze T., Sone M., Takahashi K., Matsuda Y., Shibata H., Otsuki M., Fujii Y., Ogo A., Miyauchi S., Yanase T., Suzuki T., Kawamura T., Asano M., Fukuoka T., Kai T., Izawa S., Yoshikawa Y., Hashimoto S., Yamada M., Sakamoto R., Chiba Y., Okamoto R., Oki K., Yabe D.

Scientific Reports 11 （ 1 ） 2021年12月

Although adrenalectomy (ADX) is an established treatment for unilateral primary aldosteronism (uPA), the influence of age on the surgical outcomes is poorly understood. Therefore, we aimed to elucidate how age affects the clinical outcomes after treatments. We analyzed 153 older (≥ 65 years) and 702 younger patients (< 65 years) with uPA, treated either with ADX or mineralocorticoid receptor antagonist (MRA) in the Japan PA Study, and compared the estimated glomerular filtration rate (eGFR) or blood pressure over a 36-month period after treatments. ADX-treated patients showed severer biochemical indicators than MRA-treated patients. During 6 and 36 months, the eGFR decreased more prominently in older but not in younger patients with ADX than in those with MRA, which remained significant after adjustment with the inverse probability of treatment weighting (IPTW). There was a significant interaction between the age-groups and the treatment choices in the change of the eGFR with IPTW-adjusted analysis. The post-treatment dose of antihypertensive medication was lower in younger and higher in older patients with ADX than those with MRA. The clinical benefit of ADX differed between younger and older patients with uPA. These findings indicate the need for further validation on whether ADX can benefit older patients with uPA.

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Diabetic condition induces hypertrophy and vacuolization in glomerular parietal epithelial cells

Kawaguchi T., Hasegawa K., Yasuda I., Muraoka H., Umino H., Tokuyama H., Hashiguchi A., Wakino S., Itoh H.

Scientific Reports 11 （ 1 ） 1515 - 1515 2021年12月

ISSN 2045-2322

Diabetic nephropathy (DN) is accompanied by characteristic changes in the glomerulus, but little is known about the effect of diabetes on parietal epithelial cells (PECs). In this study, a descriptive analysis of PECs was undertaken in diabetic db/db mice and in diabetic patients. PEC hypertrophy was significantly more prominent in diabetic mice than in nondiabetic mice, and this was evident even at the early stage. Additionally, the number of vacuoles in PECs was markedly increased in diabetic mice, suggesting the presence of cellular injury in PECs in DN. Although rare, binuclear cells were observed in mice with early diabetes. In cultured PECs, a high glucose condition, compared with normal glucose condition, induced cellular hypertrophy and apoptosis. Flow cytometry showed that some PECs in the G0 phase reentered the cell cycle but got arrested in the S phase. Finally, in human diabetic subjects, hypertrophy and vacuolization were observed in the PECs. Our data showed that PECs undergo substantial changes in DN and may participate in rearrangement for differentiation into podocytes.

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Clinical utility of 1-month postpartum random plasma glucose and glycated hemoglobin combined with pre-pregnancy body mass index for detecting postpartum glucose intolerance in Japanese women with gestational diabetes

Sugiyama K., Saisho Y., Kasuga Y., Ochiai D., Itoh H.

Journal of Diabetes Investigation 12 （ 12 ） 2242 - 2246 2021年12月

ISSN 20401116

During the coronavirus disease 2019 pandemic, the Japanese Society of Diabetes and Pregnancy proposed the use of random plasma glucose and glycated hemoglobin measured 1 month after delivery combined with pre-pregnancy body mass index to detect postpartum glucose intolerance instead of carrying out the oral glucose tolerance test in women with gestational diabetes. We retrospectively evaluated the clinical utility of this strategy to detect postpartum glucose intolerance evaluated by the oral glucose tolerance test after delivery. A total of 275 Japanese women with gestational diabetes were included in the present study. The specificity of 1-month postpartum random plasma glucose and glycated hemoglobin combined with pre-pregnancy body mass index to predict postpartum glucose intolerance was 98.0%, with a negative predictive value of 72.6%. However, sensitivity was 6.4%, with a positive predictive value of 55.6%. In conclusion, this Japanese Society of Diabetes and Pregnancy strategy showed high specificity, but low sensitivity, for detecting glucose intolerance postpartum.

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Association of visit-to-visit glycemic variability with risk of cardiovascular diseases in high-risk Japanese patients with type 2 diabetes: A subanalysis of the EMPATHY trial

Sato M., Inaishi J., Saisho Y., Sato Y., Komuro I., Itoh H.

Journal of Diabetes Investigation 12 （ 12 ） 2190 - 2196 2021年12月

ISSN 20401116

Aims/Introduction: Long-term glycemic variability is important for predicting diabetic complications, but evaluation in a Japanese population is lacking. The aim of this study was to explore the relationship between visit-to-visit glycemic variability (VVV) and cardiovascular diseases (CV) in Japanese patients with type 2 diabetes, using the prospective cohort of the EMPATHY trial. Materials and Methods: Among 4532 participants with at least three HbA1c measurements, VVV was defined using the coefficient of variation (CV-HbA1c). The outcomes were the composite cardiovascular endpoints, including cardiac, cerebral, renal, and vascular events. The odds ratios (ORs) for the development of outcomes were estimated by using logistic regression models. Results: During a median follow-up of 38 months, 190 subjects developed CV events. The risk of developing CV events increased significantly with increasing quintile of CV-HbA1c, after multivariable adjustment including the mean-HbA1c (OR for the fifth vs first quintile, 1.73; 95%CI, 1.03–2.91; P for trend test = 0.003). There was a stronger association between CV-HbA1c and CV events in patients with a mean-HbA1c of <7% compared with those with a mean-HbA1c of ≥7% (OR per 1 standard deviation, 1.51; 95%CI, 1.23–1.85 and 1.13; 95%CI, 0.98–1.29, respectively; P for interaction = 0.02). Conclusions: Increases of VVV were associated with the risk of CV events in Japanese patients with type 2 diabetes independent of the mean-HbA1c. The long-term variability of HbA1c as well as the mean HbA1c might be an important glycemic indicator in the management of patients with type 2 diabetes, especially in those with a mean-HbA1c of <7%.

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Association between testosterone and lipid profiles under statin therapy and its clinical impact on the cardiovascular event risk

Nakayama A., Morita H., Kawahara T., Itoh H., Komuro I.

Heart and Vessels 36 （ 12 ） 1794 - 1803 2021年12月

ISSN 09108327

Statin therapy may decrease the levels of serum steroid hormones, including testosterone and cortisol, accompanied by lowering low-density lipoprotein cholesterol (LDL-C) levels, which remains to be investigated. The aim of this study is to examine the association between steroid hormones and lipids under statin therapy and its clinical impact on the cardiovascular event risk from a viewpoint of steroid hormone metabolism. Using a population dataset extracted from the standard versus intEnsive statin therapy for hyper-cholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) study, we analyzed the correlation between steroid hormones and lipid profiles at registration and 1 year after registration, comparing between male patients with or without cardiovascular events (CV events) within 4 years (CV events + ; n = 100, and CV events − ; n = 100, respectively) after prognostic score matching. The risk for CV events was evaluated using conditional logistic regression analysis. Testosterone levels were lower in the CV events + group than in the CV events − group at registration (5.2 ± 2.2 vs. 7.6 ± 4.1 ng/mL, p < 0.001). Testosterone levels were lowered to 5.1 ng/mL on average in proportion with LDL-C lowering, and Δtestosterone was correlated with ΔLDL-C during 1 year after registration. Cortisol levels were not correlated with LDL-C levels. In addition, testosterone levels at 1 year after registration were not associated with cardiovascular event risk. In male hypercholesterolemic patients with diabetic retinopathy, testosterone levels were positively correlated with LDL-C levels, which were mildly lowered in proportion with LDL-C lowering under mild statin therapy. This decrease in testosterone levels under statin therapy was not related to the increase in cardiovascular event risk. Clinical trial registration: UMIN 000003486. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000004199.

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Efficacy of intensive lipid-lowering therapy with statins stratified by blood pressure levels in patients with type 2 diabetes mellitus and retinopathy: Insight from the EMPATHY study

Shinohara K., Ikeda S., Enzan N., Matsushima S., Tohyama T., Funakoshi K., Kishimoto J., Itoh H., Komuro I., Tsutsui H.

Hypertension Research 44 （ 12 ） 1606 - 1616 2021年12月

ISSN 09169636

Intensive lipid-lowering therapy is recommended in individuals exhibiting type 2 diabetes mellitus (T2DM) with microvascular complications (as high-risk patients), even without known cardiovascular disease (CVD). However, evidence is insufficient to stratify the patients who would benefit from intensive therapy among them. Hypertension is a major risk factor, and uncontrolled blood pressure (BP) is associated with increased CVD risk. We evaluated the efficacy of intensive vs. standard statin therapy for primary CVD prevention among T2DM patients with retinopathy stratified by BP levels. We used the dataset from the EMPATHY study, which compared intensive statin therapy targeting low-density lipoprotein cholesterol (LDL-C) levels of <70 mg/dL and standard therapy targeting LDL-C levels ranging from ≥100 to <120 mg/dL in T2DM patients with retinopathy without known CVD. A total of 4980 patients were divided into BP ≥ 130/80 mmHg (systolic BP ≥ 130 mmHg and/or diastolic BP ≥ 80 mmHg, n = 3335) and BP < 130/80 mmHg (n = 1645) subgroups by baseline BP levels. During the median follow-up of 36.8 months, 281 CVD events were observed. Consistent with previous studies, CVD events occurred more frequently in the BP ≥ 130/80 mmHg subgroup than in the BP < 130/80 mmHg subgroup (P < 0.001). In the BP ≥ 130/80 mmHg subgroup, intensive statin therapy was associated with lower CVD risk (HR 0.70, P = 0.015) than standard therapy after adjustment. No such association was observed in the BP < 130/80 mmHg subgroup. The interaction between BP subgroup and statin therapy was significant. In conclusion, intensive statin therapy targeting LDL-C < 70 mg/dL provided benefits in primary CVD prevention when compared with standard therapy among T2DM patients with retinopathy and BP ≥ 130/80 mmHg.

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Home-based aerobic exercise and resistance training for severe chronic kidney disease: a randomized controlled trial

Uchiyama K., Adachi K., Muraoka K., Nakayama T., Oshida T., Yasuda M., Hishikawa A., Minakuchi H., Miyashita K., Tokuyama H., Wakino S., Itoh H.

Journal of Cachexia, Sarcopenia and Muscle 12 （ 6 ） 1789 - 1802 2021年12月

ISSN 21905991

Background: The potential effects of aerobic and resistance training in patients with severe chronic kidney disease (CKD) are not fully elucidated. This study investigated the effects of a home-based exercise programme on physical functioning and health-related quality of life (HRQOL) in patients with Stage 4 CKD, equivalent to estimated glomerular filtration rate of 15–30 mL/min/1.73 m2. Methods: Forty-six patients with Stage 4 CKD (median age, 73 years; 33 men) were randomly assigned to exercise (n = 23) and control (n = 23) groups. Exercise group patients performed aerobic exercise at 40–60% peak heart rate thrice weekly and resistance training at 70% of one-repetition maximum twice weekly at home for 6 months. Control patients received no specific intervention. Primary outcomes were distance in incremental shuttle walking test and HRQOL assessed using the Kidney Disease Quality of Life—Short Form questionnaire. Secondary outcomes included kidney function assessed with combined urea and creatinine clearance, urinary biomarkers, and anthropometric and biochemical parameters associated with CKD. Results: Improvement in incremental shuttle walking test was significantly greater in the exercise group compared with controls (39.4 ± 54.6 vs. −21.3 ± 46.1; P < 0.001). Among Kidney Disease Quality of Life domains, significant mean differences were observed between the exercise group and the control group in work status, quality of social interaction, and kidney disease component summary outcomes (12.76 ± 5.76, P = 0.03; 5.97 ± 2.59, P = 0.03; and 4.81 ± 1.71, P = 0.007, respectively). There were greater reductions in natural log (ln)-transformed urinary excretion of liver-type fatty acid-binding protein, ln serum C-reactive protein, and acylcarnitine to free carnitine ratio in the exercise group compared with controls, with significant between-group differences of −0.579 ± 0.217 (P = 0.008), −1.13 ± 0.35 (P = 0.003), and −0. 058 ± 0.024 (P = 0.01), respectively. Conclusions: Our 6 month home-based exercise programme improved aerobic capacity and HRQOL in patients with Stage 4 CKD, with possible beneficial effects on kidney function and CKD-related parameters.

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Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians

Sato Y., Atarashi K., Plichta D.R., Arai Y., Sasajima S., Kearney S.M., Suda W., Takeshita K., Sasaki T., Okamoto S., Skelly A.N., Okamura Y., Vlamakis H., Li Y., Tanoue T., Takei H., Nittono H., Narushima S., Irie J., Itoh H., Moriya K., Sugiura Y., Suematsu M., Moritoki N., Shibata S., Littman D.R., Fischbach M.A., Uwamino Y., Inoue T., Honda A., Hattori M., Murai T., Xavier R.J., Hirose N., Honda K.

Nature 599 （ 7885 ） 458 - 464 2021年11月

ISSN 00280836

Centenarians have a decreased susceptibility to ageing-associated illnesses, chronic inflammation and infectious diseases1–3. Here we show that centenarians have a distinct gut microbiome that is enriched in microorganisms that are capable of generating unique secondary bile acids, including various isoforms of lithocholic acid (LCA): iso-, 3-oxo-, allo-, 3-oxoallo- and isoallolithocholic acid. Among these bile acids, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from the faecal microbiota of a centenarian, we identified Odoribacteraceae strains as effective producers of isoalloLCA both in vitro and in vivo. Furthermore, we found that the enzymes 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3β-HSDH) were responsible for the production of isoalloLCA. IsoalloLCA exerted potent antimicrobial effects against Gram-positive (but not Gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecium. These findings suggest that the metabolism of specific bile acids may be involved in reducing the risk of infection with pathobionts, thereby potentially contributing to the maintenance of intestinal homeostasis.

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Risk factors for haemodynamic instability and its prolongation during laparoscopic adrenalectomy for pheochromocytoma

Takeda T., Hakozaki K., Yanai Y., Masuda T., Yasumizu Y., Tanaka N., Matsumoto K., Morita S., Kosaka T., Mizuno R., Kurihara I., Asanuma H., Itoh H., Oya M.

Clinical Endocrinology 95 （ 5 ） 716 - 726 2021年11月

ISSN 03000664

Objective: Pheochromocytoma is a rare neuroendocrine tumour that secretes catecholamines and originates in the adrenal gland. Although surgical resection is the only curative therapy for pheochromocytoma, it is associated with a risk of haemodynamic instability (HDI), such as extremely high blood pressure and/or post tumour removal hypotension and shock. We investigated the risk factors for HDI during pheochromocytoma surgery. Design and Patients: Eighty-two patients who underwent laparoscopic adrenalectomy for pheochromocytoma between July 2002 and February 2020 were examined. We excluded 3 patients with bilateral disease and 11 without detailed 24 h urinary data. We defined HDI as systolic blood pressure ≥ 200 or <80 mmHg. We investigated the risk factors for HDI during laparoscopic adrenalectomy for pheochromocytoma. Results: There were 29 males and 39 females with a median age of 50.5 years. Tumours were localised on the right adrenal gland in 28 patients and on the left in 40. The median tumour diameter was 37.5 mm and the median pneumoperitoneum time was 93.5 min. Twenty-five out of sixty-eight patients (37%) developed HDI. A multivariate analysis identified diabetes mellitus (DM; odds ratio: 3.834; 95% confidence interval: 1.062–13.83; p =.04) as an independent predictor of HDI. In terms of hormonal data, median 24 h urinary epinephrine levels (p =.04) and metanephrine levels (p =.01) were significantly higher in the HDI group. DM was also considered as a risk factor for prolonged HDI (p =.02). Conclusion: Surgeons and anaesthesiologists need to be aware of the risk of HDI and its prolongation during laparoscopic adrenalectomy for pheochromocytoma for DM patients.

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Revisiting Regulators of Human β-cell Mass to Achieve β-cell-centric Approach Toward Type 2 Diabetes

Sasaki H., Saisho Y., Inaishi J., Itoh H.

Journal of the Endocrine Society 5 （ 10 ） bvab128 2021年10月

Type 2 diabetes (T2DM) is characterized by insulin resistance and β-cell dysfunction. Because patients with T2DM have inadequate β-cell mass (BCM) and β-cell dysfunction worsens glycemic control and makes treatment difficult, therapeutic strategies to preserve and restore BCM are needed. In rodent models, obesity increases BCM about 3-fold, but the increase in BCM in humans is limited. Besides, obesity-induced changes in BCM may show racial differences between East Asians and Caucasians. Recently, the developmental origins of health and disease hypothesis, which states that the risk of developing noncommunicable diseases including T2DM is influenced by the fetal environment, has been proposed. It is known in rodents that animals with low birthweight have reduced BCM through epigenetic modifications, making them more susceptible to diabetes in the future. Similarly, in humans, we revealed that individuals born with low birthweight have lower BCM in adulthood. Because β-cell replication is more frequently observed in the 5 years after birth, and β cells are found to be more plastic in that period, a history of childhood obesity increases BCM. BCM in patients with T2DM is reduced by 20% to 65% compared with that in individuals without T2DM. However, since BCM starts to decrease from the stage of borderline diabetes, early intervention is essential for β-cell protection. In this review, we summarize the current knowledge on regulatory factors of human BCM in health and diabetes and propose the β-cell-centric concept of diabetes to enhance a more pathophysiology-based treatment approach for T2DM.

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Continuous Non-Mutagenic DNA Damage in Podocytes Activates Inflammatory Response and May Accelerate Kidney Aging

Nakamichi, R; Hishikawa, A; Hayashi, K; Itoh, H

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 32 （ 10 ） 531 - 531 2021年10月

ISSN 1046-6673

Epigenetic Alterations in Podocytes in Diabetic Nephropathy

Sugita E., Hayashi K., Hishikawa A., Itoh H.

Frontiers in Pharmacology 12 759299 - 759299 2021年09月

ISSN 1663-9812

Recently, epigenetic alterations have been shown to be involved in the pathogenesis of diabetes and its complications. Kidney podocytes, which are glomerular epithelial cells, are important cells that form a slit membrane—a barrier for proteinuria. Podocytes are terminally differentiated cells without cell division or replenishment abilities. Therefore, podocyte damage is suggested to be one of the key factors determining renal prognosis. Recent studies, including ours, suggest that epigenetic changes in podocytes are associated with chronic kidney disease, including diabetic nephropathy. Furthermore, the association between DNA damage repair and epigenetic changes in diabetic podocytes has been demonstrated. Detection of podocyte DNA damage and epigenetic changes using human samples, such as kidney biopsy and urine-derived cells, may be a promising strategy for estimating kidney damage and renal prognoses in patients with diabetes. Targeting epigenetic podocyte changes and associated DNA damage may become a novel therapeutic strategy for preventing progression to end-stage renal disease (ESRD) and provide a possible prognostic marker in diabetic nephropathy. This review summarizes recent advances regarding epigenetic changes, especially DNA methylation, in podocytes in diabetic nephropathy and addresses detection of these alterations in human samples. Additionally, we focused on DNA damage, which is increased under high-glucose conditions and associated with the generation of epigenetic changes in podocytes. Furthermore, epigenetic memory in diabetes is discussed. Understanding the role of epigenetic changes in podocytes in diabetic nephropathy may be of great importance considering the increasing diabetic nephropathy patient population in an aging society.

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Calcium phosphate microcrystals in the renal tubular fluid accelerate chronic kidney disease progression

Shiizaki K., Tsubouchi A., Miura Y., Seo K., Kuchimaru T., Hayashi H., Iwazu Y., Miura M., Battulga B., Ohno N., Hara T., Kunishige R., Masutani M., Negishi K., Kario K., Kotani K., Yamada T., Nagata D., Komuro I., Itoh H., Kurosu H., Murata M., Kuro-o M.

Journal of Clinical Investigation 131 （ 16 ） 2021年08月

ISSN 00219738

The Western pattern diet is rich not only in fat and calories but also in phosphate. The negative effects of excessive fat and calorie intake on health are widely known, but the potential harms of excessive phosphate intake are poorly recognized. Here, we show the mechanism by which dietary phosphate damages the kidney. When phosphate intake was excessive relative to the number of functioning nephrons, circulating levels of FGF23, a hormone that increases the excretion of phosphate per nephron, were increased to maintain phosphate homeostasis. FGF23 suppressed phosphate reabsorption in renal tubules and thus raised the phosphate concentration in the tubule fluid. Once it exceeded a threshold, microscopic particles containing calcium phosphate crystals appeared in the tubule lumen, which damaged tubule cells through binding to the TLR4 expressed on them. Persistent tubule damage induced interstitial fibrosis, reduced the number of nephrons, and further boosted FGF23 to trigger a deterioration spiral leading to progressive nephron loss. In humans, the progression of chronic kidney disease (CKD) ensued when serum FGF23 levels exceeded 53 pg/mL. The present study identified calcium phosphate particles in the renal tubular fluid as an effective therapeutic target to decelerate nephron loss during the course of aging and CKD progression.

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Development of nephropathy in an adult patient after Fontan palliation for cyanotic congenital heart disease

Hayashi K., Hashiguchi A., Ikemiyagi M., Tokuyama H., Wakino S., Itoh H.

CEN case reports 10 （ 3 ） 354 - 358 2021年08月

ISSN 2192-4449

Cyanotic congenital heart disease is occasionally associated with kidney dysfunction, which is known as cyanotic nephropathy or cyanotic glomerulopathy. The clinical presentation of cyanotic nephropathy includes proteinuria, decreased estimated glomerular filtration rate, hyperuricemia, thrombocytopenia, or polycythemia. Although advances in surgical procedures have improved the prognosis of cyanotic congenital heart diseases, adult cases of cyanotic nephropathy are still rare, and there are few reports of kidney biopsy in adults with cyanotic nephropathy. Here, we present the case of a 41-year-old patient with Fontan palliation who developed nephrotic range proteinuria and had a kidney biopsy, which showed glomerular hypertrophy with segmental glomerulosclerosis around vascular poles, suggesting adaptive focal segmental glomerulosclerosis. This case provides further understanding of kidney dysfunction due to cyanotic congenital heart disease and shows the need for attention in the management for prevention of progression to end-stage renal disease and in the selection of renal replacement therapy.

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Lipid-lowering statin therapy is beneficial in elderly female patients with hypercholesterolaemia and diabetic retinopathy

Saito Y., Nakayama A., Sato T., Morita H., Kawahara T., Itoh H., Komuro I.

European Journal of Preventive Cardiology 28 （ 8 ） E7 - E9 2021年08月

ISSN 20474873

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Circadian rhythms in the tissue-specificity from metabolism to immunity: insights from omics studies

Kinouchi K., Mikami Y., Kanai T., Itoh H.

Molecular Aspects of Medicine 80 100984 - 100984 2021年08月

ISSN 00982997

Creatures on earth have the capacity to preserve homeostasis in response to changing environments. The circadian clock enables organisms to adapt to daily predictable rhythms in surrounding conditions. In mammals, circadian clocks constitute hierarchical network, where the central pacemaker in hypothalamic suprachiasmatic nucleus (SCN) serves as a time-keeping machinery and governs peripheral clocks in every other organ through descending neural and humoral factors. The central clock in SCN is reset by light, whilst peripheral clocks are entrained by feeding-fasting rhythms, emphasizing the point that temporal patterns of nutrient availability specifies peripheral clock functions. Indeed, emerging evidence revealed various types of diets or timing of food intake reprogram circadian rhythms in a tissue specific manner. This advancement in understanding of mechanisms underlying tissue specific responsiveness of circadian oscillators to nutrients at the genomic and epigenomic levels is largely owing to employment of state-of-the-art technologies. Specifically, high-throughput transcriptome, proteome, and metabolome have provided insights into how genes, proteins, and metabolites behave over circadian cycles in a given tissue under a certain dietary condition in an unbiased fashion. Additionally, combinations with specialized types of sequencing such as nascent-seq and ribosomal profiling allow us to dissect how circadian rhythms are generated or obliterated at each step of gene regulation. Importantly, chromatin immunoprecipitation followed by deep sequencing methods provide chromatin landscape in terms of regulatory mechanisms of circadian gene expression. In this review, we outline recent discoveries on temporal genomic and epigenomic regulation of circadian rhythms, discussing entrainment of the circadian rhythms by feeding as a fundamental new comprehension of metabolism and immune response, and as a potential therapeutic strategy of metabolic and inflammatory diseases.

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Intensive treat-to-target statin therapy and severity of diabetic retinopathy complicated by hypercholesterolaemia

Murakami T., Kato S., Shigeeda T., Itoh H., Komuro I., Takeuchi M., Yoshimura N.

Eye (Basingstoke) 35 （ 8 ） 2221 - 2228 2021年08月

ISSN 0950222X

Objectives: To compare the effects of intensive and standard statin therapy on severity of diabetic retinopathy (DR) complicated by hypercholesterolaemia in a prespecified substudy of the standard vs. intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) study. Methods: Among 5144 patients in the multicentre, prospective, randomized EMPATHY study, this substudy considered 157 patients with seven-field fundus photographs of sufficient quality taken during study enrolment and at the 3-year visit. Eighty-five and seventy-two patients received intensive and standard statin treatments, respectively, in a treat-to-target manner. The primary endpoint was a two-step change in the Early Treatment Diabetic Retinopathy Study (ETDRS) DR severity scale at 36 months. Surrogate markers included changes in hard exudates, changes in visual acuity, and additional ocular treatments during study follow-up. Results: Intensive and standard treatment groups did not differ significantly in terms of changing two or more steps on the DR severity scale (P = 0.4380). In patients with severe DR, defined as ≥47 on the severity scale, exploratory analysis showed more frequent improvement of DR, by at least one step, with intensive vs. standard treatment (83.3% vs. 40.0%; P = 0.0346). The intensive and standard groups did not differ in changes on the hard exudates severity scale (P = 0.3460), logarithm of minimum angle of resolution visual acuity (P = 0.5500), or additional ocular treatment during follow-up. Conclusions: Intensive and standard statin treatment may have similar effects on DR in the population of all patients with DR and hypercholesterolaemia, but intensive therapy may be more beneficial in patients with severe DR.

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Reduced beta cell number rather than size is a major contributor to beta cell loss in type 2 diabetes

Sasaki H., Saisho Y., Inaishi J., Watanabe Y., Tsuchiya T., Makio M., Sato M., Nishikawa M., Kitago M., Yamada T., Itoh H.

Diabetologia 64 （ 8 ） 1816 - 1821 2021年08月

ISSN 0012186X

Aims/hypothesis: Type 2 diabetes is characterised by reduced beta cell mass (BCM). However, it remains uncertain whether the reduction in BCM in type 2 diabetes is due to a decrease in size or number of beta cells. Our aim was to examine the impact of beta cell size and number on islet morphology in humans with and without type 2 diabetes. Methods: Pancreas samples were obtained from 64 Japanese adults with (n = 26) and without (n = 38) type 2 diabetes who underwent pancreatectomy. Using pancreatic tissues stained for insulin, we estimated beta cell size based on beta cell diameter. Beta cell number was estimated from the product of fractional beta cell area and pancreas volume divided by beta cell size. The associations of beta cell size and number with islet morphology and metabolic status were examined. Results: Both beta cell size (548.7 ± 58.5 vs 606.7 ± 65.0 μm3, p < 0.01) and number (5.10 × 108 ± 2.35 × 108 vs 8.16 × 108 ± 4.27 × 108, p < 0.01) were decreased in participants with type 2 diabetes compared with those without diabetes, with the relative reduction in beta cell number (37%) being greater than for beta cell size (10%). Beta cell number but not size was positively correlated with BCM in participants with and without type 2 diabetes (r = 0.97 and r = 0.98, both p < 0.01) and negatively correlated with HbA<inf>1c</inf> (r = −0.45, p < 0.01). Conclusions/interpretation: Both beta cell size and number were reduced in participants with type 2 diabetes, with the relative reduction in beta cell number being greater. Decrease in beta cell number appears to be a major contributor to reduced BCM in type 2 diabetes. Graphical abstract: [Figure not available: see fulltext.]

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Fast Bayesian tomography of a two-qubit gate set in silicon

T. J. Evans, W. Huang, J. Yoneda, R. Harper, T. Tanttu, K. W. Chan, F. E. Hudson, K. M. Itoh, A. Saraiva, C. H. Yang, A. S. Dzurak, S. D. Bartlett

Phys. Rev. Applied 17, 024068 (2022) 2021年07月

Benchmarking and characterising quantum states and logic gates is essential
in the development of devices for quantum computing. We introduce a Bayesian
approach to self-consistent process tomography, called fast Bayesian tomography
(FBT), and experimentally demonstrate its performance in characterising a
two-qubit gate set on a silicon-based spin qubit device. FBT is built on an
adaptive self-consistent linearisation that is robust to model approximation
errors. Our method offers several advantages over other self-consistent
tomographic methods. Most notably, FBT can leverage prior information from
randomised benchmarking (or other characterisation measurements), and can be
performed in real time, providing continuously updated estimates of full
process matrices while data is acquired.

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Effectiveness of statin intensive therapy in type 2 diabetes mellitus with high visit-to-visit blood pressure variability

Ikeda S., Shinohara K., Enzan N., Matsushima S., Tohyama T., Funakoshi K., Kishimoto J., Itoh H., Komuro I., Tsutsui H.

Journal of Hypertension 39 （ 7 ） 1435 - 1443 2021年07月

ISSN 02636352

Background:Intensive lipid-lowering therapy is recommended in type 2 diabetes mellitus (T2DM) patients with target organ damage. However, the evidence is insufficient to stratify the patients who will benefit from the intensive therapy among them. High visit-to-visit variability in systolic blood pressure (SBP) is associated with increased risk of cardiovascular events. We investigated the effectiveness of intensive versus standard statin therapy in the primary prevention of cardiovascular events among T2DM patients with retinopathy stratified by visit-to-visit SBP variability.Methods:The standard versus intensive statin therapy for hypercholesterolemic patients with diabetic retinopathy study was the first trial comparing statin intensive therapy targeting low-density lipoprotein cholesterol (LDL-C) <70 mg/dl and standard therapy targeting LDL-C ≥100 to <120 mg/dl in T2DM patients with retinopathy without known cardiovascular disease. Using this dataset, we divided the patients into two subpopulations based on standard deviation (SD) and average real variability (ARV) of clinic SBP within the initial 6 months.Results:In a total of 4899 patients, 240 composite cardiovascular events were observed during a median follow-up of 37.3 months. In multivariable-adjusted model comparing intensive versus standard therapy, the hazard ratios for composite cardiovascular events were 0.64 (95% CI 0.45-0.90) and 1.21 (95% CI 0.82-1.80) in patients with high and low SBP variability as defined by SD, respectively. Interaction between SBP variability and statin therapy was significant (P = 0.018). The analysis using ARV of SBP showed similar results.Conclusion:Statin intensive therapy targeting LDL-C <70 mg/dl had benefits in primary prevention of cardiovascular events compared with standard therapy among T2DM patients with retinopathy having high, but not low, visit-to-visit SBP variability.

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One-year estimated glomerular filtration rate decline as a risk factor of cardiovascular and renal end-points in high-risk Japanese patients

Meguro S., Inaishi J., Sato Y., Komuro I., Itoh H.

Journal of Diabetes Investigation 12 （ 7 ） 1212 - 1219 2021年07月

ISSN 20401116

Aims/Introduction: As estimated glomerular filtration rate (eGFR) progression might correlate with cardiovascular prognosis, the correlation between 1-year decline in eGFR and cardiovascular incidences and renal outcome was investigated. Materials and Methods: The 1-year percentage decline in eGFR at the first observation year was calculated in a cohort of the standard versus intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) trial participants. The primary end-point was the composite cardiovascular end-point including the renal end-point. The associations between the incidence of each end-point and clinical markers were analyzed using the Cox proportional hazards regression model. Results: A total of 4,461 patients were analyzed. The mean observation period was 765.3 ± 363.1 days. The best cut-off value of 1-year eGFR decline was 0.099 in the first year for renal end-point prediction by receiver operating characteristic curve analysis. The area under the curve of the model including the 1-year eGFR decline of the first year was significantly larger than the model without it (0.943, 95% confidence interval 0.915–0.971 to 0.967, 95% confidence interval 0.950–0.983, P = 0.019). Primary end-point incidences and the renal end-point were much higher in rapid eGFR decliners compared with non-decliners (P < 0.0001). The cardiovascular end-point incidence, except for the renal end-point, was not different between the groups. According to Cox regression analysis, 1-year eGFR decline during the first year was a significant risk factor for the end-points, including the renal end-point, independent of albuminuria and eGFR at baseline. Conclusions: The 1-year eGFR decline rate provided useful information for cardiovascular end-point predictions, including the renal end-point, in addition to the conventional risk factors.

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BO Ceti: Dwarf Nova Showing Both IW And and SU UMa-Type Features

Taichi Kato, Yusuke Tampo, Naoto Kojiguchi, Masaaki Shibata, Junpei Ito, Keisuke Isogai, Hiroshi Itoh, Franz-Josef Hambsch, Berto Monard, Seiichiro Kiyota, Tonny Vanmunster, Aleksei A. Sosnovskij, Elena P. Pavlenko, Pavol A. Dubovsky, Igor Kudzej, Tomas Medulka

2021年06月

IW And stars are a recently recognized subgroup of dwarf novae which are
characterized by (often repetitive) slowly rising standstills terminated by
brightening, but the exact mechanism for this variation is not yet identified.
We have identified BO Cet, which had been considered as a novalike cataclysmic
variable, as a new member of IW And stars based on the behavior in 2019-2020.
In addition to this, the object showed dwarf nova-type outbursts in 2020-2021,
and superhumps having a period 7.8% longer than the orbital one developed at
least during one long outburst. This object has been confirmed as an SU
UMa-type dwarf nova with an exceptionally long orbital period (0.1398 d). BO
Cet is thus the first cataclysmic variable showing both SU UMa-type and IW
And-type features. We obtained a mass ratio (q) of 0.31-0.34 from the
superhumps in the growing phase (stage A superhumps). At this q, the radius of
the 3:1 resonance, responsible for tidal instability and superhumps, and the
tidal truncation radius are very similar. We interpret that in some occasions
this object showed IW And-type variation when the disk size was not large
enough, but that the radius of the 3:1 resonance could be reached as the result
of thermal instability. We also discuss that there are SU UMa-type dwarf novae
above q=0.30, which is above the previously considered limit (q~0.25) derived
from numerical simulations and that this is possible since the radius of the
3:1 resonance is inside the tidal truncation radius. We constrained the mass of
the white dwarf larger than 1.0Msol, which may be responsible for the IW
And-type behavior and the observed strength of the He II emission. The exact
reason, however, why this object is unique in that it shows both SU UMa-type
and IW And-type features is still unsolved.

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Association of childhood anthropometric measurements and laboratory parameters with high blood pressure in young adults

Azegami T., Uchida K., Arima F., Sato Y., Awazu M., Inokuchi M., Murai-Takeda A., Itoh H., Tokumura M., Mori M.

Hypertension Research 44 （ 6 ） 711 - 719 2021年06月

ISSN 09169636

Early intervention to manage high blood pressure (BP) in young adulthood is a promising approach for the prevention of future cardiovascular diseases. We aimed to examine the ability of childhood health information to predict the incidence of young adults with high BP. This cohort study included baseline clinical data of Japanese individuals aged 12–13 years. A total of 1129 participants were followed up for an average of 8.6 years. We examined the association of childhood variables consisting of body weight, body mass index, systolic BP, white blood cell count, red blood cell count, hemoglobin, hematocrit, platelet count, uric acid, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol with the development of high BP defined as ≥120/80 mmHg at 18–22 years old. At follow-up, the prevalence of high BP was 42.2% in men and 7.7% in women. Young men with high BP had childhood baseline characteristics that included higher body weight, body mass index, systolic BP, red blood cell count, hemoglobin, hematocrit, and uric acid than normotensive men. Young women with high BP had higher body weight, systolic BP, and uric acid at baseline. Multivariable logistic regression analysis revealed that a model including body weight, systolic BP, hematocrit, and uric acid had the highest predictive power (AUC 0.65 [95% CI, 0.62–0.69]) for men, and a model including body weight, systolic BP, and uric acid had the highest predictive power (AUC 0.70 [95% CI, 0.58–0.81]) for women. Comprehensive childhood health information contributes to the prediction of high BP in young adults.

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Pre-emptive short-term nicotinamide mononucleotide treatment in a mouse model of diabetic nephropathy

Yasuda I., Hasegawa K., Sakamaki Y., Muraoka H., Kawaguchi T., Kusahana E., Ono T., Kanda T., Tokuyama H., Wakino S., Itoh H.

Journal of the American Society of Nephrology 32 （ 6 ） 1355 - 1370 2021年06月

ISSN 10466673

Background The activation of NAD1-dependent deacetylase, Sirt1, by the administration of nicotinamide mononucleotide (NMN) ameliorates various aging-related diseases. Methods Diabetic db/db mice were treated with NMN transiently for 2 weeks and observed for effects on diabetic nephropathy (DN). Results At 14 weeks after the treatment period, NMN attenuated the increases in urinary albumin excretion in db/db mice without ameliorating hemoglobin A1c levels. Short-term NMN treatment mitigated mesangium expansion and foot process effacement, while ameliorating decreased Sirt1 expression and increased claudin-1 expression in the kidneys of db/db mice. This treatment also improved the decrease in the expression of H3K9me2 and DNMT1. Short-term NMN treatment also increased kidney concentrations of NAD1 and the expression of Sirt1 and nicotinamide phosphoribosyltransferase (Nampt), and it maintained nicotinamide mononucleotide adenyltransferase1 (Nmnat1) expression in the kidneys. In addition, survival rates improved after NMN treatment. Conclusions: Short-term NMN treatment in early-stage DN has remote renal protective effects through the upregulation of Sirt1 and activation of the NAD1 salvage pathway, both of which indicate NMN legacy effects on DN.

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Effect of the Nonsteroidal Mineralocorticoid Receptor Blocker, Esaxerenone, on Nocturnal Hypertension: A Post Hoc Analysis of the ESAX-HTN Study

Kario, K; Ito, S; Itoh, H; Rakugi, H; Okuda, Y; Yoshimura, M; Yamakawa, S

AMERICAN JOURNAL OF HYPERTENSION 34 （ 5 ） 540 - 551 2021年05月

ISSN 0895-7061

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Effect of the Nonsteroidal Mineralocorticoid Receptor Blocker, Esaxerenone, on Nocturnal Hypertension: A Post Hoc Analysis of the ESAX-HTN Study.

Kazuomi Kario, Sadayoshi Ito, Hiroshi Itoh, Hiromi Rakugi, Yasuyuki Okuda, Motonobu Yoshimura, Satoru Yamakawa

American journal of hypertension 34 （ 5 ） 540 - 551 2021年05月

BACKGROUND: Nocturnal hypertension is an important phenotype of abnormal diurnal blood pressure (BP) variability and a known risk marker for target organ damage and cardiovascular events. This study aimed to assess the differential BP-lowering effects of esaxerenone vs. eplerenone on nocturnal BP in hypertensive patients with different nocturnal dipping patterns. METHODS: This was a post hoc analysis of the "Esaxerenone (CS-3150) Compared to Eplerenone in Patients with Essential Hypertension" study (NCT02890173), which was a phase 3, multicenter, randomized, controlled, double-blind, parallel-group clinical study conducted in Japan. Ambulatory BP monitoring data were collected. RESULTS: Patients (n = 1,001) were randomized to esaxerenone 2.5 mg/day (n = 331) or 5 mg/day (n = 338), or eplerenone 50 mg/day (n = 332). Reductions in nighttime systolic BP (95% confidence interval) were significantly greater with 2.5 and 5 mg/day esaxerenone vs. eplerenone (-2.6 [-5.0, -0.2] and -6.4 mm Hg [-8.8, -4.0], respectively). Esaxerenone significantly reduced nighttime BP from baseline compared with eplerenone in non-dippers with previously uncontrolled BP. In addition, esaxerenone did not markedly alter nighttime BP in extreme dipper patients. In the esaxerenone 5 mg/day group, esaxerenone-induced decreases in nighttime BP were greater than eplerenone-induced decreases in older patients. CONCLUSIONS: Esaxerenone may be an effective treatment option for nocturnal hypertension, especially in older patients and those with a non-dipper pattern of nocturnal BP.

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Effect of the Nonsteroidal Mineralocorticoid Receptor Blocker, Esaxerenone, on Nocturnal Hypertension: A Post Hoc Analysis of the ESAX-HTN Study.

Kario K, Ito S, Itoh H, Rakugi H, Okuda Y, Yoshimura M, Yamakawa S

American journal of hypertension 34 （ 5 ） 540 - 551 2021年05月

ISSN 0895-7061

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Diverse pathological lesions of primary aldosteronism and their clinical significance

Nishimoto K., Umakoshi H., Seki T., Yasuda M., Araki R., Otsuki M., Katabami T., Shibata H., Ogawa Y., Wada N., Sone M., Okamura S., Izawa S., Miyauchi S., Yoshimoto T., Tsuiki M., Naruse M., Fukuda H., Tanaka Y., Takeda Y., Kurihara I., Itoh H., Umakoshi H., Ichijo T., Shibayama Y., Yoshimoto T., Ogawa Y., Kawashima J., Inagaki N., Takahashi K., Fujita M., Watanabe M., Matsuda Y., Kobayashi H., Kamemura K., Otsuki M., Fujii Y., Rakugi H., Yamamoto K., Ogo A., Yanase T., Suzuki T., Kawamura T., Fukuoka T., Kai T., Yoshikawa Y., Hashimoto S., Yamada M., Sakamoto R., Yoshiro C.

Hypertension Research 44 （ 5 ） 498 - 507 2021年05月

ISSN 09169636

Primary aldosteronism (PA) is mainly clinically classified as unilateral aldosterone-producing adenoma (APA) or bilateral idiopathic hyperaldosteronism. Immunohistochemistry for aldosterone synthase reveals a diverse PA pathology, including pathological APA and aldosterone-producing cell clusters. The relationship between PA pathology and adrenalectomy outcomes was examined herein. Data from 219 unilaterally adrenalectomized PA cases were analyzed. Pathological analyses revealed diverse putative aldosterone-producing lesions. Postoperative biochemical outcomes in 114 cases (test cohort) were classified as complete success (n = 85), partial success (n = 19), and absent success (n = 10). Outcomes in the large and small PA lesion groups, rather than between PA lesion types, were compared at five threshold values for PA lesion sizes (2–6 mm with 1-mm increments) to streamline the results. The proportion of complete success was significantly higher in the large PA lesion group than in the small PA lesion group at the 5-mm threshold only. The proportion of absent success was significantly higher in the small PA lesion group than in the large PA lesion group at all thresholds. Univariate and multivariate analyses of the test cohort identified serum K as an independent predictive factor for the small PA lesion group, which was confirmed in the 105-case validation cohort. Chi-squared automatic interaction detector analysis revealed that the best threshold of serum K for predicting large PA lesions was 2.82 mEq/L. These results will be beneficial for treating PA in clinical settings because patients with low serum K levels and apparent adrenal masses on CT may be subjected to adrenalectomy even if the adrenal venous sampling test is unavailable.

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Malignancy-associated membranous nephropathy with PLA2R double-positive for glomeruli and carcinoma

Yasuda I., Tokuyama H., Hashiguchi A., Hasegawa K., Uchiyama K., Ryuzaki M., Yasuda M., Mizuno R., Ishidoya S., Wakino S., Itoh H.

Cen Case Reports 10 （ 2 ） 281 - 286 2021年05月

ISSN 2192-4449

Phospholipase A2 receptor (PLA2R) is the most common primary target antigen of idiopathic membranous nephropathy (MN) although PLA2R antibodies are also reported to be present in malignancy-associated MN. However, a case of PLA2R-positive MN secondary to PLA2R-positive carcinoma has not been reported. A 26-year-old Japanese woman presented with general fatigue, fever, and nonproductive cough. Computed tomography demonstrated a left kidney mass with pathologic diagnosis of Xp11.2 translocation renal cell carcinoma (RCC). After the second time of administration with Sunitinib, the patients exhibited significant proteinuria and hypoalbuminemia. Renal biopsy revealed a diagnosis of diffuse MN secondary to RCC. Immunofluorescence staining showed granular patterns positive for immunoglobulin (Ig) G, IgA, and C3c. PLA2R and IgG1-3 were positive, while IgG4 was negative. For the treatment of severe nephrotic syndrome, we attempted steroid therapy without any clinical improvement. Open nephrectomy was performed and surprisingly, RCC was stained for PLA2R with polarity for the basal side. At outpatient follow-up, 4 months after the operation, urinary protein had still persisted, although serum albumin was slightly increased. We report a case of PLA2R-positive MN secondary to PLA2R-positive RCC.

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Effect of the nonsteroidal mineralocorticoid receptor blocker, esaxerenone, on nocturnal hypertension: A post hoc analysis of the esax-htn study

Kario K., Ito S., Itoh H., Rakugi H., Okuda Y., Yoshimura M., Yamakawa S.

American Journal of Hypertension 34 （ 5 ） 540 - 551 2021年05月

ISSN 08957061

BACKGROUND Nocturnal hypertension is an important phenotype of abnormal diurnal blood pressure (BP) variability and a known risk marker for target organ damage and cardiovascular events. This study aimed to assess the differential BP-lowering effects of esaxerenone vs. eplerenone on nocturnal BP in hypertensive patients with different nocturnal dipping patterns. METHODS This was a post hoc analysis of the "Esaxerenone (CS-3150) Compared to Eplerenone in Patients with Essential Hypertension" study (NCT02890173), which was a phase 3, multicenter, randomized, controlled, double-blind, parallel-group clinical study conducted in Japan. Ambulatory BP monitoring data were collected. RESULTS Patients (n = 1,001) were randomized to esaxerenone 2.5 mg/day (n = 331) or 5 mg/day (n = 338), or eplerenone 50 mg/day (n = 332). Reductions in nighttime systolic BP (95% confidence interval) were significantly greater with 2.5 and 5 mg/day esaxerenone vs. eplerenone (-2.6 [-5.0, -0.2] and -6.4 mm Hg [-8.8, -4.0], respectively). Esaxerenone significantly reduced nighttime BP from baseline compared with eplerenone in non-dippers with previously uncontrolled BP. In addition, esaxerenone did not markedly alter nighttime BP in extreme dipper patients. In the esaxerenone 5 mg/day group, esaxerenone-induced decreases in nighttime BP were greater than eplerenone-induced decreases in older patients. CONCLUSIONS Esaxerenone may be an effective treatment option for nocturnal hypertension, especially in older patients and those with a non-dipper pattern of nocturnal BP.

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Antihypertensive effects and safety of esaxerenone in patients with moderate kidney dysfunction

Ito S., Itoh H., Rakugi H., Okuda Y., Iijima S.

Hypertension Research 44 （ 5 ） 489 - 497 2021年05月

ISSN 09169636

Renin–angiotensin system inhibitors are recommended for treating hypertension with chronic kidney disease. The addition of a mineralocorticoid receptor blocker may be one option to achieve target blood pressure. We investigated the efficacy and safety of esaxerenone, a mineralocorticoid receptor blocker, in Japanese hypertensive patients with moderate kidney dysfunction. Two multicenter, open-label, nonrandomized dose escalation studies were conducted to investigate esaxerenone monotherapy and add-on therapy to renin–angiotensin system inhibitor treatment. Esaxerenone therapy was initiated at 1.25 mg/day and titrated to 2.5 and then 5 mg/day for a treatment duration of 12 weeks. Primary endpoints were changes from baseline in sitting systolic and diastolic blood pressure. Safety, pharmacokinetics, and urinary albumin-to-creatinine ratios were also assessed. Thirty-three patients received monotherapy, and 58 received add-on therapy; the mean baseline estimated glomerular filtration rates were 51.9 and 50.9 mL/min/1.73 m2, respectively. The esaxerenone dosage was increased to ≥2.5 mg/day in 100% (n = 33) and 93.1% (n = 54) of patients receiving monotherapy and add-on therapy, respectively. Reductions in sitting blood pressure from baseline to the end of treatment were similar (monotherapy: −18.5/−8.8 mmHg; add-on therapy: −17.8/−8.1 mmHg; both P < 0.001). The antihypertensive effects of esaxerenone were consistent across patient subgroups. A serum K+ level ≥5.5 mEq/L was observed in seven patients (12.1%) receiving add-on therapy but in none receiving monotherapy. All increases in serum K+ levels were transient, and no patient met predefined serum K+ level criteria for dose reduction or therapy discontinuation. No patient discontinued treatment owing to kidney function decline. Esaxerenone was effective and well tolerated in hypertensive patients with moderate kidney dysfunction.

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Effect of the Nonsteroidal Mineralocorticoid Receptor Blocker, Esaxerenone, on Nocturnal Hypertension: A Post Hoc Analysis of the ESAX-HTN Study

Kario, K; Ito, S; Itoh, H; Rakugi, H; Okuda, Y; Yoshimura, M; Yamakawa, S

AMERICAN JOURNAL OF HYPERTENSION 34 （ 5 ） 540 - 551 2021年05月

ISSN 0895-7061

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A CASE OF ACUTE KIDNEY INJURY CAUSED BY INTERSTITIAL NEPHRITIS COMPLICATED WITH DRESS SYNDROME

Oshima, Y; Tokuyama, H; Minakuchi, H; Wakino, S; Itoh, H

JOURNAL OF HYPERTENSION 39 E297 - E298 2021年04月

ISSN 0263-6352

CLINICAL AND BIOCHEMICAL OUTCOMES AFTER RADIOFREQUENCY ABLATION FOR ALDOSTERONE-PRODUCING ADENOMA AT KEIO UNIVERSITY HOSPITAL-2020 ANNUAL REPORT

Kozuma, T; Kurihara, I; Kobayashi, S; Yokota, K; Miyashita, K; Kohata, N; Takase, K; Nakatsuka, S; Itoh, H

JOURNAL OF HYPERTENSION 39 E221 - E221 2021年04月

ISSN 0263-6352

CASZ1b is a novel transcriptional corepressor of mineralocorticoid receptor

Yokota K., Shibata H., Kurihara I., Kobayashi S., Murai-Takeda A., Itoh H.

Hypertension Research 44 （ 4 ） 407 - 416 2021年04月

ISSN 09169636

Aldosterone is a biological ligand for mineralocorticoid receptor (MR) that elevates blood pressure by promoting sodium reabsorption in the kidneys. However, the molecular mechanisms of aldosterone-MR-mediated transcription and the role of this transcription in hypertension remain largely unknown. In this study, we aimed to identify novel MR coregulators and elucidate one of the molecular mechanisms of hypertension. We purified MR-interacting factors from HEK293F cells stably expressing FLAG-MR through a biochemical approach and identified the zinc finger protein castor homolog 1 isoform b (CASZ1b) as a candidate novel MR coregulator via liquid chromatography—tandem mass spectrometry analysis. The CASZ1 gene has been implicated in hypertension in genome-wide single-nucleotide polymorphism studies, but its role in the development of hypertension remains unclear. We found that CASZ1b colocalized with MR in the kidneys and interacted with MR in an aldosterone-dependent manner. In luciferase assays using HEK293F cells, overexpression of CASZ1b reduced aldosterone-dependent MR transcriptional activity by ~50%. In contrast, knockdown of CASZ1b via RNA interference increased the expression levels of the aldosterone-induced MR target genes epithelial Na+ channel-α (ENaCα) and serum/glucocorticoid regulated kinase 1 (SGK1) by approximately twofold and 2.3-fold, respectively. Upon aldosterone-MR binding, CASZ1b interacted with MR and formed a protein complex with nucleosome remodeling deacetylase (Mi-2/NuRD), a corepressor complex with chromatin remodeling and histone deacetylation activity, which suppressed ENaCα and SGK1. These findings reveal a critical role of CASZ1b in regulating MR-mediated transcriptional activity and provide new insights into the pathophysiology of hypertension.

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BIRTH WEIGHT AND RISK FACTORS FOR ATHEROSCLEROSIS -RETROSPECTIVE COHORT STUDY IN JAPANESE WORKERS

Azegami, T; Takeda, A; Yokoyama, H; Wainai, Y; Hirose, H; Makino, S; Nishimura, T; Goto, N; Itoh, H; Mori, M

JOURNAL OF HYPERTENSION 39 E170 - E171 2021年04月

ISSN 0263-6352

ASSOCIATION OF CHILDHOOD PHYSICAL EXAMINATION AND LABORATORY PARAMETERS WITH HIGH BLOOD PRESSURE IN JAPANESE YOUNG ADULTS

Azegami, T; Uchida, K; Arima, F; Sato, Y; Awazu, M; Inokuchi, M; Takeda, A; Itoh, H; Tokumura, M; Mori, M

JOURNAL OF HYPERTENSION 39 E41 - E41 2021年04月

ISSN 0263-6352

ANTIHYPERTENSIVE EFFECTS AND SAFETY OF ESAXERENONE IN HYPERTENSIVE PATIENTS WITH MODERATE KIDNEY DYSFUNCTION

Ito, S; Itoh, H; Rakugi, H; Okuda, Y; Iijima, S

JOURNAL OF HYPERTENSION 39 E53 - E53 2021年04月

ISSN 0263-6352

ACUTE MYOCARDIAL INFARCTION AND STROKE PREVENTION WITH AMLODIPINE/ ATORVASTATIN SINGLE-PILL THERAPY FOR PATIENTS WITH HYPERTENSION AND DYSLIPIDEMIA

Nakaya, H; Sasamura, H; Saito, I; Inoue, Y; Kobayashi, M; Itoh, H

JOURNAL OF HYPERTENSION 39 E377 - E377 2021年04月

ISSN 0263-6352

ACTIVE IMMUNOTHERAPY AGAINST RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS ATTENUATES THE PROGRESSION OF DIABETIC KIDNEY DISEASE

Azegami, T; Hayashi, K; Hishikawa, A; Yoshimoto, N; Nakayama, T; Itoh, H

JOURNAL OF HYPERTENSION 39 E303 - E303 2021年04月

ISSN 0263-6352

EFFECT OF MINERALOCORTICOID RECEPTOR BLOCKER, ESAXERENONE, ON NOCTURNAL HYPERTENSION: A POST HOC ANALYSIS OF ESAX-HTN STUDY

Kario, K; Ito, S; Itoh, H; Rakugi, H; Okuda, Y; Yamakawa, S

JOURNAL OF HYPERTENSION 39 E374 - E374 2021年04月

ISSN 0263-6352

Efficacy and safety of esaxerenone (CS-3150), a newly available nonsteroidal mineralocorticoid receptor blocker, in hypertensive patients with primary aldosteronism

Satoh F., Ito S., Itoh H., Rakugi H., Shibata H., Ichihara A., Omura M., Takahashi K., Okuda Y., Iijima S.

Hypertension Research 44 （ 4 ） 464 - 472 2021年04月

ISSN 09169636

Mineralocorticoid receptor (MR) blockers are very beneficial for patients with hypertension and primary aldosteronism (PA). We investigated the efficacy and safety of a newly available nonsteroidal MR blocker, esaxerenone, in Japanese patients with hypertension and PA. A multicenter, open-label study was conducted in Japan between October 2016 and July 2017. Patients with hypertension and PA received 12 weeks of treatment with esaxerenone, initiated at 2.5 mg/day and escalated to 5 mg/day during week 2 or 4 of treatment, based on individual response. The only other permitted antihypertensive therapies were stable dosages of a Ca2+ channel blocker or α-blocker. The primary efficacy outcome was a change in sitting systolic and diastolic blood pressure (SBP/DBP) from baseline to the end of treatment. Forty-four patients were included; dose escalation to 5 mg/day was implemented for 41 of these patients. Significant decreases in SBP and DBP were observed (point estimates [95% confidence interval] −17.7 [−20.6, −14.7] and −9.5 [−11.7, −7.3] mmHg, respectively; both p < 0.0001 at the end of treatment). Significant BP reductions were evident from week 2 and continued through to week 8; BP remained stable until week 12. The antihypertensive effect of esaxerenone on SBP was significantly greater in females and in patients receiving monotherapy. The major drug-related adverse events were serum K+ increase and estimated glomerular filtration rate decrease (both 4.5%, n = 2); no gynecomastia or breast pain was observed. We conclude that esaxerenone is a potent MR blocker with favorable efficacy and safety profiles in patients with hypertension and PA.

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RELATIONSHIP BETWEEN SERUM TOTAL BILIRUBIN CONCENTRATION AND MACROVASCULAR COMPLICATIONS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Tanaka, M; Nishimura, T; Meguro, S; Irie, J; Saisho, Y; Mitsuishi, M; Itoh, A; Inaishi, J; Nakajima, Y; Itoh, H

JOURNAL OF HYPERTENSION 39 E208 - E208 2021年04月

ISSN 0263-6352

Importance of Adipose Tissue NAD+Biology in Regulating Metabolic Flexibility

Franczyk M.P., Qi N., Stromsdorfer K.L., Li C., Yamaguchi S., Itoh H., Yoshino M., Sasaki Y., Brookheart R.T., Finck B.N., Debosch B.J., Klein S., Yoshino J.

Endocrinology (United States) 162 （ 3 ） 2021年03月

ISSN 00137227

Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme that regulates cellular energy metabolism in many cell types. The major purpose of the present study was to test the hypothesis that NAD+ in white adipose tissue (WAT) is a regulator of whole-body metabolic flexibility in response to changes in insulin sensitivity and with respect to substrate availability and use during feeding and fasting conditions. To this end, we first evaluated the relationship between WAT NAD+ concentration and metabolic flexibility in mice and humans. We found that WAT NAD+ concentration was increased in mice after calorie restriction and exercise, 2 enhancers of metabolic flexibility. Bariatric surgery-induced 20% weight loss increased plasma adiponectin concentration, skeletal muscle insulin sensitivity, and WAT NAD+ concentration in people with obesity. We next analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) mice, which have markedly decreased NAD+ concentrations in WAT. ANKO mice oxidized more glucose during the light period and after fasting than control mice. In contrast, the normal postprandial stimulation of glucose oxidation and suppression of fat oxidation were impaired in ANKO mice. Data obtained from RNA-sequencing of WAT suggest that loss of NAMPT increases inflammation, and impairs insulin sensitivity, glucose oxidation, lipolysis, branched-chain amino acid catabolism, and mitochondrial function in WAT, which are features of metabolic inflexibility. These results demonstrate a novel function of WAT NAMPT-mediated NAD+ biosynthesis in regulating whole-body metabolic flexibility, and provide new insights into the role of adipose tissue NAD+ biology in metabolic health.

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C-C motif chemokine receptor 9 regulates obesity-induced insulin resistance via inflammation of the small intestine in mice

Amiya T., Nakamoto N., Irie J., Taniki N., Chu P.S., Koda Y., Miyamoto K., Yamaguchi A., Shiba S., Morikawa R., Itoh H., Kanai T.

Diabetologia 64 （ 3 ） 603 - 617 2021年03月

ISSN 0012186X

Aims/hypothesis: Accumulation of adipose tissue macrophages is considered pivotal in the development of obesity-associated inflammation and insulin resistance. In addition, recent studies suggest an involvement of the intestine as the primary organ in inducing hyperglycaemia and insulin resistance. We have reported that the C-C motif chemokine receptor (CCR) CCR9 is associated with intestinal immunity and has a pathogenic role in various liver diseases. However, its contribution to type 2 diabetes is unknown. In the current study, we aimed to clarify the involvement of CCR9 in the pathology of type 2 diabetes and the potential underlying mechanisms. Methods: To elucidate how CCR9 affects the development of metabolic phenotypes, we examined the impact of CCR9 deficiency on the pathogenesis of type 2 diabetes using male C57BL/6J (wild-type [WT]) and CCR9-deficient (CCR9 knockout [KO]) mice fed a 60% high-fat diet (HFD) for 12 weeks. Results: WT and Ccr9KO mice fed an HFD exhibited a comparable weight gain; however, glucose tolerance and insulin resistance were significantly improved in Ccr9KO mice. Moreover, visceral adipose tissue (VAT) and the liver of Ccr9KO mice presented with less inflammation and increased expression of glucose metabolism-related genes than WT mice. Ccr9 and Ccl25 expression were specifically higher in the small intestine but was not altered by HFD feeding and type 2 diabetes development. Accumulation of IFN-γ-producing CD4+ T lymphocytes and increased intestinal permeability in the small intestine was observed in WT mice following HFD feeding, but these changes were suppressed in HFD-fed Ccr9KO mice. Adoptive transfer of gut-tropic CCR9-expressing T lymphocytes partially reversed the favourable glucose tolerance found in Ccr9KO mice via exacerbated inflammation in the small intestine and VAT. Conclusions/interpretation: CCR9 plays a central role in the pathogenesis of type 2 diabetes by inducing an inflammatory shift in the small intestine. Our findings support CCR9 as a new therapeutic target for type 2 diabetes via the gut–VAT–liver axis. Graphical abstract: [Figure not available: see fulltext.]

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4）Kidney-Gut axisから見た慢性腎不全

脇野修, 松井歩, 内山清貴, 伊藤裕, 吉藤歩

日本内科学会雑誌（一般社団法人日本内科学会） 110 （ Suppl ） 93a - 93a 2021年02月

ISSN 00215384

Difficulty in managing nephrotic syndrome-associated cerebral venous thrombosis

Nakayama T., Mitsuno R., Torimitsu T., Yoshimoto N., Kanda T., Tokuyama H., Wakino S., Itoh H.

CEN case reports 10 （ 1 ） 132 - 138 2021年02月

ISSN 2192-4449

Thromboembolism is one of the most serious complications of nephrotic syndrome (NS). Although the occurrence of renal vein thrombosis or deep vein thrombosis is well recognized in NS patients, they rarely develop cerebral venous thrombosis (CVT). The mortality rate of CVT patients is still approximately 10%, and 6-10% of patients who survive have a severe and permanent disability. Herein, we report the case of a 26-year-old woman with multiple thrombotic risk factors, including the presence of NS, use of oral contraceptives, smoking, and alcohol consumption who developed wide-range CVT. Undetermined fraction heparin, albumin and AT-III transfusion, and direct mechanical catheter thrombectomy were insufficient for the improvement of CVT. However, CVT eventually improved along with the remission of NS by prednisolone administration. This process indicates that in the management of CVT associated with NS, it is crucial to control the activity of NS. Currently, knowledge on the treatment for NS associated with CVT is limited, and this is a subject of urgent investigation.

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Effects of high glucose and lipotoxicity on diabetic podocytes

Nakamichi R., Hayashi K., Itoh H.

Nutrients 13 （ 1 ） 1 - 11 2021年01月

Glomerular podocytes are highly differentiated cells that cover glomerular capillaries from the outside and have a characteristic morphology with numerous foot processes. The formation of slit membranes between the foot processes serves as a final filtration barrier for urine filtration from the blood. Podocyte damage causes disruption of the slit membrane, subsequent proteinuria and finally glomerulosclerosis, which is a common pathway in various types of chronic kidney disease (CKD). In recent years, there has been an increase in diabetes, due to rapid lifestyle changes, which is the main cause of CKD. Therefore, understanding the effect of diabetic status on podocytes is of great importance to establish a strategy for preventing CKD progression. In this review, we summarize altered glucose and lipid metabolism in diabetic podocytes and also discuss the reversibility of the changes in podocyte phenotype.

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A Case of New-Onset Systemic Lupus Erythematosus With Serositis in a Maintenance Hemodialysis Patient

Kosugi S., Yoshida T., Yoshimoto N., Itoh H., Oya M.

Clinical Medicine Insights: Case Reports 14 11795476211056172 - 11795476211056172 2021年

ISSN 1179-5476

A 61-year-old woman with a 4-year history of maintenance hemodialysis due to end-stage renal disease of unknown cause was admitted because of a recurrent fever and abdominal pain lasting for 3 months. She had rheumatoid arthritis as a complication and had taken sulfasalazine for over 4 years. Laboratory data revealed thrombocytopenia, hypocomplementemia, a high C-reactive protein level, and positivity for antinuclear antibody and anti-double strand DNA antibody. Gallium scintigraphy showed pericarditis, pleuritis, and peritonitis. Nonscarring alopecia was also noted. She was diagnosed as having systemic lupus erythematosus (SLE). Drug-induced lupus elicited by sulfasalazine was ruled out because the symptoms did not improve even after the discontinuation of the drug upon admission. Oral prednisolone treatment markedly improved her symptoms and laboratory data. However, she later died of sepsis arising from proctitis on day 71 of admission. This report underscores the necessity of considering new-onset SLE in patients with unexplained fever and serositis, including pleuritis, peritonitis, or pericarditis, even if they are receiving maintenance dialysis.

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Bullous pemphigoid in patients receiving peritoneal dialysis: a case series and a literature survey

Morimoto K., Yoshida T., Washida N., Uchiyama K., Nakayama T., Itoh H., Oya M.

Renal Failure 43 （ 1 ） 651 - 657 2021年

ISSN 0886022X

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease. Although several cases of BP in end-stage renal disease patients receiving peritoneal dialysis (PD) or hemodialysis have been reported, the incidence of BP in these patients remains unknown. We recently experienced three PD patients diagnosed with BP. The skin injury was likely to be a trigger of BP in all the three PD patients. Nifedipine and icodextrin exposures were possible factors directly or indirectly affecting the onset of BP, because they were common in the three cases. We also report that the incidence of BP in PD patients was 3/478.3 person-years in a single-center 10-year study. This case series with a literature survey describes that the skin and tissue injuries are potential triggers responsible for the onset of BP in dialysis patients and that the incidence of BP in these patients seems to be much higher than that in the general population.

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Exercise Parameters Predict Technique Survival in Patients on Peritoneal Dialysis

Nakayama T., Uchiyama K., Washida N., Morimoto K., Muraoka K., Adachi K., Kasai T., Miyashita K., Wakino S., Itoh H.

Blood Purification 50 （ 3 ） 380 - 389 2021年

ISSN 02535068

Objective: The incremental shuttle walking test (ISWT) is an important marker of aerobic capacity in patients on peritoneal dialysis (PD). This study aimed to evaluate its predictive value for PD-related outcomes. Methods: This single-center cohort study recruited outpatients on maintenance PD from our hospital between March 2017 and March 2018. Exercise capacity was assessed using measurement of ISWT and handgrip and quadriceps strength. Patients were divided into 2 groups according to the median of exercise capacity and prospectively followed up until cessation of PD, death, or the study end (October 2019). The primary end point of this study was technique survival rate, and secondary outcomes were rates of peritonitis-free survival and PD-related hospitalization-free survival. Results: Among the 50 participants, age and PD vintage were [median (IQR)] 62.5 (58.3-70) and 3.5 (1.3-6.5) years, respectively. At the end of the study, 3 of the 28 participants (11%) in the long-ISWT group and 13 of the 22 participants (59%) in the short-ISWT group were transferred to hemodialysis. The short-ISWT group showed lower technique survival rate (p < 0.001), peritonitis-free survival rate (p = 0.01), and PD-related hospitalization-free survival rate (p < 0.01) than the long-ISWT group, whereas those survival rates did not differ when participants were divided by handgrip or quadriceps strength. Multivariate analysis revealed lower ISWT to be independently associated with technique failure (p = 0.002). Conclusion: The ISWT is an important predictor of technique survival for patients on PD. Monitoring and enhancing ISWT as a marker of aerobic capacity might improve PD-related outcomes.

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Mediastinal cystic parathyroid adenoma diagnosed by somatostatin receptor scintigraphy

Yokota K., Kurihara I., Matsusaka Y., Emoto K., Hishida T., Oshida T., Kobayashi S., Murai-Takeda A., Miyashita K., Matsuda K., Nakagomi T., Matsuda K., Itoh H.

Internal Medicine （一般社団法人日本内科学会） 60 （ 10 ） 1555 - 1560 2021年

ISSN 09182918

A 71-year-old man complained of nausea and loss of appetite for eight months prior to admission. He was transported to a hospital with disorientation and diagnosed with primary hyperparathyroidism by laboratory examinations. However, ultrasonography, computed tomography, and technetium-99m labeled methoxyisobutyl isonitrile (99mTc-MIBI) with single-photon emission computed tomography did not yield definite results. In contrast, somatostatin receptor scintigraphy successfully identified the lesion responsible for the oversecretion of parathyroid hormone within the middle mediastinum. The tumor was successfully resected by surgery, and a histopathological analysis confirmed the parathyroid adenoma nature of the tumor.

Effect of long-term amiodarone treatment on thyroid function in euthyroid Japanese patients: a 12-month retrospective analysis.

Sugiyama K, Kobayashi S, Kurihara I, Miyashita K, Yokota K, Kohno T, Yoshimura Noh J, Itoh H

Endocrine journal 67 （ 12 ） 1247 - 1252 2020年12月

ISSN 0918-8959

Amiodarone is an effective antiarrhythmic drug. However, it is associated with changes in thyroid function in euthyroid patients due to its high iodine content and intrinsic drug effects. Studies have been conducted in iodine-deficient and iodine-sufficient countries; however, data from countries with excessive iodine intake are lacking. Thus, this study aimed to evaluate the effect of long-term amiodarone treatment on thyroid function in euthyroid Japanese patients. Japanese adults aged ≥18 years who were treated with amiodarone for at least 90 consecutive days were included in this retrospective chart review. Patients with abnormal thyroid function test results at baseline were excluded. Serial changes in thyroid function tests at baseline and at days 30, 90, 180, 270, and 360 were analyzed using a mixed-effects model for repeated measures. In total, 46 patients with a mean age of 63.7 years were evaluated. The mean TSH level significantly increased from 1.62 μIU/mL at baseline to 3.43, 2.75, 2.84, 2.78, and 2.65 μIU/mL at days 30, 90, 180, 270, and 360, respectively. The mean free T4 level significantly increased from 1.3 ng/dL at baseline to 1.4, 1.5, 1.5, 1.5, and 1.5 ng/dL at days 30, 90, 180, 270, and 360, respectively. The mean free T3 level significantly decreased from 2.8 pg/mL at baseline to 2.4, 2.3, 2.3, 2.4, and 2.4 pg/mL at days 30, 90, 180, 270, and 360, respectively. In conclusion, significant changes in thyroid function persisted not only in the acute phase but also in the chronic phase of long-term amiodarone treatment.

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Identification of unique bile acid-metabolizing bacteria from the microbiome of centenarians

Kenya Honda, Yuko Sato, Koji Atarashi, Damian Plichta, Yasumichi Arai, Satoshi Sasajima, Sean Kearney, Wataru Suda, Kozue Takeshita, Takahiro Sasaki, Shoki Okamoto, Ashwin Skelly, Yuki Okamura, Hera Vlamakis, Youxian Li, Takeshi Tanoue, Hajime Takei, Hiroshi Nittono, Seiko Narushima, Junichiro Irie, Hiroshi Itoh, Kyoji Moriya, Yuki Sugiura, Makoto Suematsu, Nobuko Moritoki, Shinsuke Shibata, Dan Littman, Michael Fischbach, Masahira Hattori, Tsuyoshi Murai, Ramnik Xavier, Nobuyoshi Hirose

（Research Square Platform LLC） 2020年12月

<title>Abstract</title>
Centenarians, or individuals who have lived more than a century, represent the ultimate model of successful longevity associated with decreased susceptibility to ageing-associated illness and chronic inflammation. The gut microbiota is considered to be a critical determinant of human health and longevity. Here we show that centenarians (average 107 yo) have a distinct gut microbiome enriched in microbes capable of generating unique secondary bile acids, including iso-, 3-oxo-, and isoallo-lithocholic acid (LCA), as compared to elderly (85-89 yo) and young (21-55 yo) controls. Among these bile acids, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from a centenarian’s faecal microbiota, we identified <italic>Parabacteroides merdae</italic> and <italic>Odoribacteraceae</italic> strains as effective producers of isoalloLCA. Furthermore, we generated and tested mutant strains of <italic>P. merdae</italic> to show that the enzymes 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3βHSDH) were responsible for isoalloLCA production. This secondary bile acid derivative exerted the most potent antimicrobial effects among the tested bile acid compounds against gram-positive (but not gram-negative) multidrug-resistant pathogens, including <italic>Clostridioides difficile</italic> and vancomycin-resistant <italic>Enterococcus faecium</italic>. These findings suggest that specific bile acid metabolism may be involved in reducing the risk of pathobiont infection, thereby potentially contributing to longevity.

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Effects of exercise on residual renal function in patients undergoing peritoneal dialysis: A post-hoc analysis of a randomized controlled trial.

Uchiyama K, Washida N, Morimoto K, Muraoka K, Nakayama T, Adachi K, Kasai T, Miyashita K, Wakino S, Itoh H

Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 24 （ 6 ） 668 - 676 2020年12月

ISSN 1744-9979

We aimed to investigate the effects of exercise on renal outcomes in patients undergoing peritoneal dialysis (PD). In a post-hoc analysis of a randomized controlled trial of a 12-week home-based exercise program involving 47 patients undergoing PD, we excluded 18 patients with anuria and analyzed 13 and 16 patients in the usual care and exercise groups, respectively. The primary outcomes were weekly renal creatinine clearance (CCr) and urinary biomarkers: liver-type fatty acid-binding protein (L-FABP) and the microalbumin-to-creatinine ratio (ACR). Although the maintenance of weekly renal CCr in the exercise group was not significantly different compared with that in the usual care group (P = .09), urinary L-FABP levels (P = .02) and ACR (P = .04) were significantly decreased in the exercise group. To the best of our knowledge, this is the first study to demonstrate the beneficial effects of exercise on renal outcomes in patients undergoing PD.

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Calcified cerebral embolism due to aortic valve calcification.

Nakayama T, Wakino S, Itoh H

Clinical and experimental nephrology 24 （ 11 ） 1084 - 1085 2020年11月

ISSN 1342-1751

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JSH Statement: Tokyo declaration promoting salt reduction by the Japanese Society of Hypertension-the JSH Tokyo declaration.

Tsuchihashi T, Ishimitsu T, Ando K, Kusaka M, Ichihara A, Miura K, Kawano Y, Ishida T, Kumagai H, Sakima A, Takase H, Hayabuchi H, Itoh H

Hypertension research : official journal of the Japanese Society of Hypertension 43 （ 11 ） 1133 - 1134 2020年11月

ISSN 0916-9636

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Proton pump inhibitors may hinder hypophosphatemic effect of lanthanum carbonate, but not of ferric citrate hydrate or sucroferric oxyhydroxide, in hemodialysis patients.

Minakuchi H, Yoshida T, Kaburagi N, Fujino T, Endo S, Takemitsu TY, Yamashita N, Itoh H, Oya M

Renal failure 42 （ 1 ） 799 - 806 2020年11月

ISSN 0886-022X

Because end-stage renal disease patients undergoing hemodialysis frequently take acid suppressants for the treatment or prevention of gastrointestinal diseases, it is important to clarify the drug-interactions between acid suppressants and phosphate binders on the control of serum phosphate levels. In the present study, we examined whether the phosphate-lowering effects of three phosphate binders, lanthanum carbonate (LC), ferric citrate hydrate (FCH), and sucroferric oxyhydroxide (SFOH), were affected by proton pump inhibitors (PPIs) in maintenance hemodialysis patients. Laboratory data for 71 patients who had been newly prescribed one of the three phosphate binders were examined. LC at a dosage of 500 ± 217 mg/day significantly decreased serum phosphate levels by -18% in the absence of a PPI (n = 9), while a dosage of 700 ± 230 mg/day only decreased it by -3% in the presence of a PPI (n = 10). Thus, the efficacy of LC in reducing serum phosphate levels was significantly hindered by the presence of PPIs. FCH significantly decreased serum phosphate levels by -18% in the absence of a PPI (n = 7, FCH: 571 ± 189 mg/day) and by -17% in the presence of a PPI (n = 20, FCH: 638 ± 151 mg/day). The decrease in serum phosphate levels by SFOH (393 ± 197 mg/day) was -7% in the absence of a PPI (n = 7), and SFOH at a dosage of 556 ± 316 mg/day significantly decreased serum phosphate levels by -13% in the presence of a PPI (n = 18). These results suggest that the phosphate-lowering effect of LC, but not of FCH or SFOH, is diminished in the presence of PPIs in hemodialysis patients.

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Conformational equilibrium shift underlies altered K(+) channel gating as revealed by NMR.

Iwahashi Y, Toyama Y, Imai S, Itoh H, Osawa M, Inoue M, Shimada I

Nature communications 11 （ 1 ） 5168 2020年10月

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Hypertension and related diseases in the era of COVID-19: a report from the Japanese Society of Hypertension Task Force on COVID-19.

Shibata S, Arima H, Asayama K, Hoshide S, Ichihara A, Ishimitsu T, Kario K, Kishi T, Mogi M, Nishiyama A, Ohishi M, Ohkubo T, Tamura K, Tanaka M, Yamamoto E, Yamamoto K, Itoh H

Hypertension research : official journal of the Japanese Society of Hypertension 43 （ 10 ） 1028 - 1046 2020年10月

ISSN 0916-9636

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected more than seven million people worldwide, contributing to 0.4 million deaths as of June 2020. The fact that the virus uses angiotensin-converting enzyme (ACE)-2 as the cell entry receptor and that hypertension as well as cardiovascular disorders frequently coexist with COVID-19 have generated considerable discussion on the management of patients with hypertension. In addition, the COVID-19 pandemic necessitates the development of and adaptation to a "New Normal" lifestyle, which will have a profound impact not only on communicable diseases but also on noncommunicable diseases, including hypertension. Summarizing what is known and what requires further investigation in this field may help to address the challenges we face. In the present review, we critically evaluate the existing evidence for the epidemiological association between COVID-19 and hypertension. We also summarize the current knowledge regarding the pathophysiology of SARS-CoV-2 infection with an emphasis on ACE2, the cardiovascular system, and the kidney. Finally, we review evidence on the use of antihypertensive medication, namely, ACE inhibitors and angiotensin receptor blockers, in patients with COVID-19.

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Asperuloside Improves Obesity and Type 2 Diabetes through Modulation of Gut Microbiota and Metabolic Signaling.

Nakamura A, Yokoyama Y, Tanaka K, Benegiamo G, Hirayama A, Zhu Q, Kitamura N, Sugizaki T, Morimoto K, Itoh H, Fukuda S, Auwerx J, Tsubota K, Watanabe M

iScience 23 （ 9 ） 101522 - 101522 2020年09月

Asperuloside (ASP) is an iridoid glycoside that is extracted from Eucommia leaves. Eucommia is used in traditional Chinese medicine and has a long history of benefits on health and longevity. Here, we investigated the impact of ASP on obesity-related metabolic disorders and show that ASP reduces body weight gain, glucose intolerance, and insulin resistance effectively in mice fed with a high-fat diet (HFD). Intestinal dysbiosis is closely linked with metabolic disorders. Our data indicate that ASP achieves these benefits on metabolic homeostasis by reversing HFD-induced gut dysbiosis and by changing gut-derived secondary metabolites and metabolic signaling. Our results indicate that ASP may be used to regulate gut microbiota for the treatment of obesity and type 2 diabetes.

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Contribution of uremic dysbiosis to insulin resistance and sarcopenia.

Uchiyama K, Wakino S, Irie J, Miyamoto J, Matsui A, Tajima T, Itoh T, Oshima Y, Yoshifuji A, Kimura I, Itoh H

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 35 （ 9 ） 1501 - 1517 2020年09月

ISSN 0931-0509

BACKGROUND: Chronic kidney disease (CKD) leads to insulin resistance (IR) and sarcopenia, which are associated with a high mortality risk in CKD patients; however, their pathophysiologies remain unclear. Recently, alterations in gut microbiota have been reported to be associated with CKD. We aimed to determine whether uremic dysbiosis contributes to CKD-associated IR and sarcopenia. METHODS: CKD was induced in specific pathogen-free mice via an adenine-containing diet; control animals were fed a normal diet. Fecal microbiota transplantation (FMT) was performed by oral gavage in healthy germ-free mice using cecal bacterial samples obtained from either control mice (control-FMT) or CKD mice (CKD-FMT). Vehicle mice were gavaged with sterile phosphate-buffered saline. Two weeks after inoculation, mice phenotypes, including IR and sarcopenia, were evaluated. RESULTS: IR and sarcopenia were evident in CKD mice compared with control mice. These features were reproduced in CKD-FMT mice compared with control-FMT and vehicle mice with attenuated insulin-induced signal transduction and mitochondrial dysfunction in skeletal muscles. Intestinal tight junction protein expression and adipocyte sizes were lower in CKD-FMT mice than in control-FMT mice. Furthermore, CKD-FMT mice showed systemic microinflammation, increased concentrations of serum uremic solutes, fecal bacterial fermentation products and elevated lipid content in skeletal muscle. The differences in gut microbiota between CKD and control mice were mostly consistent between CKD-FMT and control-FMT mice. CONCLUSIONS: Uremic dysbiosis induces IR and sarcopenia, leaky gut and lipodystrophy.

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A new normal for hypertension medicine with coronavirus disease-2019 (COVID-19): proposal from the president of the Japanese Society of Hypertension.

Itoh H

Hypertension research : official journal of the Japanese Society of Hypertension 43 （ 9 ） 857 - 858 2020年09月

ISSN 0916-9636

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Low birth weight trends: possible impacts on the prevalences of hypertension and chronic kidney disease.

Kanda T, Murai-Takeda A, Kawabe H, Itoh H

Hypertension research : official journal of the Japanese Society of Hypertension 43 （ 9 ） 859 - 868 2020年09月

ISSN 0916-9636

Worldwide, hypertension and chronic kidney disease (CKD) are highly prevalent disorders and are strong risk factors for cardiovascular disease and end-stage renal disease (ESRD). The developmental origins of health and disease (DOHAD) concept suggests that undesirable perinatal environmental conditions, such as malnutrition, contribute to disease development in adults. Among the known hypertension and CKD risk factors, DOHAD plays a potential role in determining susceptibility to the onset of these diseases in later adulthood. Since low birth weight (LBW) is a surrogate marker for adverse fetal environmental conditions, the high incidence of LBW in developing countries and its increasing incidence in most developed countries (attributed to multiple pregnancies and prepregnancy maternal factors, such as undernutrition, advanced maternal age, and smoking) is concerning. Thus, LBW is an important public health problem not only because of the associated infant mortality and morbidity but also because it is a risk factor for adult-onset hypertension/CKD. During their reproductive years, pregnant women who were born with LBWs have an increased risk of hypertensive disorders of pregnancy, which contribute to the risk of developing cardiovascular disease and ESRD. The offspring of LBW females are also likely to be LBW, which suggests that susceptibility to hypertension/CKD may reflect transgenerational inheritance. Therefore, there is global concern about the increasing prevalence of LBW-related diseases. This review summarizes the relevance of hypertension and CKD in conjunction with DOHAD and discusses recent studies that have examined the impact of the upward LBW trend on renal function and blood pressure.

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Relationship between daily and visit-to-visit glycemic variability in patients with type 2 diabetes.

Tsuchiya T, Saisho Y, Murakami R, Watanabe Y, Inaishi J, Itoh H

Endocrine journal 67 （ 8 ） 877 - 881 2020年08月

ISSN 0918-8959

The aim of the study was to explore the relationship between daily glycemic variability (GV) and visit-to-visit glycemic variability (VVV) in patients with type 2 diabetes (T2DM). A total of 156 outpatients with T2DM who had undergone continuous glucose monitoring (CGM) for 5 days were included in this study. Indices of GV, i.e., standard deviation and coefficient of variation (CV) of glucose, mean amplitude of glycemic excursion (MAGE) and mean of the daily differences (MODD) were calculated from the CGM data. VVV was calculated as CV of HbA1c or glycated albumin (GA) from HbA1c or GA measured for 3 years. Relationships among clinical parameters, GV and VVV were evaluated. Age was positively, and BMI and C-peptide index were inversely correlated with GV such as CV glucose and MAGE, while BMI was positively correlated with VVV. Mean glucose rather than GV was correlated with VVV. In contrast, time in range (TIR, 70-180 mg/dL) was correlated with both mean HbA1c or GA and VVV. In conclusion, GV and VVV were differently correlated with clinical parameters and were hardly correlated with each other. TIR was correlated with both mean HbA1c and VVV, suggesting that efforts to achieve optimal TIR are practical strategies to reduce VVV in patients with T2DM.

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Appropriate timing for a biochemical evaluation after adrenalectomy for unilateral aldosterone-producing adenoma.

Takamatsu K, Takeda T, Hattori S, Tanaka N, Morita S, Matsumoto K, Kosaka T, Mizuno R, Shinojima T, Kikuchi E, Asanuma H, Kurihara I, Itoh H, Oya M

Clinical endocrinology 92 （ 6 ） 503 - 508 2020年06月

ISSN 0300-0664

CONTEXT: The oversecretion of plasma aldosterone by unilateral aldosterone-producing adenoma (APA) can be cured by adrenalectomy. However, the time needed for the endocrine environment to normalize remains unclear. OBJECTIVE: To clarify adequate timing for a biochemical evaluation in unilateral APA patients after adrenalectomy. DESIGN AND PATIENTS: A total of 166 unilateral APA patients were retrospectively reviewed. We evaluated the plasma aldosterone concentration (PAC) (pg/mL), active renin concentration (ARC) (pg/mL), aldosterone-renin ratio (ARR; PAC/ARC), serum potassium concentration and estimated glomerular filtration rate (eGFR) at 1, 3 and 6 postoperation months (POM). RESULTS: PAC was significantly lower at 1POM than at presurgery (presurgery; 407.2, 1 POM; 90.0 pg/mL, P < .001). ARC did not increase from baseline at 1POM, but significantly increased at 3POM (presurgery; 4.43, 1POM; 4.87, 3POM; 11.3 pg/mL, P < .001). ARR significantly decreased at 1POM (presurgery; 146.9, 1 POM; 26.3, P < .001) although ARC did not increase at 1POM. Among the 34 patients who had hypokalaemia presurgery, it was resolved in 28 (82%) at 1POM and in all (100%) at 3POM. The biochemical outcomes at 1POM were 131 (79%) complete, 20 (12%) partial and 15 (9%) absent successes, while at 3POM, 147 (89%) were complete, 9 (5%) partial and 10 (6%) absent. Twenty-three (14%) patients were reclassified into different biochemical outcomes between 1 and 3POM, whereas only 5 (3%) changed between 3 and 6POM. CONCLUSION: The appropriate timing for a biochemical evaluation of unilateral APA patients treated with laparoscopic adrenalectomy appears to be 3 months or more after surgery.

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A case of cerebral infarction caused by painless acute aortic dissection in autosomal dominant polycystic kidney disease.

Yamaguchi S, Wakino S, Tokuyama H, Itoh H

CEN case reports 9 （ 2 ） 177 - 181 2020年05月

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder, characterized by the progressive formation of renal cysts. Although ADPKD is strongly associated with cerebral and cardiovascular complications, cerebral ischemia caused by dissection of thoracic and carotid arteries has rarely been reported. We report the case of a 71-year-old Japanese woman who complained of hemiparesis. She required maintenance hemodialysis therapy with a background of ADPKD. Cerebral infarction was initially diagnosed by excluding intracranial hemorrhage and aneurysm rupture that are recognized as common complications of ADPKD and thereby anticoagulation therapy was initiated. However, the patient was suspected as having painless aortic dissection because a chest X-ray examination showed expanded upper mediastinum. Sequential vascular imagings revealed dissection of the aorta, originating from brachiocephalic trunk to the right common carotid artery with mediastinal hematoma. The patient died from progression of dissection. Herein, we described a case of the ADPKD patient that an acute aortic dissection without any pain induced the occlusion of supplying vessels to the brain, resulting in cerebral ischemic symptoms. A high level of clinical vigilance for an acute aortic dissection should be maintained in the ADPKD population with sudden onset of neurological symptoms even in the absence of pain. Furthermore, the initiation of anticoagulation treatment for cerebral ischemia which may aggravate the risk of further dissection requires careful consideration.

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Nadir Aldosterone Levels After Confirmatory Tests Are Correlated With Left Ventricular Hypertrophy in Primary Aldosteronism.

Ohno Y, Sone M, Inagaki N, Kawashima A, Takeda Y, Yoneda T, Kurihara I, Itoh H, Tsuiki M, Ichijo T, Katabami T, Wada N, Sakamoto R, Ogawa Y, Yoshimoto T, Yamada T, Kawashima J, Matsuda Y, Kobayashi H, Kamemura K, Yamamoto K, Otsuki M, Okamura S, Izawa S, Okamoto R, Tamura K, Tanabe A, Naruse M, JPAS/JRAS Study Group

Hypertension (Dallas, Tex. : 1979) 75 （ 6 ） HYPERTENSIONAHA11914601 - 1482 2020年04月

査読有り, ISSN 0194-911X

Left ventricular hypertrophy (LVH) is often seen in patients with primary aldosteronism (PA), and the prevalence of LVH is reportedly higher among patients with PA than patients with essential hypertension. However, the correlation between aldosterone levels and LVH is undefined, and how aldosterone affects LVH in patients with PA remains unclear. We, therefore, retrospectively assessed a large PA database established by the multicenter JPAS (Japan Primary Aldosteronism Study) to reveal the factors associated with LVH in patients with PA without suspected autonomous cortisol secretion. In the 1186 patients with PA studied, the basal plasma aldosterone concentration, plasma renin activity, and the aldosterone-to-renin ratio did not significantly correlate with left ventricular LV mass index (LVMI) in single or multiple regression analyses. However, the plasma aldosterone concentration after the captopril challenge test or saline-infusion test, which are associated with autonomous aldosterone secretion, correlated significantly with LVMI, even after adjusting for patients' backgrounds, including age and blood pressure. In addition, hypokalemia and the unilateral subtype also correlated with LVMI. Longitudinal subanalysis of medically or surgically treated patients with PA showed significant reductions in LVMI in both the surgery (63.0±18.1 to 55.3±19.5 g/m2.7, P<0.001) and drug treatment (56.8±14.1 to 52.1±13.5 g/m2.7, P<0.001) groups. Our results suggest the autonomous aldosterone secretion level, not the basal aldosterone level itself, is relevant to LVH in patients with PA. In addition, the elevated LVMI seen in patients with PA is at least partially reversible with surgical or medical treatment.

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Associations of birthweight and history of childhood obesity with beta cell mass in Japanese adults.

Sasaki H, Saisho Y, Inaishi J, Watanabe Y, Tsuchiya T, Makio M, Sato M, Kitago M, Yamada T, Itoh H

Diabetologia 63 （ 6 ） 1199 - 1210 2020年04月

査読有り, ISSN 0012-186X

AIMS/HYPOTHESIS: Low birthweight is associated with a high risk of diabetes, but there are no reports discussing birthweight and pancreatic tissues in humans. The purpose of this study was to examine the correlation between birthweight and beta and alpha cell mass in humans. METHODS: Sixty-four Japanese adults with and without diabetes who underwent pancreatectomy and were able to recall their weight history including birthweight were included. Pancreatic tissues were stained for insulin and glucagon, and fractional beta cell area (BCA) and alpha cell area (ACA) were quantified. Islet size and density and beta cell replication were also quantified and their associations with birthweight were evaluated. RESULTS: In participants without diabetes, there was a weak positive correlation between birthweight and BCA (R = 0.34, p = 0.03). The group with a history of childhood obesity, but not the group with a history of obesity in adulthood only, showed higher BCA compared with those without a history of obesity (1.78 ± 0.74% vs 0.99 ± 0.53%, p = 0.01), and the correlation coefficient between birthweight and BCA increased after excluding those with a history of childhood obesity (R = 0.51, p < 0.01). In those with diabetes, there was no correlation between birthweight and BCA. No correlation was found between birthweight and ACA in either those with or without diabetes. CONCLUSIONS/INTERPRETATION: Birthweight and beta, but not alpha, cell mass are positively correlated in non-diabetic adults, and a history of childhood obesity may affect beta cell mass. Graphical abstract.

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Effect of cosyntropin during adrenal venous sampling on subtype of primary aldosteronism: analysis of surgical outcome.

Kobayashi H, Nakamura Y, Abe M, Kurihara I, Itoh H, Ichijo T, Takeda Y, Yoneda T, Katabami T, Tsuiki M, Wada N, Ogawa Y, Sakamoto R, Kawashima J, Sone M, Inagaki N, Yoshimoto T, Yamada T, Okamoto R, Matsuda Y, Fujita M, Watanabe M, Tamura K, Tanabe A, Naruse M, JPAS/JRAS Study Group

European journal of endocrinology 182 （ 3 ） 265 - 273 2020年03月

査読有り, ISSN 0804-4643

Objectives: We investigated the clinical significance of ACTH stimulation during adrenal venous sampling (AVS) by surgical outcome of primary aldosteronism (PA). Design: Multicenter retrospective study by Japan PA study. Method: We allocated 314 patients with both basal and ACTH-stimulated AVS data who underwent adrenalectomy to three groups: basal lateralization index (LI) ≥2 with ACTH-stimulated LI ≥4 on the ipsilateral side (Unilateral (U) to U group, n = 245); basal LI <2 with ACTH-stimulated LI ≥4 (Bilateral (B) to U group, n = 15); and basal LI ≥2 with ACTH-stimulated LI <4 (U to B group, n = 54). We compared surgical outcomes among the groups using the Primary Aldosteronism Surgical Outcome (PASO) criteria. Results: Compared with U to U group, U to B group had poor clinical and biochemical outcomes and low rates of adrenal adenoma as pathological findings (P = 0.044, 0.006, and 0.048, respectively), although there were no significant differences between U to U and B to U groups. All patients in U to B group with clinical and biochemical benefits, however, had adrenal adenoma as pathological findings and could be well differentiated from those with poor surgical outcomes via basal LI (>8.3), but not ACTH-stimulated LI. These results were similar even when we defined each group based on a cut-off value of 4 for basal LI. Conclusions: Although PA patients in U to B group had worse surgical outcomes than did those in U to U group, basal LI could discriminate among patients with better surgical outcomes in U to B group.

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DNA damage and expression of DNA methylation modulators in urine-derived cells of patients with hypertension and diabetes.

Hishikawa A, Hayashi K, Yoshimoto N, Nakamichi R, Homma K, Itoh H

Scientific reports 10 （ 1 ） 3377 - 3377 2020年02月

Diabetes and hypertension have become the primary causes of chronic kidney disease worldwide. However, there are no established markers for early diagnosis or predicting renal prognosis. Here, we investigated the expression profiles of DNA repair and DNA methylation factors in human urine-derived cells as a possible diagnostic or renal prognosis-predicting marker. A total of 75 subjects, aged 63.3 ± 1.9 years old, were included in this study. DNA and RNA were extracted from 50 mL of urine samples. We evaluated DNA double-strand breaks (DSBs) by the quantitative long distance-PCR method and performed real-time RT-PCR analysis to analyze the expression of renal cell-specific markers, DNA DSB repair factor KAT5, DNA methyltransferases DNMTs, and demethylation enzymes TETs. In patients with hypertension and diabetes, DNA DSBs of the nephrin gene increased with decreased urine KAT5/nephrin expression, consistent with our previous study (Cell Rep 2019). In patients with hypertension, DNA DSBs of the AQP1 gene were increased with elevated urine DNMTs/AQP1 and TETs/AQP1 expression. Moreover, urine DNMTs/AQP1 expression was significantly correlated with the annual eGFR decline rate after adjustment for age, baseline eGFR, the presence of diabetes and the amount of albuminuria, suggesting a possible role as a renal prognosis predictor.

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Association of glucose tolerance status with pancreatic β- and α-cell mass in community-based autopsy samples of Japanese individuals: The Hisayama Study.

Inaishi J, Saisho Y, Hirakawa Y, Yoshida D, Hata J, Mukai N, Watanabe Y, Oda Y, Itoh H, Ninomiya T

Journal of diabetes investigation 11 （ 5 ） 1197 - 1206 2020年02月

査読有り, ISSN 2040-1116

AIMS/INTRODUCTION: Changes in histologically quantified β- and α-cell mass during the development of glucose intolerance have not been fully elucidated. The aim of the present study was to explore differences in β- and α-cell mass according to the glucose tolerance status. MATERIALS AND METHODS: Autopsy samples from a total of 103 individuals (40 with normal glucose tolerance, 31 with prediabetes and 32 with type 2 diabetes mellitus) who underwent a 75-g oral glucose tolerance test within 5 years before death were selected from 643 community-based autopsy samples collected from 2002 to 2016. Fractional β-cell area (BCA) and α-cell area were quantified with Image Pro Plus software. Associations of BCA and α-cell area with glucose tolerance status were assessed using a linear regression analysis, and Spearman's correlation coefficients between glycemic markers and β-cell function were estimated. RESULTS: The mean values of BCA decreased significantly with worsening glucose tolerance status (mean ± standard error 1.85 ± 0.10% in normal glucose tolerance, 1.59 ± 0.11% in prediabetes and 1.17 ± 0.11% in type 2 diabetes mellitus, P for trend < 0.001), whereas there was no significant association between α-cell area and glucose tolerance status. BCA was inversely correlated with fasting and 2-h plasma glucose levels during oral glucose tolerance test and glycated hemoglobin measurement, and positively correlated with disposition index (all P < 0.01). CONCLUSIONS: β-Cell mass decreased significantly with worsening glucose tolerance, from the stage of prediabetes, in the Japanese population. Prevention of declining β-cell mass before the onset of glucose intolerance is important to reduce the burden of type 2 diabetes mellitus.

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Fasting and Non-Fasting Triglycerides and Risk of Cardiovascular Events in Diabetic Patients Under Statin Therapy.

Tada H, Nomura A, Yoshimura K, Itoh H, Komuro I, Yamagishi M, Takamura M, Kawashiri MA

Circulation journal : official journal of the Japanese Circulation Society 84 （ 3 ） 509 - 515 2020年02月

査読有り, ISSN 1346-9843

BACKGROUND: Few data specifically investigate associations between fasting/non-fasting triglycerides (TG) and cardiovascular (CV) events under statin therapy among Japanese diabetic patients.Methods and Results:We recruited 4,988 participants with diabetes from the EMPATHY study. Median follow-up was 3 years. We evaluated associations between serum fasting/non-fasting TG and first CV events in Cox-regression hazard models adjusted by classical risk factors. CV events were defined as (1) major adverse cardiac events (MACE) including myocardial infarction, stroke, or cardiac death; and (2) CV diseases (CVD) including myocardial infarction, unstable angina, ischemic stroke, or large artery disease or peripheral arterial disease. Fasting as well as non-fasting TG were associated with MACE (adjusted hazard ratio [HR]: 1.017 per 10 mg/dL; 95% confidence interval [CI]: 1.000-1.037; P=0.046, adjusted HR: 1.028 per 10 mg/dL; 95% CI: 1.006-1.050; P=0.0091) and CVD (adjusted HR: 1.024 per 10 mg/dL; 95% CI: 1.011-1.038; P=4.4×10-3, adjusted HR: 1.028 per 10 mg/dL; 95% CI: 1.010-1.046; P=4.9×10-3). Comparing the top quartile with the bottom quartile of non-fasting TG, adjusted HR significantly increased 5.18 (95% CI: 1.38-18.3, P=0.014) for MACE, and 2.40 (95% CI: 1.11-4.75, P=0.021) for CVD, while adjusted HR did not change when divided into quartile of fasting TG. CONCLUSIONS: Non-fasting TG could be considered as a substitute for fasting TG as a risk stratification for future CV events among Japanese diabetic patients.

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FCoR-Foxo1 Axis Regulates α-Cell Mass through Repression of Arx Expression.

Kodani N, Nakae J, Kobayashi M, Kikuchi O, Kitamura T, Itoh H

iScience 23 （ 1 ） 100798 - 100798 2020年01月

Pancreatic endocrine cell development into differentiated α- and β-cells is highly regulated and involves multiple transcription factors. However, the mechanisms behind the determination of α- and β-cell masses remains unclear. We previously identified Foxo1 CoRepressor (FCoR), which inhibits Foxo1 by acetylation. Here we demonstrate that Fcor-knockout mice (FcorKO) exhibit significantly increased α-cell mass, expression of the master α-cell regulatory transcription factor Aristaless-related homeobox (Arx), which can be normalized by β-cell-specific FCoR overexpression (FcorKO-βFcor), and exhibit β-to-α-cell conversion. Compared with FcorKO, β-cell-specific Foxo1 knockout in the FcorKO (DKO) led to decreased Arx expression and α-cell mass. Foxo1 binding to Arx promoter led to DNA methyltransferase 3a (Dnmt3a) dissociation, Arx promoter hypomethylation, and increased Arx expression. In contrast, FCoR suppressed Arx through Foxo1 inhibition and Dnmt3a recruitment to Arx promoter and increased Arx promoter methylation. Our findings suggest that the FCoR-Foxo1 axis regulates pancreatic α-cell mass by suppressing Arx expression.

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Association of glomerular DNA damage and DNA methylation with one-year eGFR decline in IgA nephropathy.

Hayashi K, Hishikawa A, Hashiguchi A, Azegami T, Yoshimoto N, Nakamichi R, Tokuyama H, Itoh H

Scientific reports 10 （ 1 ） 237 - 237 2020年01月

Accumulation of DNA double-strand breaks (DSBs) is linked to aging and age-related diseases. We recently reported the possible association of DNA DSBs with altered DNA methylation in murine models of kidney disease. However, DSBs and DNA methylation in human kidneys was not adequately investigated. This study was a cross-sectional observational study to evaluate the glomerular DNA DSB marker γH2AX and phosphorylated Ataxia Telangiectasia Mutated (pATM), and the DNA methylation marker 5-methyl cytosine (5mC) by immunostaining, and investigated the association with pathological features and clinical parameters in 29 patients with IgA nephropathy. To evaluate podocyte DSBs, quantitative long-distance PCR of the nephrin gene using laser-microdissected glomerular samples and immunofluorescent double-staining with WT1 and γH2AX were performed. Glomerular γH2AX level was associated with glomerular DNA methylation level in IgA nephropathy. Podocytopathic features were associated with increased number of WT1(+)γH2AX(+) cells and reduced amount of PCR product of the nephrin gene, which indicate podocyte DNA DSBs. Glomerular γH2AX and 5mC levels were significantly associated with the slope of eGFR decline over one year in IgA nephropathy patients using multiple regression analysis adjusted for age, baseline eGFR, amount of proteinuria at biopsy and immunosuppressive therapy after biopsy. Glomerular γH2AX level was associated with DNA methylation level, both of which may be a good predictor of renal outcome in IgA nephropathy.

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Double-Blind Randomized Phase 3 Study Comparing Esaxerenone (CS-3150) and Eplerenone in Patients With Essential Hypertension (ESAX-HTN Study).

Ito S, Itoh H, Rakugi H, Okuda Y, Yoshimura M, Yamakawa S

Hypertension (Dallas, Tex. : 1979) 75 （ 1 ） 51 - 58 2020年01月

査読有り, ISSN 0194-911X

Mineralocorticoid receptors (MRs) are implicated in the pathology of hypertension. MR blockers are recommended for the treatment of salt-sensitive or resistant hypertension. However, use of currently available MR blockers is limited by adverse events. This phase 3 multicenter, randomized, double-blind study compared the efficacy and safety of esaxerenone, a new selective nonsteroidal MR blocker, at 2.5 and 5 mg/day and eplerenone 50 mg/day in Japanese patients with essential hypertension. After a 4-week washout period, 1001 eligible adults with hypertension were randomized evenly to esaxerenone 2.5 or 5 mg/day or eplerenone 50 mg/day treatments, taken orally once daily for 12 weeks. Primary end points were changes in sitting systolic or diastolic blood pressure (BP) from baseline at the end of treatment. Esaxerenone 2.5 mg/day was noninferior to eplerenone for reductions in sitting and 24-hour BP. Reductions in BP with esaxerenone 5 mg/day were significantly greater than those with esaxerenone 2.5 mg/day. Changes in diurnal BP showed persistent 24-hour antihypertensive effects in all treatment groups. The proportions of patients achieving target sitting BP (<140/90 mm Hg) were 31.5%, 41.2%, and 27.5% with esaxerenone 2.5 and 5 mg/day and eplerenone 50 mg/day, respectively. Incidences of adverse events (all mild or moderate) were similar across treatment groups. These results indicate that esaxerenone is an effective and well-tolerated MR blocker in Japanese patients with essential hypertension, with BP-lowering activity at least equivalent to eplerenone. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT02890173.

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Historical changes and between-facility differences in adrenal venous sampling for primary aldosteronism in Japan.

Fujii Y, Takeda Y, Kurihara I, Itoh H, Katabami T, Ichijo T, Wada N, Shibayama Y, Yoshimoto T, Ogawa Y, Kawashima J, Sone M, Inagaki N, Takahashi K, Watanabe M, Matsuda Y, Kobayashi H, Shibata H, Kamemura K, Otsuki M, Yamamto K, Ogo A, Yanase T, Okamura S, Miyauchi S, Fujita M, Suzuki T, Umakoshi H, Ogasawara T, Tsuiki M, Naruse M, JPAS Study Group

Journal of human hypertension 34 （ 1 ） 34 - 42 2020年01月

査読有り, ISSN 0950-9240

Primary aldosteronism (PA) is a common curable cause of hypertension. Adrenal venous sampling (AVS) is recommended for subtype diagnosis but is a difficult procedure. Recently, an increased prevalence of PA was reported, creating a greater demand for treatment of the condition in clinical facilities. The aim of the present study was to identify the historical changes over time and the differences between facilities in the success rate and subtype diagnosis of PA. The database of the PA registry developed by the Japan PA Study (JPAS) was used. A total of 2599 patients with PA who underwent AVS were evaluated. The overall success rate of AVS was 88%. The bilateral subtype was the dominant subtype, comprising 69% of cases. During the period 2004-2011 to 2011-2017, there were significant changes in the total number of AVS procedures (from 562 to 1732), ratio of ACTH administration with AVS (75 to 97%), success rate (79 to 90%), and proportion with bilateral subtype diagnosis (53 to 72%). There were also significant inter-facility differences in the number of AVS procedures (6 to 322), success rate (59 to 97%), and proportion with the bilateral subtype (44 to 86%). The principal enrolled department was Endocrinology (86%), and the ratio of unilateral PA was significantly higher in this department than in others (32% vs. 25%). In conclusion, the number of AVS procedures performed, the success rate, and the proportion with the bilateral subtype increased over time after normalizing the centre difference. Significant differences were observed between the centres.

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Maternal gut microbiota in pregnancy influences offspring metabolic phenotype in mice

• Kimura I*, Miyamoto J, Ohue-Kitano R, Watanabe K, Yamada T, Onuki M, Aoki R, Isobe Y, Kashihara D, Inoue D, Inaba A, Takamura Y, Taira S, Kumaki S, Watanabe M, Ito M, Nakagawa F, Irie J, Kakuta H, Shinohara M, Iwatsuki K, Tsujimoto G, Ohno H, Arita M, Itoh H, Hase K

Science 367 （ 6481 ） 8429 2020年

査読有り, ISSN 0036-8075

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Foxo in T Cells Regulates Thermogenic Program through Ccr4/Ccl22 Axis.

Kikuchi T, Nakae J, Kawano Y, Watanabe N, Onodera M, Itoh H

iScience 22 81 - 96 2019年12月

Crosstalk between immunity and the thermogenic program has provided insight into metabolic energy regulation. Here, we generated thermogenic program-accelerating mice (T-QKO), in which Foxo1 is knockout and Foxo3 is hetero-knockout in CD4+ T cells. T-QKO exhibit lean phenotype under HFD due to increased energy expenditure. Cold exposure significantly increased expression of the thermogenic genes (Ppargc1a and Ucp1), Th2 cytokines (Il4 and Il13), and Th2 marker gene (Gata3) in subcutaneous adipose tissue (SC) of T-QKO. Furthermore, Ccr4 expression was significantly increased in Th2 cells of T-QKO, and cold exposure induced Ccl22 expression in SC, leading to increased accumulation of Th2 cell population in SC of T-QKO. These data reveal a mechanism by which cold exposure induces selective recruitment of Th2 cells into SC, leading to regulation of energy expenditure by generating beige adipocyte and suggest that inhibition of Foxo in T cells may support a strategy to prevent and treat obesity.

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Home-based Aerobic Exercise and Resistance Training in Peritoneal Dialysis Patients: A Randomized Controlled Trial

Uchiyama K., Washida N., Morimoto K., Muraoka K., Kasai T., Yamaki K., Miyashita K., Wakino S., Itoh H.

Scientific Reports （Scientific Reports） 9 （ 1 ） 2019年12月

© 2019, The Author(s). Potential effects of aerobic and resistance training in peritoneal dialysis (PD) patients have been partially elucidated. We investigated effects of a home-based exercise program on physical functioning and health-related quality of life (HRQOL) in PD patients. Patients were randomly assigned to exercise (n = 24) and usual care (n = 23) groups. The exercise patients performed aerobic exercise thrice weekly and resistance training twice weekly at home for 12 weeks. The usual care patients received no specific intervention. The distance in incremental shuttle walking test significantly improved in the exercise group compared with the usual care group (P = 0.02). Among the HRQOL subscales assessed using the Kidney Disease Quality of Life-Short Form questionnaire, kidney disease component summary (P = 0.03), physical role functioning (P = 0.01), emotional role functioning (P < 0.01), and role/social component summary (P < 0.01) significantly improved in the exercise group. Moreover, serum albumin was significantly maintained in the exercise group (P = 0.03). There were no reported adverse events associated with the intervention. To our knowledge, this is the first randomized controlled trial to indicate the beneficial effects of a 12-week home-based exercise program exclusively in PD patients.

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Induction of human pluripotent stem cells into kidney tissues by synthetic mRNAs encoding transcription factors

Hiratsuka K., Monkawa T., Akiyama T., Nakatake Y., Oda M., Goparaju S., Kimura H., Chikazawa-Nohtomi N., Sato S., Ishiguro K., Yamaguchi S., Suzuki S., Morizane R., Ko S., Itoh H., Ko M.

Scientific Reports （Scientific Reports） 9 （ 1 ） 2019年12月

© 2019, The Author(s). The derivation of kidney tissues from human pluripotent stem cells (hPSCs) and its application for replacement therapy in end-stage renal disease have been widely discussed. Here we report that consecutive transfections of two sets of synthetic mRNAs encoding transcription factors can induce rapid and efficient differentiation of hPSCs into kidney tissues, termed induced nephron-like organoids (iNephLOs). The first set - FIGLA, PITX2, ASCL1 and TFAP2C, differentiated hPSCs into SIX2 + SALL1 + nephron progenitor cells with 92% efficiency within 2 days. Subsequently, the second set - HNF1A, GATA3, GATA1 and EMX2, differentiated these cells into PAX8 + LHX1 + pretubular aggregates in another 2 days. Further culture in both 2-dimensional and 3-dimensional conditions produced iNephLOs containing cells characterized as podocytes, proximal tubules, and distal tubules in an additional 10 days. Global gene expression profiles showed similarities between iNephLOs and the human adult kidney, suggesting possible uses of iNephLOs as in vitro models for kidneys.

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Long-term phase 3 study of esaxerenone as mono or combination therapy with other antihypertensive drugs in patients with essential hypertension.

Rakugi H, Ito S, Itoh H, Okuda Y, Yamakawa S

Hypertension research : official journal of the Japanese Society of Hypertension 42 （ 12 ） 1932 - 1941 2019年12月

査読有り, ISSN 0916-9636

This study investigated the long-term antihypertensive effects of esaxerenone, a novel nonsteroidal mineralocorticoid receptor blocker, alone or in combination with a calcium channel blocker (CCB) or a renin-angiotensin system (RAS) inhibitor, in Japanese patients with essential hypertension. Patients were treated with esaxerenone starting at 2.5 mg/day increasing to 5 mg/day if required to achieve blood pressure (BP) targets as a monotherapy or with a CCB or RAS inhibitor. After the first 12 weeks of treatment, an additional antihypertensive agent could be added if required to achieve the target BP; the total treatment period was 28 or 52 weeks. The primary endpoint was a change from baseline in sitting BP. Of the 368 enrolled patients, 245 received monotherapy, and 59 and 64, respectively, took a CCB or RAS inhibitor concurrently. Mean changes from baseline in sitting systolic/diastolic BP (95% confidence intervals) at weeks 12, 28 and 52 were -16.1 (-17.3, -14.9)/-7.7 (-8.4, -6.9), -18.9 (-20.2, -17.7)/-9.9 (-10.7, -9.2), and -23.1 (-25.0, -21.1)/-12.5 (-13.6, -11.3) mmHg, respectively (all P < 0.0001 vs baseline). Similar BP reductions at these weeks were observed between all patient subgroups stratified by age, and the observed decreases in 24-h ambulatory BP were consistent with the efficacy observed in sitting BP. Esaxerenone was also well-tolerated with a rate of hyperkalemia at 5.4% (serum potassium ≥5.5 mEq/L), indicating a good safety profile for treatment over the long-term or in combination with a CCB or RAS inhibitor. In conclusion, esaxerenone may be a promising treatment option for patients with hypertension.

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Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions.

Miyamoto J, Ohue-Kitano R, Mukouyama H, Nishida A, Watanabe K, Igarashi M, Irie J, Tsujimoto G, Satoh-Asahara N, Itoh H, Kimura I

Proceedings of the National Academy of Sciences of the United States of America 116 （ 47 ） 23813 - 23821 2019年11月

ISSN 0027-8424

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Predictors of Clinical Success After Surgery for Primary Aldosteronism in the Japanese Nationwide Cohort.

Morisaki M, Kurihara I, Itoh H, Naruse M, Takeda Y, Katabami T, Ichijo T, Wada N, Yoshimoto T, Ogawa Y, Sone M, Tsuiki M, Shibata H, Kawashima J, Fujita M, Watanabe M, Matsuda Y, Kobayashi H, Suzuki T, JPAS Study Group

Journal of the Endocrine Society 3 （ 11 ） 2012 - 2022 2019年11月

査読有り

Context: Aldosterone-producing adenomas are a curable subtype of primary aldosteronism (PA); however, hypertension persists in some patients after adrenalectomy. Objective: To identify factors associated with, and develop prediction models for, blood pressure (BP) normalization or improvement after adrenalectomy. Design: Retrospective analysis of patients treated between 2006 and 2018, with a 6-month follow-up. Setting: A nationwide, 29-center Japanese registry encompassing 15 university hospitals and 14 city hospitals. Patients: We categorized 574 participants in the Japan Primary Aldosteronism Study, who were diagnosed with PA and underwent adrenalectomy, as BP normalized or improved, on the basis of their presentations at 6 months postsurgery. Main Outcome Measure: The rate of complete, partial, and absent clinical success. Predictive factors related to BP outcomes after PA surgery were also evaluated. Results: Complete clinical success was achieved in 32.6% and partial clinical success was achieved in 53.0% of the patients at 6 months postsurgery. The following five variables were independent predictors for BP normalization: ≤7 years of hypertension, body mass index ≤25 kg/m2, no more than one antihypertensive medication, absence of medical history of diabetes, and female sex. The area under the receiver operator characteristic curve was 0.797 in the BP normalization model. Conclusion: We established models that predicted postoperative BP normalization in patients with PA. These should be useful for shared decision-making regarding adrenalectomy for PA.

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Application of Japanese guidelines for gestational weight gain to multiple pregnancy outcomes and its optimal range in 101,336 Japanese women

Nomura K, Nagashima K, Suzuki S, Itoh H

Scientific Reports 9 （ 1 ） 17310 2019年11月

査読有り

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Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men.

Irie J, Inagaki E, Fujita M, Nakaya H, Mitsuishi M, Yamaguchi S, Yamashita K, Shigaki S, Ono T, Yukioka H, Okano H, Nabeshima YI, Imai SI, Yasui M, Tsubota K, Itoh H

Endocrine journal 67 （ 2 ） 153 - 160 2019年11月

査読有り, ISSN 0918-8959

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GLP-1受容体作動薬により過食の軽減が認められた2型糖尿病合併高度肥満症の一例

後藤伸子, 入江潤一郎, 清水真美子, 喜田素子, 伊藤裕

肥満研究（(一社)日本肥満学会） 25 （ Suppl. ） 310 - 310 2019年10月

査読有り, ISSN 1343-229X

Efficacy and safety of once-weekly exenatide after switching from twice-daily exenatide in patients with type 2 diabetes.

Watanabe Y, Saisho Y, Inaishi J, Kou K, Yamauchi A, Kanazawa Y, Okubo Y, Tokui M, Imai T, Murakami R, Tsuchiya T, Sasaki H, Masaoka T, Irie J, Meguro S, Itoh H, Twin-exenatide Study Group

Journal of diabetes investigation 11 （ 2 ） 382 - 388 2019年09月

査読有り, ISSN 2040-1116

AIMS/INTRODUCTION: To evaluate the efficacy and safety of once-weekly (q.w.) extended-release exenatide after switching from twice-daily (b.i.d.) exenatide in patients with type 2 diabetes. MATERIALS AND METHODS: This was an investigator-initiated, prospective, single-arm, multicenter study. Individuals with type 2 diabetes who had been treated with exenatide b.i.d. for at least 3 months were enrolled and switched to exenatide q.w. for 24 weeks. The primary end-point was change in HbA1c at week 24 to test the glucose-lowering effect of exenatide q.w. versus exenatide b.i.d. RESULTS: A total of 58 Japanese individuals with type 2 diabetes completed the study. Glycated hemoglobin was reduced by 0.2% at week 24 (7.2 ± 1.2% vs 7.0 ± 1.2% [56 ± 13 vs 53 ± 13 mmol/mol], 95% confidence interval -0.4 to -0.03%, P < 0.005 for non-inferiority, P = 0.01 for superiority). Fasting plasma glucose was reduced by 12 mg/dL at week 24 (154 ± 46 vs 142 ± 46 mg/dL, P = 0.02). β-Cell function assessed by homeostasis model assessment of β-cell function and C-peptide index was significantly improved at week 24. The incidence of self-reported hypoglycemia was reduced, and treatment satisfaction assessed by the Diabetes Treatment Satisfaction Questionnaire and Diabetes Medication Satisfaction Questionnaire was improved at week 24, with no change in body weight. There was no serious adverse event related to the study drug. CONCLUSIONS: Switching from exenatide b.i.d. to exenatide q.w. resulted in a reduction in glycated hemoglobin, fasting plasma glucose and the incidence of hypoglycemia, and improvement in β-cell function and treatment satisfaction in patients with type 2 diabetes. These findings will be useful for selecting optimal treatment in individuals with type 2 diabetes.

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Low birth weight is associated with decline in renal function in Japanese male and female adolescents.

Murai-Takeda A, Kanda T, Azegami T, Hirose H, Inokuchi M, Tokuyama H, Wakino S, Tokumura M, Kawabe H, Mori M, Itoh H

Clinical and Experimental Nephrology 23 （ 12 ） 1364 - 1372 2019年09月

査読有り, ISSN 1342-1751

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Association Between Acute Fall in Estimated Glomerular Filtration Rate After Treatment for Primary Aldosteronism and Long-Term Decline in Renal Function.

Kobayashi H, Abe M, Nakamura Y, Takahashi K, Fujita M, Takeda Y, Yoneda T, Kurihara I, Itoh H, Tsuiki M, Wada N, Ichijo T, Katabami T, Ogawa Y, Kawashima J, Yoshimoto T, Sone M, Inagaki N, Watanabe M, Kamemura K, Matsuda Y, Izawa S, Tanabe M, Tanabe A, Suzuki T, Naruse M, JPAS/JRAS, Study Group

Hypertension (Dallas, Tex. : 1979) 74 （ 3 ） 630 - 638 2019年09月

査読有り, ISSN 0194-911X

Primary aldosteronism causes renal structural damage after glomerular hyperfiltration, and primary aldosteronism-specific treatment leads to an acute fall in estimated glomerular filtration rate (eGFR). We investigated whether this change affected the long-term eGFR slope in a retrospective cohort from the multicenter Japan Primary Aldosteronism Study. We allocated patients with primary aldosteronism to the adrenalectomy (n=202) and MR (mineralocorticoid receptor) antagonist (n=303) groups based on their treatment history and analyzed the association between the initial eGFR fall and long-term eGFR slope. The increased age, low serum potassium levels, high eGFR, and high plasma aldosterone levels were independent predictors for a large initial eGFR fall in both groups. Our analysis of tertiles based on the initial eGFR fall revealed that in the MR antagonist group, patients with a small initial eGFR fall had a significantly steeper long-term eGFR slope than those with a large initial fall (tertile 1 versus 2, P=0.025; tertile 1 versus 3, P=0.017). These associations were not identified in the adrenalectomy group. Thus, the smaller the acute fall in eGFR by initiation of MR antagonists, the greater was the rate of long-term eGFR decline. While the acute fall in eGFR induced by primary aldosteronism-specific treatment is occasionally a clinical concern, our findings highlight the favorable implications of the acute fall with respect to long-term renal outcomes.

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Gut microbiota confers host resistance to obesity by metabolizing dietary polyunsaturated fatty acids.

Miyamoto J, Igarashi M, Watanabe K, Karaki SI, Mukouyama H, Kishino S, Li X, Ichimura A, Irie J, Sugimoto Y, Mizutani T, Sugawara T, Miki T, Ogawa J, Drucker DJ, Arita M, Itoh H, Kimura I

Nature Communications 10 （ 1 ） 4007 2019年09月

査読有り

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Hypertension as a Metabolic Disorder and the Novel Role of the Gut

Tanaka M., Itoh H.

Current Hypertension Reports （Current Hypertension Reports） 21 （ 8 ） 2019年08月

ISSN 15226417

© 2019, The Author(s). Purpose of Review: Hypertension is related to impaired metabolic homeostasis and can be regarded as a metabolic disorder. This review presents possible mechanisms by which metabolic disorders increase blood pressure (BP) and discusses the importance of the gut as a novel modulator of BP. Recent Findings: Obesity and high salt intake are major risk factors for hypertension. There is a hypothesis of “salt-induced obesity”; i.e., high salt intake may tie to obesity. Heightened sympathetic nervous system (SNS) activity, especially in the kidney and brain, increases BP in obese patients. Adipokines, including adiponectin and leptin, and renin-angiotensin-aldosterone system (RAAS) contribute to hypertension. Adiponectin induced by a high-salt diet may decrease sodium/glucose cotransporter (SGLT) 2 expression in the kidney, which results in reducing BP. High salt can change secretions of adipokines and RAAS-related components. Evidence has been accumulating linking the gastrointestinal tract to BP. Glucagon-like peptide-1 (GLP-1) and ghrelin decrease BP in both rodents and humans. The sweet taste receptor in enteroendocrine cells increases SGLT1 expression and stimulates sodium/glucose absorption. Roux-en-Y gastric bypass improves glycemic and BP control due to reducing the activity of SGLT1. Na/H exchanger isoform 3 (NHE3) increases BP by stimulating the intestinal absorption of sodium. Gastrin functions as an intestinal sodium taste sensor and inhibits NHE3 activity. Intestinal mineralocorticoid receptors also regulate sodium absorption and BP due to changing ENaC activity. Gastric sensing of sodium induces natriuresis, and gastric distension increases BP. Changes in the composition and function of gut microbiota contribute to hypertension. A high-salt/fat diet may disrupt the gut barrier, which results in systemic inflammation, insulin resistance, and increased BP. Gut microbiota regulates BP by secreting vasoactive hormones and short-chain fatty acids. BP-lowering effects of probiotics and antibiotics have been reported. Bariatric surgery improves metabolic disorders and hypertension due to increasing GLP-1 secretion, decreasing leptin secretion and SNS activity, and changing gut microbiome composition. Strategies targeting the gastrointestinal system may be therapeutic options for improving metabolic abnormalities and reducing BP in humans. Summary: SNS, brain, adipocytes, RAAS, the kidney, the gastrointestinal tract, and microbiota play important roles in regulating BP. Most notably, the gut could be a novel target for treatment of hypertension as a metabolic disorder.

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DNA Damage Repair and DNA Methylation in the Kidney

Hayashi K., Hishikawa A., Itoh H.

American Journal of Nephrology （American Journal of Nephrology） 50 （ 2 ） 81 - 91 2019年07月

ISSN 02508095

© 2019 © 2019 S. Karger AG, Basel. Copyright: All rights reserved. The DNA repair system is essential for the maintenance of genome integrity and is mainly investigated in the areas of aging and cancer. The DNA repair system is strikingly cell-type specific, depending on the expression of DNA repair factors; therefore, different DNA repair systems may exist in each type of kidney cell. Importance of DNA repair in the kidney is suggested by renal phenotypes caused by both genetic mutations in the DNA repair pathway and increased stimuli of DNA damage. Recently, we reported the importance of DNA double-strand break repair in glomerular podocytes and its involvement in the alteration of DNA methylation status, which regulates podocyte phenotypes. In this review, we summarize the roles of the DNA repair system in the kidneys and possible associations with altered kidney DNA methylation, which have been infrequently reported together. Investigations of DNA damage repair and epigenetic changes in the kidneys may achieve a profound understanding of kidney aging and diseases.

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Influence of antihypertensive drugs in the subtype diagnosis of primary aldosteronism by adrenal venous sampling

Nagasawa M., Yamamoto K., Rakugi H., Takeda M., Akasaka H., Umakoshi H., Tsuiki M., Takeda Y., Kurihara I., Itoh H., Ichijo T., Katabami T., Wada N., Shibayama Y., Yoshimoto T., Ogawa Y., Kawashima J., Sone M., Inagaki N., Takahashi K., Fujita M., Watanabe M., Matsuda Y., Kobayashi H., Shibata H., Kamemura K., Otsuki M., Fujii Y., Ogo A., Okamura S., Miyauchi S., Yanase T., Suzuki T., Kawamura T., Naruse M.

Journal of Hypertension （Journal of Hypertension） 37 （ 7 ） 1493 - 1499 2019年07月

ISSN 02636352

© 2019 Wolters Kluwer Health, Inc. All rights reserved. Objectives:Because of the influence on the renin-angiotensin-aldosterone system, it is recommended to avoid, if possible, the use of angiotensin-converting-enzyme inhibitors, angiotensin II type 1 receptor blockers, diuretics, β-blockers, and mineralocorticoid receptor antagonists during the diagnostic period of primary aldosteronism. A laterality index more than 4 in adrenocorticotropic hormone (ACTH)-stimulated adrenal venous sampling (ACTH-AVS) is a widely used classification of the unilateral subtype that can benefit from adrenalectomy. Here, we revealed clinical features of patients taking drugs that could affect the primary aldosteronism diagnosis (DAPD) and investigated whether the classification with laterality index more than 4 in ACTH-AVS is applicable to these patients.Patients and methods:Using a large database of primary aldosteronism patients in Japan, we analyzed 2122 patients with successful ACTH-AVS.Results:Patients who received any DAPD (n = 209) showed higher prevalence of comorbidity burdens and took more antihypertensive drugs compared with patients without DAPD. In patients taking DAPD, those with laterality index more than 4 had a higher prevalence of hypokalemia, a higher aldosterone-to-renin ratio and a higher prevalence of adrenal mass than those with laterality index of 4 or less. Adrenalectomy was performed in 76% patients with laterality index more than 4 and 20% with laterality index of 4 or less. Patients who underwent adrenalectomy showed biochemical cure in 89% with laterality index more than 4 and 50% with laterality index of 4 or less (P = 0.001). Multivariate regression analysis showed that laterality index more than 4 was an independent predictor of a biochemical cure. Biochemical cure rate in patients with laterality index more than 4 was consistently high, irrespective of the potential effect of individual DAPD on laterality index.Conclusion:Our findings suggest that in primary aldosteronism patients to whom DAPD were administrated due to severe clinical features, laterality index more than 4 in ACTH-AVS could accurately predict a biochemical cure after adrenalectomy.

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Efficacy and safety of esaxerenone (CS-3150) for the treatment of essential hypertension: a phase 2 randomized, placebo-controlled, double-blind study

Ito S., Itoh H., Rakugi H., Okuda Y., Yamakawa S.

Journal of Human Hypertension （Journal of Human Hypertension） 33 （ 7 ） 542 - 551 2019年07月

ISSN 09509240

© 2019, Springer Nature Limited. This was a phase 2, multicenter, randomized, double-blind, placebo-controlled, open-label comparator study to investigate the efficacy and safety of esaxerenone (CS-3150), a novel non-steroidal mineralocorticoid receptor blocker, in Japanese patients with essential hypertension. Eligible patients (n = 426) received esaxerenone (1.25, 2.5, or 5 mg/day), placebo, or eplerenone (50–100 mg/day) for 12 weeks. The primary efficacy endpoint was the change from baseline in sitting systolic and diastolic blood pressure (BP). Safety endpoints included adverse events and serum K+ elevation. There were significant dose–response reductions in the 2.5 and 5 mg/day esaxerenone groups for sitting BP (both p < 0.001) and 24-h BP (both p < 0.0001) compared with placebo, with a mean (95% confidence interval) change in sitting BP of −7.0 (−9.5 to −4.6)/−3.8 (−5.2 to −2.4) mmHg in the placebo group, and −10.7 (−13.2 to −8.2)/−5.0 (−6.4 to −3.6) mmHg, −14.3 (−16.8 to −11.9)/−7.6 (−9.1 to −6.2) mmHg, and −20.6 (−23.0 to −18.2)/ −10.4 (−11.8 to −9.0) mmHg for the 1.25, 2.5, and 5 mg/day esaxerenone groups, respectively, while the change was −17.4 (−19.9 to −15.0)/−8.5 (−9.9 to −7.1) mmHg for eplerenone. The incidence of adverse events was similar in all treatment groups. Serum K+ levels initially increased in proportion with esaxerenone dose but were stable from week 2 until week 12. Plasma esaxerenone concentration increased in proportion with the dose. In conclusion, esaxerenone is an effective and tolerable treatment option for patients with essential hypertension.

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Clinical and biochemical outcomes after adrenalectomy and medical treatment in patients with unilateral primary aldosteronism.

Takuyuki Katabami, Hisashi Fukuda, Hidekazu Tsukiyama, Yasushi Tanaka, Yoshiyu Takeda, Isao Kurihara, Hiroshi Ito, Mika Tsuiki, Takamasa Ichijo, Norio Wada, Yui Shibayama, Takanobu Yoshimoto, Yoshihiro Ogawa, Junji Kawashima, Masakatsu Sone, Nobuya Inagaki, Katsutoshi Takahashi, Megumi Fujita, Minemori Watanabe, Yuichi Matsuda, Hiroki Kobayashi, Hirotaka Shibata, Kohei Kamemura, Michio Otsuki, Yuichi Fujii, Koichi Yamamoto, Atsushi Ogo, Toshihiko Yanase, Tomoko Suzuki, Mitsuhide Naruse

Journal of hypertension 37 （ 7 ） 1513 - 1520 2019年07月

査読有り, ISSN 0263-6352

OBJECTIVES: Current clinical guidelines of primary aldosteronism recommend adrenalectomy (AdX) for unilateral primary aldosteronism based on the studies showing the potential superiority of AdX over the medical treatment. However, since most medically treated cases consisted of bilateral primary aldosteronism and all surgically treated cases consisted of unilateral primary aldosteronism, the different subtype of primary aldosteronism could be a bias for their effects. This study compared the effects of AdX and medical therapy in patients with unilateral primary aldosteronism confirmed by adrenal vein sampling. METHODS: Of the 339 patients with unilateral primary aldosteronism in the Japan Primary Pldosteronism Study data base, unilateral AdX and treatment with mineral corticoid receptor antagonists (MRAs) was done in 276 patients (AdX group) and in 63 patients (MRAs group), respectively. The effects were compared by the clinical (improvement of blood pressure) and biochemical outcomes (improvement of hypokalemia). RESULTS: At baseline, use of potassium replacement, plasma aldosterone concentration, aldosterone-to-renin ratio, estimated glomerular filtration rate, and prevalence of adrenal mass on imaging were higher in the AdX group than in the MRAs group. At 6 months after commencement of specific treatment for primary aldosteronism, clinical outcome and biochemical outcome in the AdX group were superior than those in the MRAs group. The difference of the outcome between the two groups were the case even after adjusting for the different clinical backgrounds in the two groups before the specific treatment. CONCLUSION: Our study provides evidence that AdX is the first choice of treatment in the patients with unilateral primary aldosteronism in terms of clinical and biochemical outcome.

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Greeting Messages from President of Japanese Society of Hypertension (JSH) The challenge of JSH: moonshot for "Conquest of hypertension in Japan".

Itoh H

Hypertension research : official journal of the Japanese Society of Hypertension 42 （ 7 ） 925 - 927 2019年07月

ISSN 0916-9636

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Renal impairment is closely associated with plasma aldosterone concentration in patients with primary aldosteronism.

Kawashima A, Sone M, Inagaki N, Takeda Y, Itoh H, Kurihara I, Umakoshi H, Ichijo T, Katabami T, Wada N, Ogawa Y, Kawashima J, Fujita M, Miyauchi S, Okamura S, Fukuoka T, Yanase T, Izawa S, Yoshikawa Y, Hashimoto S, Yamada M, Kai T, Suzuki T, Naruse M

European journal of endocrinology 181 （ 3 ） 339 - 350 2019年07月

査読有り, ISSN 0804-4643

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Acute Interstitial Nephritis With Karyomegalic Epithelial Cells After Nivolumab Treatment—Two Case Reports

Ryuzaki M., Tokuyama H., Uchiyama K., Nakaya H., Hasegawa K., Miyashita K., Konishi K., Hashiguchi A., Wakino S., Itoh H.

Clinical Medicine Insights: Case Reports （Clinical Medicine Insights: Case Reports） 12 2019年06月

© The Author(s) 2019. Clinical application of immune checkpoint inhibitors (CPIs) including nivolumab is expanding in the field of oncology treatment. Nivolumab is an anti-programmed death 1 protein (PD-1) antibody designed to augment an immunologic reaction against cancer cells. On the contrary, CPIs are known to cause a unique variety of side effects termed as immune-related adverse events, which can affect any organ including kidney. However, the characteristics of renal disorders by nivolumab treatment are poorly described. We describe two cases of acute kidney injury that were treated with nivolumab. Two patients, one with renal-cell carcinoma and the other with lung cancer, exhibited progressive renal dysfunction after the initiation of nivolumab treatment. By kidney biopsy, each case was diagnosed as acute interstitial nephritis (AIN). Of note, tubular epithelial cells enlarged with hyperchromatic nuclei were focally observed, and this finding was consistent with karyomegalic tubular epithelial cells. In immunostaining, most of the enlarged tubular epithelial cells were positive for Ki-67, which suggested regeneration of tubular epithelial cells. Clinically, in one case, renal function was partially recovered with the discontinuation of nivolumab, while in another case renal function was fully recovered with additional corticosteroid treatment. We presented nivolumab-induced AIN with karyomegalic changes of tubular epithelia. We propose that immunosuppressive therapy may be necessary for the full recovery from renal impairment.

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2型糖尿病患者における短時間作用型GLP-1製剤から長時間作用型GLP-1製剤への切替えの有効性及び安全性についての検討

税所芳史, 渡辺雄祐, 稲石淳, 侯金成, 山内晃, 金澤寧彦, 大久保佳昭, 徳井幹也, 今井孝俊, 村上理恵, 土屋多美, 佐々木裕伸, 菊地理恵子, 正岡建洋, 入江潤一郎, 目黒周, 伊藤裕

日本抗加齢医学会総会プログラム・抄録集（(一社)日本抗加齢医学会） 19回 231 - 231 2019年06月

査読有り

CKDにおけるdysbiosisは、筋萎縮およびミトコンドリア機能低下を伴う運動耐容能の低下を惹起する

内山清貴, 脇野修, 入江潤一郎, 伊藤裕

日本抗加齢医学会総会プログラム・抄録集（(一社)日本抗加齢医学会） 19回 194 - 194 2019年06月

査読有り

2型糖尿病患者に非定型抗精神病薬リスペリドンを使用し高血糖高浸透圧症候群を発症した1例

宇都飛鳥, 税所芳史, 入江潤一郎, 田中正巳, 目黒周, 伊藤裕

日本抗加齢医学会総会プログラム・抄録集（(一社)日本抗加齢医学会） 19回 246 - 246 2019年06月

査読有り

2型糖尿病患者における血中総ビリルビン濃度と網膜症および大血管障害との関連

田中正巳, 西村健志, 目黒周, 入江潤一郎, 税所芳史, 三石正憲, 川野義長, 伊藤裕

日本抗加齢医学会総会プログラム・抄録集（(一社)日本抗加齢医学会） 19回 249 - 249 2019年06月

査読有り

2型糖尿病患者における短時間作用型GLP-1製剤から長時間作用型GLP-1製剤への切替えの有効性及び安全性についての検討

日本抗加齢医学会総会プログラム・抄録集（(一社)日本抗加齢医学会） 19回 231 - 231 2019年06月

Foxo1-CoF Repressor (FCoR) Regulates Pancreatic Alpha- and Beta-Cell Identity by both DNA and Histone Methylation

Noriko Kodani, Masaki Kobayashi, Osamu Kikuchi, Tadahiro Kitamura, Hiroshi Itoh, Jun Nakae

DIABETES （AMER DIABETES ASSOC） 68 2019年06月

ISSN 0012-1797

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Acquired partial lipodystrophy with metabolic disease in children following hematopoietic stem cell transplantation: a report of two cases and a review of the literature.

Mayumi Hosokawa, Hironori Shibata, Takahiro Hosokawa, Junichiro Irie, Hiroshi Ito, Tomonobu Hasegawa

Journal of pediatric endocrinology & metabolism : JPEM 32 （ 5 ） 537 - 541 2019年05月

査読有り

Hematopoietic stem cell transplantation (HSCT) has been newly identified as an etiology underlying acquired lipodystrophy (ALD). We report about two children with leukemia who underwent HSCT and later manifested aberrant fat distributions consistent with acquired partial lipodystrophy (APL). Both patients manifested graft-versus-host disease (GVHD), suggesting that GVHD may trigger lipodystrophy. The patients exhibited diabetic blood glucose patterns in the oral glucose tolerance test (OGTT) with high homeostasis model assessment ratios (HOMA-Rs), hypertriglyceridemia, fatty liver, and decreased serum leptin and adiponectin levels. Both patients were diagnosed with APL with metabolic disease. A review of the data of patients with ALD after HSCT revealed common clinical features, including aberrant fat distribution, impaired glucose tolerance (IGT) or diabetes and dyslipidemia. Based on previous reports and our two cases, we speculate that GVHD in the adipose tissue supports the development of ALD after HSCT. In conclusion, children may develop APL after HSCT. Therefore, evaluations of fat distribution and metabolic disease may be important during the long-term follow-up of these patients.

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High prevalence of diabetes in patients with primary aldosteronism (PA) associated with subclinical hypercortisolism and prediabetes more prevalent in bilateral than unilateral PA: A large, multicenter cohort study in Japan

Akehi Y., Yanase T., Motonaga R., Umakoshi H., Tsuiki M., Takeda Y., Yoneda T., Kurihara I., Itoh H., Katabami T., Ichijo T., Wada N., Shibayama Y., Yoshimoto T., Ashida K., Ogawa Y., Kawashima J., Sone M., Inagaki N., Takahashi K., Fujita M., Watanabe M., Matsuda Y., Kobayashi H., Shibata H., Kamemura K., Otsuki M., Fujii Y., Yamamoto K., Ogo A., Okamura S., Miyauchi S., Fukuoka T., Izawa S., Hashimoto S., Yamada M., Yoshikawa Y., Kai T., Suzuki T., Kawamura T., Naruse M.

Diabetes Care （Diabetes Care） 42 （ 5 ） 938 - 945 2019年05月

ISSN 01495992

© 2019 by the American Diabetes Association. OBJECTIVE To investigate the prevalence and causes of diabetes in patients with primary aldosteronism (PA) in a multi-institutional cohort study in Japan. RESEARCH DESIGN AND METHODS The prevalence of diabetes was determined in 2,210 patients with PA (diagnosed or glycated hemoglobin [HbA1c] ‡6.5% [‡48 mmol/mol]; NGSP) and compared with that of the Japanese general population according to age and sex. In 1,386 patients with PA and clear laterality (unilateral or bilateral), the effects of plasma aldosterone concentration (PAC), hypokalemia (<3.5 mEq/L), suspected subclinical hypercortisolism (SH; serum cortisol ‡1.8 mg/dL after 1-mg dexamethasone suppression test), and PA laterality on the prevalence of diabetes or prediabetes (5.7% £ HbA1c <6.5% [39 mmol/mol £ HbA1c <48 mmol/mol]) were examined. RESULTS Of the 2,210 patients with PA, 477 (21.6%) had diabetes. This prevalence is higher than that in the general population (12.1%) or in 10-year cohorts aged 30–69 years. Logistic regression or x2 test revealed a significant contribution of suspected SH to diabetes. Despite more active PA profiles (e.g., higher PAC and lower potassium concentrations) in unilateral than bilateral PA, BMI and HbA1c values were significantly higher in bilateral PA. PA laterality had no effect on the prevalence of diabetes; however, the prevalence of prediabetes was significantly higher in bilateral than unilateral PA. CONCLUSIONS Individuals with PA have a high prevalence of diabetes, which is associated mainly with SH. The prevalence of prediabetes is greater for bilateral than unilateral PA, suggesting a unique metabolic cause of bilateral PA.

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β-hydroxybutyrate attenuates renal ischemia-reperfusion injury through its anti-pyroptotic effects

Tajima T., Yoshifuji A., Matsui A., Itoh T., Uchiyama K., Kanda T., Tokuyama H., Wakino S., Itoh H.

Kidney International （Kidney International） 95 （ 5 ） 1120 - 1137 2019年05月

ISSN 00852538

© 2019 International Society of Nephrology Ketone bodies including β-hydroxybutyrate (β-OHB) have been shown to protect against ischemic tissue injury when present at low concentrations. We evaluated the impact of β-OHB on renal ischemia/reperfusion injury (IRI). Mice were treated with a continuous infusion of β-OHB using an osmotic mini-pump before and after IRI. We also tested the effects of increasing endogenous serum β-OHB levels by fasting. Renal IRI was attenuated by β-OHB treatment compared to saline control, with similar results in the fasting condition. β-OHB treatment reduced the number of terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling (TUNEL)-positive cells and increased expression of forkhead transcription factor O3 (FOXO3), an upstream regulator of pyroptosis. Although β-OHB treatment did not impact markers of apoptosis, it decreased the expression of caspase-1 and proinflammatory cytokines, indicating that β-OHB blocked pyroptosis. In a human proximal tubular cell line exposed to hypoxia and reoxygenation, β-OHB reduced cell death in a FOXO3-dependent fashion. Histone acetylation was decreased in kidneys exposed to IRI and in proximal tubular cells exposed to hypoxia and reoxygenation, and this effect was ameliorated by β-OHB through the inactivation of histone deacetylases. In vitro, β-OHB treatment restored histone acetylation at the FOXO3 promoter. Consistent with epigenetic molecular effects, the renoprotective effects of β-OHB were still observed when the continuous infusion was stopped at the time of IRI. Thus, β-OHB attenuates renal IRI through anti-pyroptotic effects, likely mediated by an epigenetic effect on FOXO3 expression.

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CKDにおけるdysbiosisは腸管tight junctionの発現低下及び尿毒素蓄積からインスリン抵抗性とサルコペニアを惹起する

内山清貴, 脇野修, 入江潤一郎, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 61 （ 3 ） 400 - 400 2019年05月

査読有り, ISSN 0385-2385

Role of Nampt-Sirt6 Axis in Renal Proximal Tubules in Extracellular Matrix Deposition in Diabetic Nephropathy

Muraoka H., Hasegawa K., Sakamaki Y., Minakuchi H., Kawaguchi T., Yasuda I., Kanda T., Tokuyama H., Wakino S., Itoh H.

Cell Reports （Cell Reports） 27 （ 1 ） 199 - 212.e5 2019年04月

© 2019 The Author(s) Nicotinamide adenine dinucleotide (NAD + ) metabolism plays a critical role in kidneys. We previously reported that decreased secretion of a NAD + precursor, nicotinamide mononucleotide (NMN), from proximal tubules (PTs) can trigger diabetic albuminuria. In the present study, we investigated the role of NMN-producing enzyme nicotinamide phosphoribosyltransferase (Nampt) in diabetic nephropathy. The expression of Nampt in PTs was downregulated in streptozotocin (STZ)-treated diabetic mice when they exhibited albuminuria. This albuminuria was ameliorated in PT-specific Nampt-overexpressing transgenic (TG) mice. PT-specific Nampt-conditional knockout (Nampt CKO) mice exhibited TBM thickening and collagen deposition, which were associated with the upregulation of the profibrogenic gene TIMP-1. Nampt CKO mice also exhibited the downregulation of sirtuins, particularly in Sirt6. PT-specific Sirt6-knockout mice exhibited enhanced fibrotic phenotype resembling that of Nampt CKO mice with increased Timp1 expression. In conclusion, the Nampt-Sirt6 axis in PTs serves as a key player in fibrogenic extracellular matrix remodeling in diabetic nephropathy. Muraoka et al. reveal that the Nampt-Sirt6 axis in proximal tubules serves as a key player in fibrogenic extracellular matrix remodeling in diabetic nephropathy.

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A Case Report of Autosomal Dominant Polycystic Kidney Disease Under Peritoneal Dialysis With Cyst Infection and Culture-Positive Peritoneal Fluid

Yasuda I., Hasegawa K., Tokuyama H., Washida N., Shinozuka K., Yasuda M., Ryuzaki M., Urai H., Wakino S., Itoh H.

Clinical Medicine Insights: Case Reports （Clinical Medicine Insights: Case Reports） 12 2019年04月

© The Author(s) 2019. Background: Cyst infection is a complication sometimes seen in patients with autosomal dominant polycystic kidney disease (ADPKD) and often shows through a positive blood culture. However, there have been no reports of ADPKD patients whose cyst infection propagate to peritoneal fluid leading to positive peritoneal fluid culture. Case presentation: A 74-year-old Japanese man with ADPKD under peritoneal dialysis (PD) was presented with left flank pain, fever, and chills at our hospital. He did not show any symptoms or signs suggestive of peritonitis. There were no elevated cell counts or polymorphonuclear leucocytes in his PD fluid. There were some complicated cysts found in computed tomography and magnetic resonance imaging examinations. We clinically diagnosed him as having a renal cyst infection rather than PD-related peritonitis. We initiated treatment by administering ceftriaxone with an immediate favorable response. As the possibility of accompanying prostatitis still remained, we switched to intravenous levofloxacin on the second day. On the 10th day, Helicobacter cinaedi was detected in 2 sets of blood culture as well as in PD fluid. We switched back to ceftriaxone and this treatment was entirely successful. Conclusions: This is the first report of H cinaedi cyst infection which propagates to peritoneal fluid in a patient with ADPKD.

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Achieving LDL cholesterol target levels <1.81 mmol/L may provide extra cardiovascular protection in patients at high risk: Exploratory analysis of the Standard Versus Intensive Statin Therapy for Patients with Hypercholesterolaemia and Diabetic Retinopathy study

Itoh H., Komuro I., Takeuchi M., Akasaka T., Daida H., Egashira Y., Fujita H., Higaki J., Hirata K., Ishibashi S., Isshiki T., Ito S., Kashiwagi A., Kato S., Kitagawa K., Kitakaze M., Kitazono T., Kurabayashi M., Miyauchi K., Murakami T., Murohara T., Node K., Ogawa S., Saito Y., Seino Y., Shigeeda T., Shindo S., Sugawara M., Sugiyama S., Terauchi Y., Tsutsui H., Ueshima K., Utsunomiya K., Yamagishi M., Yamazaki T., Yo S., Yokote K., Yoshida K., Yoshimura M., Yoshimura N., Nakao K., Nagai R.

Diabetes, Obesity and Metabolism （Diabetes, Obesity and Metabolism） 21 （ 4 ） 791 - 800 2019年04月

ISSN 14628902

© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. Aims: To assess the benefits of intensive statin therapy on reducing cardiovascular (CV) events in patients with type 2 diabetes complicated with hyperlipidaemia and retinopathy in a primary prevention setting in Japan. In the intension-to-treat population, intensive therapy [targeting LDL cholesterol <1.81 mmol/L (<70 mg/dL)] was no more effective than standard therapy [LDL cholesterol ≥2.59 to <3.10 mmol/L (≥100 to <120 mg/dL)]; however, after 3 years, the intergroup difference in LDL cholesterol was only 0.72 mmol/L (27.7 mg/dL), and targeted levels were achieved in <50% of patients. We hypothesized that the intergroup difference in CV events would have been statistically significant if more patients had been successfully treated to target. Materials and Methods: This exploratory post hoc analysis focused on intergroup data from patients who achieved their target LDL cholesterol levels. The primary endpoint was the composite incidence of CV events. A Cox proportional hazards model was used to estimate hazard ratios (HRs) for incidence of the primary endpoint in patients who achieved target LDL cholesterol levels in each group. Results: Data were analysed from 1909 patients (intensive: 703; standard: 1206) who achieved target LDL cholesterol levels. LDL cholesterol at 36 months was 1.54 ± 0.30 mmol/L (59.7 ± 11.6 mg/dL) in the intensive group and 2.77 ± 0.46 mmol/L (107.1 ± 17.8 mg/dL) in the standard group (P < 0.05). After adjusting for baseline prognostic factors, the composite incidence of CV events or deaths associated with CV events was significantly lower in the intensive than the standard group (HR 0.48; 95% confidence interval 0.28-0.82; P = 0.007). Conclusions: This post hoc analysis suggests that achieving LDL cholesterol target levels <1.81 mmol/L may more effectively reduce CV events than achieving target levels ≥2.59 to <3.10 mmol/L in patients with hypercholesterolaemia and diabetic retinopathy.

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Pre-emptive medicine for hypertension and its prospects

Itoh H., Hayashi K., Miyashita K.

Hypertension Research （Hypertension Research） 42 （ 3 ） 301 - 305 2019年03月

ISSN 09169636

© 2018, The Japanese Society of Hypertension. Pre-emptive medicine is a novel medical concept proposed in Japan that aims to precisely predict the onset and progression of diseases and to provide therapeutic interventions during early stages, before symptoms appear. The concept of pre-emptive medicine considers the time-course of a disease in each individual and seeks medical interventions to prevent disease progression. Suitable and promising targets for pre-emptive medicine are non-communicable diseases, including hypertension. Recent advances in genomic analysis, information technology, and artificial intelligence should make this medical concept feasible in the near future. In this review, we focused on pre-emptive medicine for hypertension, referring to concrete plans for the future direction of this research. The ultimate goal of pre-emptive medicine is to completely prevent the onset and progression of hypertension by precisely predicting the elevation of blood pressure and performing interventions to avoid it. The diagnostic processes of hypertension, from the standpoint of pre-emptive medicine, should include the detection of abnormal blood pressure regulation as the earliest manifestation of the disease, the depiction of the present status of hypertension in an individual (“nowcasting”), and a prediction of the future trajectory of the disease (“forecasting”). Novel therapeutic strategies for hypertension, from the standpoint of pre-emptive medicine, should aim for the regression of hypertension through early treatments and the remission of hypertension through intermittent intensive therapies. An efficient modification of lifestyle and therapies, according to the progression of hypertension, should be required. If pre-emptive medicine for hypertension becomes established, it would greatly contribute to the extension of a healthy lifespan, which cannot yet be satisfactorily achieved.

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Association of Genetic and Clinical Aspects of Congenital Long QT Syndrome With Life-Threatening Arrhythmias in Japanese Patients.

Shimizu W, Makimoto H, Yamagata K, Kamakura T, Wada M, Miyamoto K, Inoue-Yamada Y, Okamura H, Ishibashi K, Noda T, Nagase S, Miyazaki A, Sakaguchi H, Shiraishi I, Makiyama T, Ohno S, Itoh H, Watanabe H, Hayashi K, Yamagishi M, Morita H, Yoshinaga M, Aizawa Y, Kusano K, Miyamoto Y, Kamakura S, Yasuda S, Ogawa H, Tanaka T, Sumitomo N, Hagiwara N, Fukuda K, Ogawa S, Aizawa Y, Makita N, Ohe T, Horie M, Aiba T

JAMA cardiology 4 （ 3 ） 246 - 254 2019年03月

査読有り, ISSN 2380-6583

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Usefulness of hemoglobin a1c and glycated albumin measurements for insulinoma screening: An observational case-control study

Torimoto K., Okada Y., Tanaka Y., Matsuoka A., Hirota Y., Ogawa W., Saisho Y., Kurihara I., Itoh H., Inada S., Koga M.

BMC Cancer （BMC Cancer） 19 （ 1 ） 2019年02月

© 2019 The Author(s). Background: Insulinoma represents hypoglycemia as a predominant symptom; the autonomic symptoms may be resolved by chronically recurrent hypoglycemia resulting in the persistence of non-specific symptoms alone. Therefore, it has been estimated that there are many patients in whom the disease takes longer to diagnose and has remained undiagnosed. Although some parameters exist for the definitive diagnosis of the disease, there are currently no indices for early screening. Indices of glycemic control, hemoglobin A1c (HbA1c), and glycated albumin (GA) may be useful for the screening of patients with insulinoma having chronic hypoglycemia because the values become low in such a condition. Because there are no articles that have reported the point, we examine the effective cutoff values of HbA1c and GA for the diagnosis of insulinoma in the present study. Methods: In a multicenter cross-sectional study, 31 patients with insulinoma were included for comparison with 120 control subjects with normal glucose tolerance based on 75 g oral glucose tolerance tests whose characteristics were matched to the patients. The primary outcomes were optimal cutoff values of HbA1c and GA for the screening of insulinoma. Results: HbA1c was significantly lower in the insulinoma group at 4.7 ± 0.4% compared to the healthy control group at 5.7 ± 0.3% (p < 0.001), and GA was significantly lower in the insulinoma group at 11.6 ± 1.8% compared to the healthy control group at 14.5 ± 1.0% (p < 0.001). According to a receiver operating characteristic (ROC) analysis, optimal cutoff values of HbA1c and GA for the diagnosis of insulinoma were 5.0 and 12.4%, respectively. Area under the curve values of HbA1c and GA were 0.970 and 0.929, respectively, showing no significant difference (p = 0.399). Conclusions: In the present study, HbA1c and GA values in patients with insulinoma were significantly lower compared to the healthy controls, and effective cutoff values for screening were shown in the diagnosis of insulinoma for the first time. HbA1c and GA can be useful indices for insulinoma screening. Because malignant insulinoma have a similar diagnostic process to that of benign insulinoma, these could be useful for malignant insulinoma.

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Zfp238 Regulates the Thermogenic Program in Cooperation with Foxo1

Kita M., Nakae J., Kawano Y., Asahara H., Takemori H., Okado H., Itoh H.

iScience （iScience） 12 87 - 101 2019年02月

© 2019 The Author(s) Obesity has become an explicit public health concern because of its relevance to metabolic syndrome. Evidence points to the significance of beige adipocytes in regulating energy expenditure. Here, using yeast two-hybrid screening, we show that Zfp238 is a Foxo1 co-repressor and that adipose-tissue-specific ablation of Zfp238 (Adipo-Zfp238KO)in mice leads to obesity, decreased energy expenditure, and insulin resistance under normal chow diet. Adipo-Zfp238KO inhibits induction of Ucp1 expression in subcutaneous adipose tissue upon cold exposure or CL316243, but not in brown adipose tissue. Furthermore, knockdown of Zfp238 in 3T3-L1 cells decreases Ucp1 expression in response to cool incubation or forskolin significantly compared with control cells. In contrast, overexpression of Zfp238 in 3T3-L1 cells significantly increases Ucp1 expression in response to forskolin. Finally, double knockdown of both Zfp238 and Foxo1 normalizes Ucp1 induction. These data suggest that Zfp238 in adipose tissue regulates the thermogenic program in cooperation with Foxo1.

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Efficacy and safety of switching to insulin glargine 300 U/mL from 100 U/mL in Japanese patients with type 2 diabetes: A 12-month retrospective analysis

Sugiyama K., Meguro S., Saisho Y., Irie J., Tanaka M., Itoh H.

Heliyon （Heliyon） 5 （ 2 ） 2019年02月

ISSN 24058440

© 2019 The Authors Aims: To evaluate the efficacy and safety of switching to insulin glargine 300 U/mL (Gla-300) from insulin glargine 100 U/mL (Gla-100) in Japanese patients with type 2 diabetes (T2DM). Methods: This was a 12-month retrospective study comprising 109 patients. Primary endpoint was glycated hemoglobin (HbA1c) level at month 12. Secondary endpoints were hypoglycemia for the overall study period as well as body weight and insulin dose at month 12. Results: Similar glycemic control was achieved with mean (standard deviation) HbA1c level of 7.7 (1.1)% (61 [12] mmol/mol) at baseline and 7.7 (1.3)% (61 [14] mmol/mol) at month 12. Fewer confirmed (<3.0 mmol/L [< 54 mg/dL]) or severe hypoglycemic events were observed (0.52 vs. 0.85 events per patient-year; rate ratio 0.61; 95% confidence interval 0.38–0.97; p = 0.037), but the percent of patients experiencing ≥1 hypoglycemic event did not differ. There was no difference in confirmed (≤3.9 mmol/L [≤ 70 mg/dL]) or severe hypoglycemia and nocturnal hypoglycemia. Conclusions: In Japanese patients with T2DM who switched to Gla-300 from Gla-100, similar glycemic control was achieved with fewer confirmed (<3.0 mmol/L [< 54 mg/dL]) or severe hypoglycemic events over a 12-month period, although the absolute benefit was marginal.

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Decreased KAT5 Expression Impairs DNA Repair and Induces Altered DNA Methylation in Kidney Podocytes

Hishikawa A., Hayashi K., Abe T., Kaneko M., Yokoi H., Azegami T., Nakamura M., Yoshimoto N., Kanda T., Sakamaki Y., Itoh H.

Cell Reports （Cell Reports） 26 （ 5 ） 1318 - 1332.e4 2019年01月

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Exercise capacity and association with quality of life in peritoneal dialysis patients

Uchiyama K., Washida N., Muraoka K., Morimoto K., Kasai T., Yamaki K., Miyashita K., Wakino S., Itoh H.

Peritoneal Dialysis International （Peritoneal Dialysis International） 39 （ 1 ） 66 - 73 2019年01月

ISSN 08968608

© 2019 International Society for Peritoneal Dialysis. Background: Muscle wasting, common and progressive in uremic patients, is associated with a high probability for morbidity, lower health-related quality of life (HRQOL), and mortality. However, exercise tolerance in peritoneal dialysis (PD) patients has not been fully elucidated. The aim of this study was to evaluate exercise capacity, its determinants, and its association with HRQOL in PD patients. ♦♦ Methods: Outpatients treated with PD at Keio University Hospital from December 2016 to March 2018 were included in this single-center cross-sectional observational study. Exercise capacity was assessed by incremental shuttle walking test (ISWT) and handgrip and quadriceps strength. In addition to evaluation of PD-related parameters, HRQOL was assessed by the Kidney Disease Quality of Life-Short Form questionnaire. ♦♦ Results: Among the 50 recruited PD outpatients, age and PD vintage were 63.8 ± 9.6 and 3.8 ± 2.8 years, respectively. Physical examination revealed ISWT of 312.0 ± 138.2 m, handgrip strength of 27.5 ± 6.9 kg, and quadriceps strength of 23.3 ± 10.0 kg. Multivariate analysis showed that younger age and male sex were significantly associated with higher ISWT and handgrip and quadriceps strength. Skeletal mass index (SMI) remained a significant predictor of handgrip and quadriceps strength. Moreover, only ISWT was strongly correlated with higher HRQOL scores, including physical, mental, and kidney-specific domains, even after adjustment for age and sex. ♦♦ Conclusions: Exercise tolerance in PD patients was partially determined by age, sex, and SMI. Moreover, this is the first study to demonstrate the strong relationship between aerobic capacity and HRQOL in PD patients.

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Treatment preference for weekly versus daily DPP-4 inhibitors in patients with type 2 diabetes mellitus: outcomes from the TRINITY trial

Meguro S., Matsui S., Itoh H.

Current Medical Research and Opinion （Current Medical Research and Opinion） 2019年

ISSN 03007995

© 2019, © 2019 Takeda Pharmaceutical Company Limited. Published by Informa UK Limited, trading as Taylor & Francis Group. Objective: To examine patient preference for treatment with the oral once-weekly dipeptidyl peptidase-4 inhibitor (DPP-4i), trelagliptin, and oral once-daily DPP-4i, alogliptin, administered for 8 weeks each in patients with type 2 diabetes mellitus prescribed a daily DPP-4i. Methods: In this randomized, open-label, two-way crossover study, patients received trelagliptin followed by alogliptin (T-A group) or alogliptin followed by trelagliptin (A-T group), for 8 weeks each (NCT03231709, JapicCTI-173662). Treatment preference was assessed using a standardized questionnaire in the overall population and by baseline characteristics. Other outcomes included patient satisfaction with diabetes treatment (assessed using the Diabetes Treatment Satisfaction Questionnaire [DTSQ]), hemoglobin A1c (HbA1c) levels after 8 weeks of treatment with each agent, and safety. Results: Sixty patients from two clinical sites were randomized 1:1 to T-A and A-T groups (each n = 30); baseline characteristics were similar between groups. After 16 weeks of treatment, 51.7% of patients preferred treatment with alogliptin compared with 30.0% selecting trelagliptin (p =.014); preference for alogliptin was consistently greater than for trelagliptin in the secondary analyses by baseline characteristics. DTSQ score and HbA1c levels were similar between treatments after 8 weeks of therapy. Both treatments demonstrated favorable safety and tolerability profiles. Conclusions: Patients expressed a significantly greater treatment preference for once-daily alogliptin than once-weekly trelagliptin, although patient satisfaction and HbA1c levels were similar across treatments. The decision to administer a once-weekly or once-daily DPP-4i is likely to depend on patient preference, patient-physician discussions, and treatment practices of the prescribing physician.

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Satisfaction level of glycemic control in patients with diabetes and its related factors

Saisho Y., Itoh H.

Journal of the Japan Diabetes Society （Journal of the Japan Diabetes Society） 62 （ 1 ） 1 - 8 2019年

ISSN 0021437X

© 2019 Japan Diabetes Society. All rights reserved. Although the current guidelines recommend the use of "individualized" HbA1c goals for patient-centered diabetes care, information regarding the satisfaction of patients with their glycemic control is insufficient. In this study, we aimed to clarify the satisfaction of patients with their glycemic control and to determine the related factors. Outpatients with diabetes were asked to answer questionnaires that included a question about their satisfaction with their glycemic control, and responses were obtained from 254 patients with type 2 diabetes and 22 patients with type 1 diabetes. Twenty-eight percent of the patients answered "satisfied", while 18 % answered "not satisfied". The satisfaction with glycemic control was significantly correlated with HbA1c, adherence to dietary therapy, satisfaction with doctor and clinic, satisfaction with medical cost, intention to drop out and satisfaction with diabetes treatment. Thus, patient satisfaction with glycemic control should be recognized as an important patient-reported outcome, and may be affected by the self-efficacy of dietary therapy and the patient's relationship with medical staff.

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Efficacy and safety of dosage-escalation of low-dosage esaxerenone added to a RAS inhibitor in hypertensive patients with type 2 diabetes and albuminuria: a single-arm, open-label study

Itoh H., Ito S., Rakugi H., Okuda Y., Nishioka S.

Hypertension Research （Hypertension Research） 2019年

ISSN 09169636

© 2019, The Author(s). The stimulation of mineralocorticoid receptors is linked to the development of hypertension and cardiovascular or renal damage in patients with diabetes, and the blockade of these receptors may be an effective treatment option. This open-label study with a 12-week treatment period assessed the antihypertensive (primary) and antialbuminuric (secondary) efficacy and safety of esaxerenone as an add-on therapy to a renin–angiotensin system inhibitor in hypertensive patients with type 2 diabetes and albuminuria (urinary albumin-creatinine ratio 30 to <1000 mg/g•Cr). Esaxerenone was administered over 12 weeks at a starting dosage of 1.25 mg/day, which was gradually titrated to 2.5 mg/day and 5 mg/day at weeks 4, 6, or 8 according to the dosage-escalation criteria based on serum K+ levels, the estimated glomerular filtration rate, and the likelihood/occurrence of hypotension. Of the 51 patients enrolled, 44 (86.3%) reached an esaxerenone dosage of 2.5 or 5 mg/day. The changes from the baseline in sitting systolic and diastolic blood pressures were −13.7 mmHg (p < 0.05) and −6.2 mmHg (p < 0.05), respectively. Significant decreases in blood pressure occurred regardless of age, baseline systolic blood pressure, glycated hemoglobin level, and estimated glomerular filtration rate. The urinary albumin-creatinine ratio decreased by 32.4% from the baseline (p < 0.05). Two consecutive serum K+ measurements ≥ 5.5 mEq/L occurred in one patient but resolved after dosage reduction. Esaxerenone showed antihypertensive and antialbuminuric effects and a low risk of hyperkalemia with dosage titration from 1.25 mg in Japanese hypertensive patients with type 2 diabetes and albuminuria receiving a renin–angiotensin system inhibitor.

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Ketone body receptor GPR43 regulates lipid metabolism under ketogenic condition

• Miyamoto J, Ohue-Kitano R, Mukouyama H, Nishida A, Watanabe K, Igarashi M, Irie J, Tsujimoto G, Satoh-Asahara N, Itoh H, Kimura I*

Proc Natl Acad Sci U S A 116 23813 - 23821 2019年

査読有り

CD44 variant inhibits insulin secretion in pancreatic β cells by attenuating LAT1-mediated amino acid uptake

Kobayashi N., Okazaki S., Sampetrean O., Irie J., Itoh H., Saya H.

Scientific Reports （Scientific Reports） 8 （ 1 ） 2018年12月

© 2018 The Author(s). CD44 variant (CD44v) contributes to cancer stemness by stabilizing the xCT subunit of system xc(-) and thereby promoting its glutamate-cystine antiporter activity. CD44 has also been implicated in autoimmune insulitis and inflammation in diabetic islets, but whether CD44v regulates insulin secretion has remained unclear. Here we show that CD44v inhibits insulin secretion by attenuating amino acid transport mediated by the L-type amino acid transporter LAT1. CD44v expression level was inversely related to insulin content in islets of normal and diabetic model mice. Knockdown of CD44 increased insulin secretion, the intracellular insulin level, and the transport of neutral amino acids mediated by LAT1 in Min6 cells. Attenuation of the uptake of neutral amino acids with a LAT inhibitor reduced insulin secretion and insulin content in Min6 cells, whereas overexpression of LAT1 increased insulin secretion. Moreover, inhibition of LAT1 prevented the increase in insulin secretion and content induced by CD44 depletion in Min6 cells. Our results thus implicate CD44v in the regulation of insulin secretion and reveal that amino acid transport is rate limiting for such secretion. They further suggest that amino acid transport mediated by LAT1 is a potential therapeutic target for diabetes.

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NNMT activation can contribute to the development of fatty liver disease by modulating the NAD + metabolism

Komatsu M., Kanda T., Urai H., Kurokochi A., Kitahama R., Shigaki S., Ono T., Yukioka H., Hasegawa K., Tokuyama H., Kawabe H., Wakino S., Itoh H.

Scientific Reports （Scientific Reports） 8 （ 1 ） 2018年12月

© 2018 The Author(s). Nicotinamide N-methyltransferase (NNMT) catalyses the reaction between nicotinamide (NAM) and S-adenosylmethionine to produce 1-methylnicotinamide and S-adenosylhomocysteine. Recently, this enzyme has also been reported to modulate hepatic nutrient metabolism, but its role in the liver has not been fully elucidated. We developed transgenic mice overexpressing NNMT to elucidate its role in hepatic nutrient metabolism. When fed a high fat diet containing NAM, a precursor for nicotinamide adenine dinucleotide (NAD)+, these NNMT-overexpressing mice exhibit fatty liver deterioration following increased expression of the genes mediating fatty acid uptake and decreased very low-density lipoprotein secretion. NNMT overactivation decreased the NAD+ content in the liver and also decreased gene activity related to fatty acid oxidation by inhibiting NAD+-dependent deacetylase Sirt3 function. Moreover, the transgenic mice showed liver fibrosis, with the induction of inflammatory and fibrosis genes. Induced NNMT expression decreased the tissue methylation capacity, thereby reducing methylation of the connective tissue growth factor (CTGF) gene promoter, resulting in increased CTGF expression. These data indicate that NNMT links the NAD+ and methionine metabolic pathways and promotes liver steatosis and fibrosis. Therefore, targeting NNMT may serve as a therapeutic strategy for treating fatty liver and fibrosis.

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High Basolateral Glucose Increases Sodium-Glucose Cotransporter 2 and Reduces Sirtuin-1 in Renal Tubules through Glucose Transporter-2 Detection

Umino H., Hasegawa K., Minakuchi H., Muraoka H., Kawaguchi T., Kanda T., Tokuyama H., Wakino S., Itoh H.

Scientific Reports （Scientific Reports） 8 （ 1 ） 2018年12月

© 2018 The Author(s). Under diabetic conditions, sodium-glucose cotransporter 2 (SGLT2) for glucose uptake in proximal tubules (PTs) increases, whereas NAD+-dependent protein deacetylase silent mating type information regulation 2 homolog 1 (Sirtuin-1; SIRT1) for PT survival decreases. Therefore, we hypothesized that increased glucose influx by SGLT2 reduces SIRT1 expression. To test this hypothesis, db/db mice with diabetes and high-glucose (HG)-cultured porcine PT LLC-PK1 cells in a two-chamber system were treated with the SGLT2 inhibitor canagliflozin. We also examined SIRT1 and SGLT2 expression in human kidney biopsies. In db/db mice, SGLT2 expression increased with concomitant decreases in SIRT1, but was inhibited by canagliflozin. For determination of the polarity of SGLT2 and SIRT1 expression, LLC-PK1 cells were seeded into Transwell chambers (pore size, 0.4 μm; Becton Dickinson, Oxford, UK). HG medium was added to either or to both of the upper and lower chambers, which corresponded to the apical and basolateral sides of the cells, respectively. In this system, the lower chamber with HG showed increased SGLT2 and decreased SIRT1 expression. Canagliflozin reversed HG-induced SIRT1 downregulation. Gene silencing and inhibitors for glucose transporter 2 (GLUT2) blocked HG-induced SGLT2 expression upregulation. Gene silencing for the hepatic nuclear factor-1α (HNF-1α), whose nuclear translocation was enhanced by HG, blocked HG-induced SGLT2 expression upregulation. Similarly, gene silencing for importin-α1, a chaperone protein bound to GLUT2, blocked HG-induced HNF-1α nuclear translocation and SGLT2 expression upregulation. In human kidney, SIRT1 immunostaining was negatively correlated with SGLT2 immunostaining. Thus, under diabetic conditions, SIRT1 expression in PTs was downregulated by an increase in SGLT2 expression, which was stimulated by basolateral HG through activation of the GLUT2/importin-α1/HNF-1α pathway.

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2型糖尿病患者におけるweekly DPP4阻害薬トレラグリプチンの有効性・安全性の検討

田中正巳, 西村健志, 目黒周, 入江潤一郎, 税所芳史, 三石正憲, 川野義長, 伊藤裕

日本内分泌学会雑誌（(一社)日本内分泌学会） 94 （ 4 ） 1577 - 1577 2018年12月

査読有り, ISSN 0029-0661

2型糖尿病患者における収縮期血圧、総ビリルビン濃度と網膜症との関連

田中正巳, 西村健志, 目黒周, 入江潤一郎, 税所芳史, 三石正憲, 川野義長, 伊藤裕

日本内分泌学会雑誌（(一社)日本内分泌学会） 94 （ 4 ） 1577 - 1577 2018年12月

査読有り, ISSN 0029-0661

GLP-1受容体作動薬は抗CD3抗体誘導マウス非アルコール性脂肪肝を抑制する

入江潤一郎, 伊藤新, 加藤まり, 田中久美子, 菊地理恵子, 藤田真隆, 中島裕也, 山田悟, 河合俊英, 伊藤裕

日本内分泌学会雑誌（(一社)日本内分泌学会） 94 （ 4 ） 1575 - 1575 2018年12月

査読有り, ISSN 0029-0661

Penile calciphylaxis in a patient on combined peritoneal dialysis and hemodialysis

Kasai T., Washida N., Muraoka H., Fujii K., Uchiyama K., Shinozuka K., Morimoto K., Tokuyama H., Wakino S., Itoh H.

CEN case reports （CEN case reports） 7 （ 2 ） 204 - 207 2018年11月

Calciphylaxis presents with painful purpura and intractable skin ulcers on the trunk and particularly the distal extremities, and it mainly occurs in patients on chronic dialysis. A 66-year-old man with renal failure due to diabetic nephropathy was on peritoneal dialysis alone for 1 year, followed by peritoneal dialysis combined with hemodialysis for 3 years. He developed calciphylaxis of the penis, which was diagnosed from the skin biopsy findings and clinical observation. To treat this condition, PD was stopped and HD was performed three times a week. In addition, warfarin therapy was discontinued and infusion of sodium thiosulfate was performed. The penile ulcers decreased in size and pain was markedly improved, so the patient was discharged from hospital. Following discharge, PD was resumed after changing the peritoneal dialysis fluid to bicarbonate-buffered dialysate. The penile ulcers eventually resolved completely. There have been very few reports about calciphylaxis in patients on combined dialysis modalities. In our patient, penile calciphylaxis progressed when lactate-buffered peritoneal dialysis fluid was used and resolved after switching to bicarbonate-buffered fluid together with cessation of warfarin therapy and infusion of sodium thiosulfate.

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The impact of a remote monitoring system of healthcare resource consumption in patients on automated peritoneal dialysis (APD): A simulation study

Uchiyama K., Washida N., Yube N., Kasai T., Shinozuka K., Morimoto K., Hishikawa A., Inoue H., Urai H., Hagiwara A., Fujii K., Wakino S., Deenitchina S., Itoh H.

Clinical Nephrology （Clinical Nephrology） 90 （ 5 ） 334 - 340 2018年11月

ISSN 03010430

©2018 Dustri-Verlag Dr. K. Feistle Aims: Remote monitoring (RM) can improve management of chronic diseases. We evaluated the impact of RM in automated peritoneal dialysis (APD) in a simulation study. Materials and methods: We simulated 12 patient scenarios with common clinical problems and estimated the likely healthcare resource consumption with and without the availability of RM (RM+ and RM- groups, respectively). Scenarios were evaluated 4 times by randomly allocated nephrologist-nurse teams or nephrologist-alone assessors. Results: The RM+ group was assessed as having significantly lower total healthcare resource consumption compared with the RM- group (36.8 vs. 107.5 total episodes of resource consumption, p = 0.002). The RM+ group showed significantly lower “unplanned hospital visits” (2.3 vs. 11.3, p = 0.005), “emergency room visits” (0.5 vs. 5.3, p = 0.003), “home visits” (0.5 vs. 5.8, p = 0.016), “exchanges over the telephone” (18.5 vs. 57.8, p = 0.002), and “change to hemodialysis” (0.5 vs. 2.5, p = 0.003). Evaluations did not differ between nephrologist-nurse teams vs. nephrologist-alone assessors. Conclusion: RM can be expected to reduce healthcare resource consumption in APD patients.

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Achieving LDL-C target levels less than 70 mg/dL may provide extra cardiovascular protection in high-risk patients: exploratory analysis of the Standard Versus Intensive Statin Therapy for Patients With Hypercholesterolemia and Diabetic Retinopathy Study

上嶋健治

Diabetes Obes Metab 2018年11月

査読有り

Clinical characteristics and postoperative outcomes of primary aldosteronism in the elderly

Takeda M., Yamamoto K., Akasaka H., Rakugi H., Naruse M., Takeda Y., Kurihara I., Itoh H., Umakoshi H., Tsuiki M., Ichijo T., Katabami T., Wada N., Shibayama Y., Yoshimoto T., Ogawa Y., Kawashima J., Sone M., Inagaki N., Takahashi K., Fujita M., Watanabe M., Matsuda Y., Kobayashi H., Shibata H., Kamemura K., Otsuki M., Fujii Y., Ogo A., Okamura S., Miyauchi S., Yanase T., Suzuki T., Kawamura T.

Journal of Clinical Endocrinology and Metabolism （Journal of Clinical Endocrinology and Metabolism） 103 （ 10 ） 3620 - 3629 2018年10月

ISSN 0021972X

© 2018 Oxford University Press. All rights reserved. Context: Primary aldosteronism (PA) in the elderly has increased in importance in association with population aging. Objective: To investigate the characteristics and outcomes of elderly patients with PA undergoing adrenalectomy. Patients and Methods: Using a database of patients with PA who underwent adrenal venous sampling (AVS),wecompared elderly patients (65 years old)with nonelderly patients (,65 years old) in terms of characteristics, subtype classification in ACTH-stimulated AVS, and outcomes after adrenalectomy. Results: The elderly group had a higher prevalence of comorbidities than the nonelderly group. The proportion of the unilateral subtype [defined as a lateralization index (LI) .4] was comparable between the age groups. In patients who received adrenalectomy, biochemical cure was comparable between the groups, whereas persistent hypertension was more common in the elderly group. The prevalences of hyperkalemia and renal impairment (chronic kidney disease stage 3b or higher) were higher in the elderly group. Multiple regression analysis showed that the duration of hypertension predicted persistent hypertension and hyperkalemia and that preoperative estimated glomerular filtration rate predicted renal impairment in the elderly group. LI .4 in AVS was an independent predictor of biochemical cure after adrenalectomy in the elderly group but not in the nonelderly group. Age was negatively associated with biochemical cure in patients with LI #4. Conclusion: Adrenalectomy contributes to biochemical improvement in elderly patients if determined in accordance with AVS. The treatment strategy should be determined considering the high postoperative incidence of persistent hypertension and hyperkalemia in elderly patients with a long history of hypertension or renal impairment in those with reduced renal function.

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Organ memory: a key principle for understanding the pathophysiology of hypertension and other non-communicable diseases

Itoh H., Kurihara I., Miyashita K.

Hypertension Research （Hypertension Research） 41 （ 10 ） 771 - 779 2018年10月

ISSN 09169636

© 2018, The Japanese Society of Hypertension. In recent years, several post-interventional analyses of large-scale randomized controlled clinical trials have given us a new concept regarding the risk management of hypertension and cardiovascular diseases. The beneficial effects of intensive treatments were extended even after the interventions ended. This phenomenon is known as “metabolic memory” or “legacy effect”, and we recognized its clinical significance. A certain level of evidence in human and animal studies employing organ transplantation techniques has indicated that this type of “memory” resides in each organ and could be transferrable, erasable, and rewritable, which is similar to neuronal and immune “memory”. In this review, we define this memory as “organ memory” and summarize the current picture and future direction of this concept. “Organ memory” can be observed in many clinical settings, including in the control of hypertension, diabetes mellitus, and dyslipidemia. Several intensive treatments were demonstrated to have the potential to rewrite “organ memory”, leading to the curability of targeted diseases. “Organ memory” is the engraved phenotype of altered organ responsiveness acquired by a time-dependent accumulation of organ stress responses. Not only is the epigenetic change of key genes involved in the formation of “organ memory” but the alteration of multiple factors, including low molecular weight energy metabolites, immune mediators, and tissue structures, is involved as well. These factors intercommunicate during every stress response and carry out incessant remodeling in a certain direction in a spiral fashion through positive feedback mechanisms. Future studies should be directed toward the identification of the core unit of “organ memory” and its manipulation.

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Oral adsorbent AST-120 ameliorates gut environment and protects against the progression of renal impairment in CKD rats

Yoshifuji A., Wakino S., Irie J., Matsui A., Hasegawa K., Tokuyama H., Hayashi K., Itoh H.

Clinical and Experimental Nephrology （Clinical and Experimental Nephrology） 22 （ 5 ） 1069 - 1078 2018年10月

ISSN 13421751

© 2018, The Author(s). Background: Oral charcoal adsorbent AST-120 (AST) is reported to ameliorate renal dysfunction by the absorption of toxic substance in the gut. Recent study revealed that, in CKD, gut environment is disturbed including the decrease in tight junctions and Lactobacillus (Lact). In this study, we examined whether AST improves the renal dysfunction through gut environment. Method: Six-week-old spontaneously hypertensive rats (SHR) were rendered CKD by 5/6th nephrectomy (Nx). SHRs were divided into SHR (Sham), SHR with Nx (Nx), and Nx given AST (Nx + AST) (n = 10, each). After 12 weeks, rats were killed and biochemical parameters were explored. The gut flora was analyzed. Furthermore, gut molecular changes in tight junctions and toll-like receptors were examined. We also investigated the effects of the combination therapy with AST and Lact. Results: The increase in serum urea nitrogen and urinary protein excretion in Nx was restored in Nx + AST. The increased renal glomerulosclerosis in Nx was ameliorated in Nx + AST. Increases in serum uremic toxins and IL-6 in Nx were ameliorated in Nx + AST. The gut flora analysis revealed that the decrease in Lact in Nx was restored in Nx + AST. The downregulation in the tight junction and TLR2 in Nx was mitigated by AST. However, combination therapy failed to exhibit additional effects. Conclusion: AST ameliorated renal function with the restoration of Lact and tight junction through TLR pathway, which would mitigate systemic inflammation and contributed to their renoprotective effects. Our study provides a novel mechanism of the renoprotective effects by AST.

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Epidermal growth factor receptor/extracellular signal-regulated kinase pathway enhances mineralocorticoid receptor transcriptional activity through protein stabilization

Mitsuishi Y., Shibata H., Kurihara I., Kobayashi S., Yokota K., Murai-Takeda A., Hayashi T., Jo R., Nakamura T., Morisaki M., Itoh H.

Molecular and Cellular Endocrinology （Molecular and Cellular Endocrinology） 473 89 - 99 2018年09月

ISSN 03037207

© 2018 Elsevier B.V. Activation of mineralocorticoid receptor (MR) is evoked by aldosterone, and it induces hypertension and cardiovascular disease when it's concomitant with excessive salt loading. We have proposed the notion of “MR-associated hypertension” in which add-on therapy of MR blockers is effective even though serum aldosterone level is within normal range. To elucidate its underlying molecular mechanism, we focused on the effect of epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) activation on MR activity. Epidermal growth factor (EGF) administration increased MR transcriptional activity through EGFR/ERK pathway and increased protein level by counteracting MR ubiquitylation in vitro. EGF administration in vivo also increased MR protein level and target gene expression in kidney, which were decreased by EGFR inhibitor. In addition, the administration of EGFR inhibitor lowered systolic blood pressure and MR activity in DOCA/salt-treated mice. In conclusion, EGFR/ERK pathway activation is considered as one of the underlying mechanisms of aberrant MR activation and EGFR/ERK pathway blockade could be an alternative approach for the prevention of MR-related cardiovascular events.

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Difference of seasonal variation between glycated albumin and glycated haemoglobin

Tanaka K., Meguro S., Tanaka M., Irie J., Saisho Y., Itoh H.

Annals of Clinical Biochemistry （Annals of Clinical Biochemistry） 55 （ 5 ） 583 - 587 2018年09月

ISSN 00045632

© The Author(s) 2018. Background: Glycated albumin reflects 2–3-week glycaemic controls, and in addition to glycated haemoglobin, it has been used as a glycaemic control indicator. We presumed that glycated albumin also has seasonal variations and is related to temperature, similar to glycated haemoglobin. Methods: The subjects were diabetic outpatients from April 2007 to March 2013. This resulted in the enrolment of 2246 subjects and the collection of a total of 53,968 measurements. Mean glycated haemoglobin, glycated albumin, and plasma glucose were calculated for each month over six years. The associations of the measures with each other and the average temperature for each month in Tokyo were assessed using Spearman rank correlation coefficients. Results: Plasma glucose was highest in January and lowest in May. Glycated haemoglobin was highest in March and lowest in September. Glycated albumin was highest in May and lowest in December. Glycated albumin tended to have a disjunction with plasma glucose in winter. Glycated haemoglobin had seasonal variation, but glycated albumin did not. Plasma glucose and glycated haemoglobin showed significant negative correlations with temperature (rs = −0.359, P < 0.001, rs = −0.449, P < 0.001, respectively), but glycated albumin did not. However, glycated albumin was inter-correlated with plasma glucose (rs = 0.396, P < 0.001) and glycated haemoglobin (rs = 0.685, P < 0.001), and glycated haemoglobin was inter-correlated with plasma glucose (rs = 0.465, P < 0.001). Conclusion: Glycated albumin and glycated haemoglobin showed different seasonal variations from each other over the six-year study period. Thus, further studies to identify factors that contribute to glycated albumin are needed.

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Pulmonary nocardiosis mimicking small cell lung cancer in ectopic ACTH syndrome associated with transformation of olfactory neuroblastoma: A case report

Kobayashi K., Asakura T., Ishii M., Ueda S., Irie H., Ozawa H., Saitoh K., Kurihara I., Itoh H., Betsuyaku T.

BMC Pulmonary Medicine （BMC Pulmonary Medicine） 18 （ 1 ） 2018年08月

© 2018 The Author(s). Background: Pulmonary nocardiosis frequently develops as an opportunistic infection in cell-mediated immunosuppressive patients, and sometimes requires differentiation from pulmonary malignancy. Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a neoplastic disorder which leads to impaired cell-mediated immunity, and is commonly associated with small cell lung cancer (SCLC). Because pulmonary infection and causative malignancy can appear as pulmonary lesions with EAS, differentiation of these diseases remains a critical issue for physicians. Case presentation: A 52-year-old woman with progressive lower limb paralysis and general fatigue was referred to us. She had been diagnosed with olfactory neuroblastoma (ONB) and treated with surgery and radiation therapy 10 years before the referral and had required stereotactic radiosurgery and chemotherapy 4 years later for a relapse of the ONB. On referral, she presented with Cushing's syndrome with elevated cortisol and ACTH levels. Potassium supplement improved her symptoms; however, a month later, she was urgently hospitalized due to acute pleuritic chest pain on inspiration. Chest computed tomography revealed left lower lobular consolidations and a contralateral nodule in the right middle lobe. The clinical history and laboratory work-up suggested that her Cushing's syndrome had most likely arisen from EAS. Additionally, the lungs were suspected as the ACTH source due to high levels of progastrin-releasing peptide and progressive pulmonary consolidation with a contralateral nodule, suggesting SCLC. However, histological examination from bronchoscopy revealed no evidence of malignancy, and Nocardia cyriacigeorgica was isolated from bronchoalveolar lavage fluid. Sulfamethoxazole/trimethoprim improved her pulmonary lesions. Somatostatin receptor scintigraphy revealed strong tracer uptake in the ONB lesions, indicating that the origin of the EAS was the olfactory tumor. However, histological examination of ONB specimens resected 10 years earlier showed no intracytoplasmic immunopositivity for ACTH. Conclusions: We highlight a rare case of pulmonary nocardiosis, which was associated with EAS mimicking SCLC, and was related to ONB transformation. Nocardiosis has to be considered even though anamnestic, clinical, and radiological aspects suggest the presence of metastasis. Additionally, physicians should carefully monitor patients with ONB for the development of Cushing's symptoms because the tumor can transform into an ACTH-producing form, even after long-term follow-up.

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Expanding Phenotype of Nephronophthisis-Related Ciliopathy: An Elderly Patient with Homozygous RPGRIP1L Mutation

Kawaguchi T., Yoshida T., Hirahashi J., Uehara T., Takenouchi T., Kosaki K., Itoh H., Hayashi M.

Nephron （Nephron） 140 （ 1 ） 74 - 78 2018年08月

ISSN 16608151

© 2018 S. Karger AG, Basel. Nephronophthisis-related ciliopathies (NPHP-RC) are autosomal recessive disorders characterized by renal corticomedullary cysts with the extrarenal symptoms. Typically, patients with NPHP-RC reach end-stage kidney disease (ESKD) before the age of 30 years. We herein report a Japanese woman with NPHP-RC who had unusually delayed progression to ESKD after 6 decades. She exhibited liver dysfunction at the age of 23 years. She also showed mild renal dysfunction at the age of 43 years. Ultrasonography revealed bilateral multiple renal cysts with loss of corticomedullary differentiation. Her liver and renal functions gradually deteriorated. She was diagnosed with liver fibrosis as a result of biopsy, and initiated the maintenance hemodiafiltration therapy for ESKD at the age of 61 years. Because of a unique combination of multiple renal cysts and liver fibrosis, ciliopathy was suspected and medical exome analysis was performed. A novel homozygous missense mutation was identified in RPGRIP1L (c.1810G>A p.Glu604Lys), a causative gene for NPHP-RC. To the best of our knowledge, this patient is the oldest one who progressed to ESKD in NPHP-RC. Our case illustrates that NPHP-RC should be included in the differential diagnosis of the patient with corticomedullary polycystic kidneys accompanied by the extrarenal organ involvements, even if the patient is elderly.

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Correlation Between Lateralization Index of Adrenal Venous Sampling and Standardized Outcome in Primary Aldosteronism.

Umakoshi H, Tsuiki M, Yokomoto-Umakoshi M, Takeda Y, Takashi Y, Kurihara I, Itoh H, Katabami T, Ichijo T, Wada N, Shibayama Y, Yoshimoto T, Ashida K, Ogawa Y, Kawashima J, Sone M, Inagaki N, Takahashi K, Watanabe M, Matsuda Y, Kobayashi H, Shibata H, Kamemura K, Otsuki M, Fujii Y, Yamamto K, Ogo A, Okamura S, Miyauchi S, Fukuoka T, Izawa S, Yanase T, Hashimoto S, Yamada M, Yoshikawa Y, Kai T, Suzuki T, Kawamura T, Naruse M

Journal of the Endocrine Society 2 （ 8 ） 893 - 902 2018年08月

査読有り

Objectives: The aim of this study was to investigate the impact of adrenal venous sampling (AVS) lateralization cutoffs on surgical outcomes. Patients and Methods: Cosyntropin-stimulated AVS was used to guide surgical management of 377 patients with primary aldosteronism (PA) who were evaluated 6 months after surgery. Main Outcome Measures: The proportion of patients that achieved clinical benefit and complete biochemical success based on the AVS aldosterone lateralization index (LI) was determined. Results: Clinical benefit was achieved in 29 of 47 patients with an LI between 2 and 4, in 66 of 101 with an LI between 4 and 10, and in 158 of 203 with an LI > 10 (P < 0.01 for trend). Complete biochemical success was achieved in 27 of 42 with an LI between 2 and 4, in 60 of 76 with an LI between 4 and 10, and in 127 of 155 with an LI > 10 (P = 0.024 for trend). After adjustment for confounders and using those patients with an LI between 2 and 4 as a reference, a clinical benefit was associated only with those with an LI > 10 (OR, 2.30; 95% CI, 1.03 to 5.16), whereas complete biochemical success was associated with those with an LI between 4 and 10 (OR, 2.83; 95% CI, 1.14 to 7.01) or LI > 10 (OR, 3.55; 95% CI, 1.47 to 8.55). Conclusions: Difference of clinical outcome was relatively small when strict LI diagnostic threshold was used; biochemical cure was sufficiently achieved when an LI > 4 was used. Our study by standardized outcome measures validated that an LI > 4 may be appropriate for determining unilateral disease in PA.

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Intestinal mineralocorticoid receptor contributes to epithelial sodium channel–mediated intestinal sodium absorption and blood pressure regulation

Nakamura T., Kurihara I., Kobayashi S., Yokota K., Murai-Takeda A., Mitsuishi Y., Morisaki M., Kohata N., Oshima Y., Minami Y., Shibata H., Itoh H.

Journal of the American Heart Association （Journal of the American Heart Association） 7 （ 13 ） 2018年07月

© 2018 The Authors. Background-—Mineralocorticoid receptor (MR) has pathological roles in various cell types, including renal tubule cells, myocytes, and smooth muscle cells; however, the role of MR in intestinal epithelial cells (IECs) has not been sufficiently evaluated. The intestine is the sensing organ of ingested sodium; accordingly, intestinal MR is expected to have essential roles in blood pressure (BP) regulation. Methods and Results-—We generated IEC-specific MR knockout (IEC-MR-KO) mice. With a standard diet, fecal sodium excretion was 1.5-fold higher in IEC-MR-KO mice, with markedly decreased colonic expression of b- and c-epithelial sodium channel, than in control mice. Urinary sodium excretion in IEC-MR-KO mice decreased by 30%, maintaining sodium balance; however, a low-salt diet caused significant reductions in body weight and BP in IEC-MR-KO mice, and plasma aldosterone exhibited a compensatory increase. With a high-salt diet, intestinal sodium absorption markedly increased to similar levels in both genotypes, without an elevation in BP. Deoxycorticosterone/salt treatment elevated BP and increased intestinal sodium absorption in both genotypes. Notably, the increase in BP was significantly smaller in IEC-MR-KO mice than in control mice. The addition of the MR antagonist spironolactone to deoxycorticosterone/salt treatment eliminated the differences in BP and intestinal sodium absorption between genotypes. Conclusions-—Intestinal MR regulates intestinal sodium absorption in the colon and contributes to BP regulation. These regulatory effects are associated with variation in epithelial sodium channel expression. These findings suggest that intestinal MR is a new target for studying the molecular mechanism of hypertension and cardiovascular diseases.

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Adhesive intestinal obstruction increases the risk of intestinal perforation in peritoneal dialysis patients: A case report

Fujii K., Washida N., Arai E., Tsuruta M., Wakino S., Itoh H.

BMC Nephrology （BMC Nephrology） 19 （ 1 ） 2018年06月

© 2018 The Author(s). Background: Peritonitis secondary to bowel perforation is a rare and potentially fatal complication in peritoneal dialysis (PD) patients. However, the early diagnosis of bowel perforation is difficult in PD patients because the initial symptoms and signs of bowel perforation are similar to those of PD-associated peritonitis. Furthermore, the risk of bowel perforation in PD patients is unclear. Here, we present a case of intestinal perforation located at the site of adhesive intestinal obstruction in a PD patient. Case presentation: A 73-year-old man on PD presented with progressive worsening of abdominal pain and cloudy peritoneal fluid. The peritoneal fluid cell count was increased to 980/ml and peritoneal dialysis-associated peritonitis was diagnosed. Computed tomography showed local adhesions causing agglomeration of the dilated intestine. He initially responded to antibiotic treatment; however, his abdominal pain was rapidly worsened after resumption of oral intake. On hospital day 23, computed tomography showed loss of contents from the dilated intestine and discharge of fecal material from the PD tube was noted. Thus, small bowel perforation was diagnosed, and he underwent ileocecal resection with colostomy creation. As indicators of EPS was not evident, PD catheter was removed. Since then, he has been on maintenance of hemodialysis since then. Conclusion: The findings of the present case suggest that adhesive intestinal obstruction in PD patients can increase the risk of intestinal perforation. Careful monitoring for the early detection of intestinal perforation is required in such cases.

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Greater reductions in plasma aldosterone with aliskiren in hypertensive patients with higher soluble (Pro)renin receptor level article

Bokuda K., Morimoto S., Seki Y., Yatabe M., Watanabe D., Yatabe J., Ando T., Shimizu S., Itoh H., Ichihara A.

Hypertension Research （Hypertension Research） 41 （ 6 ） 435 - 443 2018年06月

ISSN 09169636

© 2018 The Japanese Society of Hypertension. The (pro)renin receptor is important in the regulation of the tissue renin-angiotensin-aldosterone system. The benefits and safety of single-aliskiren treatment without other renin-angiotensin-aldosterone system inhibitors remain unclear. The serum level of the soluble form of the (pro)renin receptor is thought to be a biomarker reflecting the activity of the tissue renin-angiotensin-aldosterone system. We investigated the effects of single renin-angiotensin-aldosterone system blockade with aliskiren on renal and vascular functions and determined if serum level of the soluble (pro)renin receptor was a predictor of aliskiren efficacy in hypertensive patients with chronic kidney disease. Thirty-nine essential hypertensive patients with chronic kidney disease in our outpatient clinic were randomly assigned to receive either aliskiren or amlodipine. The parameters associated with renal and vascular functions and indices of renin-angiotensin-aldosterone system components, including serum levels of the soluble form, were evaluated before and after 12-week and 24-week treatment. Blood pressure was not significantly different between the groups. No significant changes in serum levels were observed in the soluble (pro)renin receptor in either group. Urinary albumin, protein excretion, and cardio-ankle vascular index significantly decreased in the aliskiren group. In the aliskiren group, there was a significant negative correlation between the basal level of the soluble (pro)renin receptor and the change in plasma aldosterone concentration. Single renin-angiotensin-aldosterone system blockade with aliskiren showed renal and vascular protective effects independent of blood pressure reduction. Serum levels of the soluble (pro)renin receptor may indicate aldosterone production via the (pro)renin receptor in the adrenal gland.

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The Impact of Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass on Intestinal Microbiota Differs from that of Laparoscopic Sleeve Gastrectomy in Japanese Patients with Obesity

Kikuchi R., Irie J., Yamada-Goto N., Kikkawa E., Seki Y., Kasama K., Itoh H.

Clinical Drug Investigation （Clinical Drug Investigation） 38 （ 6 ） 545 - 552 2018年06月

ISSN 11732563

© 2018, Springer International Publishing AG, part of Springer Nature. Background and Objectives: Bariatric surgery improves metabolic diseases and alters the intestinal microbiota in animals and humans, but different procedures reportedly have different impacts on the intestinal microbiota. We developed laparoscopic sleeve gastrectomy with duodenojejunal bypass (LSG-DJB) as an alternative to laparoscopic Roux-en-Y gastric bypass (LRYGB) in addition to laparoscopic sleeve gastrectomy (LSG) for Japanese patients with obesity. We investigated the precise change in the intestinal microbiota induced by these procedures in the present study. Methods: A prospective observational study of 44 Japanese patients with obesity was conducted [22 patients underwent LSG, 18 underwent LSG-DJB, and 4 underwent laparoscopic adjustable gastric banding (LAGB)]. The patients’ clinical parameters and intestinal microbiota were investigated before and for 6 months after surgery. The microbiota was analyzed by a 16S rDNA method. Results: LSG and LSG-DJB significantly improved the metabolic disorders in the patients with obesity. The proportion of the phylum Bacteroidetes and order Lactobacillales increased significantly in the LSG group, and that of the order Enterobacteriales increased significantly in the LSG-DJB group. Conclusions: LSG and LSG-DJB improved obesity and type 2 diabetes in Japanese patients with obesity, but the impact of LSG-DJB on the intestinal microbiota differed from that of LSG. This difference in the impact on the intestinal environment could explain the different efficacies of LSG and LSG-DJB in terms of their ability to resolve metabolic disorders in the clinical setting.

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Intensive treat-to-target statin therapy in high-risk Japanese patients with hypercholesterolemia and diabetic retinopathy: Report of a randomized study

Diabetes Care （Diabetes Care） 41 （ 6 ） 1275 - 1284 2018年06月

ISSN 01495992

© 2018 by the American Diabetes Association. OBJECTIVE Diabetes is associated with high risk of cardiovascular (CV) events, particularly in patients with dyslipidemia and diabetic complications. We investigated the incidence of CV events with intensive or standard lipid-lowering therapy in patients with hypercholesterolemia, diabetic retinopathy, and no history of coronary artery disease (treat-to-target approach). RESEARCH DESIGN AND METHODS In this multicenter, prospective, randomized, open-label, blinded end point study, eligible patients were randomly assigned (1:1) to intensive statin therapy targeting LDL cholesterol (LDL-C) <70 mg/dL (n = 2,518) or standard statin therapy targeting LDL-C 100-120 mg/dL (n = 2,524). RESULTS Mean follow-up was 37± 13months. LDL-C at 36 months was 76.5± 21.6mg/dL in the intensive group and 104.1 ± 22.1 mg/dL in the standard group (P < 0.001). The primary end point events occurred in 129 intensive group patients and 153 standard group patients (hazard ratio [HR] 0.84 [95% CI 0.67-1.07]; P = 0.15). The relationship between the LDL-C difference in the two groups and the event reduction rate was consistent with primary prevention studies in patients with diabetes. Exploratory findings showed significantly fewer cerebral events in the intensive group (HR 0.52 [95% CI 0.31-0.88]; P = 0.01). Safety did not differ significantly between the two groups. CONCLUSIONS We found no significant decrease in CV events or CV-associated deaths with intensive therapy, possibly because our between-group difference of LDL-C was lower than expected (27.7 mg/dL at 36 months of treatment). The potential benefit of achieving LDL-C <70 mg/dL in a treat-to-target strategy in high-risk patients deserves further investigation.

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Nanogel-based nasal vaccines for infectious and lifestyle-related diseases

Azegami T., Yuki Y., Nakahashi R., Itoh H., Kiyono H.

Molecular Immunology （Molecular Immunology） 98 19 - 24 2018年06月

ISSN 01615890

© 2017 Because the mucosa is the major entry route for most pathogens, the development of mucosal vaccines is a rational approach for protecting against these undesired agents. Mucosal administration of vaccine antigen is useful for non-infectious chronic diseases as well, because of its advantages over injection routes, including comparable efficacy in the induction of systemic immune responses, less pain, and no risk of adverse events at the injection site. However, because it is difficult to effectively induce and regulate antigen-specific mucosal and systemic immune responses when antigen alone is mucosally administered, an appropriate form of mucosal delivery vehicle must be used. Antigen delivery systems involving nanogels, which act as artificial chaperones and mucosal adhesives, are a promising approach to overcoming this problem. Here, we introduce current perspectives regarding the development of nanogel-based nasal vaccines for both infectious and lifestyle-related diseases.

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2型糖尿病患者において低ビリルビン血症は網膜症と大血管障害の高い合併率と関連する

田中正巳, 西村健志, 目黒周, 入江潤一郎, 税所芳文, 三石正憲, 川野義長, 伊藤裕

日本内分泌学会雑誌（(一社)日本内分泌学会） 94 （ Suppl.Update ） 69 - 71 2018年06月

査読有り, ISSN 0029-0661

2型糖尿病644名を対象に、血清ビリルビン濃度、糖尿病性網膜症、大血管障害(脳卒中、虚血性心疾患、末梢動脈性疾患)の関連について検討した。網膜症の合併は42%、大血管障害の合併は34%にみられ、非合併例と比較して網膜症合併例では大血管障害の合併率が有意に高く、網膜症合併症例、大血管障害合併例では総ビリルビン濃度が有意に低かった。また、ロジスティック回帰分析では網膜症合併が大血管障害のリスク因子である可能性、低ビリルビン血症が網膜症、大血管障害の共通したリスク因子である可能性が示唆された。2型糖尿病患者において低ビリルビン血症は細小血管障害、大血管障害を有する患者を発見するためのバイオマーカーとして有用である可能性があること、ビリルビンは網膜症と大血管障害の両者に対して保護的な作用を発揮している可能性があることが示された。

Serum total bilirubin concentration in patients with type 2 diabetes as a possible biomarker of polyvascular disease

Nishimura T., Tanaka M., Sekioka R., Itoh H.

Diabetology International （Diabetology International） 9 （ 2 ） 129 - 135 2018年05月

ISSN 21901678

© 2017, The Japan Diabetes Society. Aims: The aim of this study was to investigate the association between serum total bilirubin concentration and complicated macrovascular diseases, such as cerebrovascular disease (CBVD), cardiovascular disease (CAD), and peripheral arterial disease (PAD), in patients with type 2 diabetes. Methods: We performed a retrospective cross-sectional study in 674 patients with type 2 diabetes. Serum total bilirubin concentration was compared between patients with and without CBVD, CAD, and PAD. Logistic regression analyses were performed to identify risk factors for CBVD, CAD, and PAD. Associations between total bilirubin concentration and the number of complicated macrovascular diseases were analyzed. Results: Patients with CBVD and PAD showed significantly lower serum total bilirubin concentrations than did those patients without those diseases. However, the bilirubin concentration did not differ between patients with and without CAD. Total bilirubin concentration was an independent predictor of CBVD, but not of CAD or PAD. There was a statistically significant trend for a decrease in bilirubin concentration in the presence of an increasing number of macrovascular diseases. Conclusion: The presence of more than one macrovascular disease, called polyvascular disease, carries a high risk for cardiovascular mortality. Serum total bilirubin concentration may be useful as a clinical biomarker of polyvascular disease.

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Accuracy of adrenal computed tomography in predicting the unilateral subtype in young patients with hypokalaemia and elevation of aldosterone in primary aldosteronism

Umakoshi H., Ogasawara T., Takeda Y., Kurihara I., Itoh H., Katabami T., Ichijo T., Wada N., Shibayama Y., Yoshimoto T., Ogawa Y., Kawashima J., Sone M., Inagaki N., Takahashi K., Watanabe M., Matsuda Y., Kobayashi H., Shibata H., Kamemura K., Otsuki M., Fujii Y., Yamamto K., Ogo A., Yanase T., Okamura S., Miyauchi S., Suzuki T., Tsuiki M., Naruse M.

Clinical Endocrinology （Clinical Endocrinology） 88 （ 5 ） 645 - 651 2018年05月

ISSN 03000664

© 2018 John Wiley & Sons Ltd Context: The current Endocrine Society Guideline suggests that patients aged <35 years with marked primary aldosteronism (PA) and unilateral adrenal lesions on adrenal computed tomography (CT) scan may not need adrenal vein sampling (AVS) before proceeding to unilateral adrenalectomy. This suggestion is, however, based on the data from only one report in the literature. Objective: We sought to determine the accuracy of CT findings in young PA patients who had unilateral adrenal disease on CT with hypokalaemia and elevation of aldosterone. Design and patients: We retrospectively studied 358 PA patients (n = 30, aged <35 years; n = 39, aged 35-40 years; n = 289, aged ≥40 years) with hypokalaemia and elevation of aldosterone and unilateral disease on CT who had successful AVS. Main outcome measure: Accuracy of CT findings is determined by AVS findings and/or surgical outcomes in patients aged <35 years. Results: Concordance of the diagnosis between CT and AVS was 90% (27/30) in patients aged <35 years, 79% (31/39) in patients aged 35-40 years and 69% (198/289) in those aged ≥40 years (trend for P <.01). Surgical benefit was confirmed in three patients aged <35 years and in three patients aged 35-40 years with the available surgical data who had discordance between CT and AVS findings. Collectively, the diagnostic accuracy of CT findings was 100% (30/30) if aged <35 years and 87% (34/39) if aged 35-40 years. Conclusion: Primary aldosteronism patients aged <35 years with hypokalaemia and elevation of aldosterone and unilateral disease on adrenal CT could be spared AVS.

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Aldosterone and Insulin Resistance: Vicious Combination in Patients on Maintenance Hemodialysis

Wakino S., Minakuchi H., Miya K., Takamatsu N., Tada H., Tani E., Inamoto H., Minakuchi J., Kawashima S., Itoh H.

Therapeutic Apheresis and Dialysis （Therapeutic Apheresis and Dialysis） 22 （ 2 ） 142 - 151 2018年04月

ISSN 17449979

© 2017 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy Recently, we demonstrated that plasma aldosterone contributed to insulin resistance in chronic kidney disease. The aim of this study is the clinical impact of this relationship in hemodialysis patients. In a cross section study using a total of 128 hemodialysis patients, multiple regression analysis revealed that plasma aldosterone levels were independently associated with HOMA-IR, insulin resistance index. This association was found to be more stringent in diabetic patients than in non-diabetic patients. Aldosterone levels were associated with cardiac hypertrophy and carotid artery stenosis. HOMA-IR was associated with cardiac hypertrophy. The patients whose aldosterone and HOMA-IR were above the top tertile of each parameter in this cohort showed more severe cardiac hypertrophy and lower contractile function as compared with the patients whose aldosterone levels and HOMA-IR are below the lowest tertile of each parameter. In conclusion, in hemodialysis patients, aldosterone levels and insulin resistance are closely interrelated and the constellation of the two is related to severe cardiovascular tissue damages.

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Barley β-glucan improves metabolic condition via short-chain fatty acids produced by gut microbial fermentation in high fat diet fed mice

Miyamoto J., Watanabe K., Taira S., Kasubuchi M., Li X., Irie J., Itoh H., Kimura I.

PLoS ONE （PLoS ONE） 13 （ 4 ） 2018年04月

© 2018 Miyamoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Dietary intake of barley β-glucan (BG) is known to affect energy metabolism. However, its underlying mechanism remains poorly understood because studies have presented inconsistent results, with both positive and negative effects reported in terms of satiety, energy intake, weight loss, and glycemic control. The objective of this study was to clarify the physiological role underlying the metabolic benefits of barley BG using a mouse model of high fat diet (HFD)-induced obesity. Male 4-wk-old C57BL/6J mice were fed an HFD with 20% barley flour containing either high BG (HBG; 2% BG) or low BG (LBG; 0.6% BG) levels under conventional and germ-free (GF) conditions for 12 wks. In addition, mice were fed either an HFD with 5% cellulose (HFC; high fiber cellulose) or 5% barley BG (HFB; high fiber β-glucan) for 12 wks. Then, metabolic parameters, gut microbial compositions, and the production of fecal short-chain fatty acids (SCFAs) were analyzed. The weight gain and fat mass of HBG-fed mice were lower than those of control mice at 16-wk-old. Moreover, the secretion of the gut hormones PYY and GLP-1 increased in HBG-fed mice, thereby reducing food intake and improving insulin sensitivity by changing the gut microbiota and increasing SCFAs (especially, butyrate) under conventional condition. These effects in HBG-fed mice were abolished under GF conditions. Moreover, the HFB diets also increased PYY and GLP-1 secretion, and decreased food intake compared with that in HFC-fed mice. These results suggest that the beneficial metabolic effects of barley BG are primary due to the suppression of appetite and improvement of insulin sensitivity, which are induced by gut hormone secretion promoted via gut microbiota-produced SCFAs.

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Non-tuberculous mycobacterial infections related to peritoneal dialysis

Inoue H., Washida N., Morimoto K., Shinozuka K., Kasai T., Uchiyama K., Tokuyama H., Wakino S., Itoh H.

Peritoneal Dialysis International （Peritoneal Dialysis International） 38 （ 2 ） 147 - 149 2018年03月

ISSN 08968608

© 2018 International Society for Peritoneal Dialysis. Most infections related to peritoneal dialysis (PD) are caused by common bacteria, and non-tuberculous mycobacteria are rare. The clinical characteristics and prognosis of PD patients with non-tuberculous mycobacterial infections were investigated at our hospital. Non-tuberculous mycobacteria were detected in 11 patients (exit-site infection, tunnel infection, and peritonitis in 3, 5, and 3 patients, respectively). Mycobacterium fortuitum, Mycobacterium chelonae, and Mycobacterium abscessus were identified in 4, 2, and 2 patients, respectively. Most patients with peritonitis or tunnel infection required catheter removal. During the study period (2007 – 2017), peritonitis occurred in 44 patients, including 3 patients (6.8%) with non-tuberculous mycobacterial peritonitis. When non-tuberculous mycobacterial infection occurs, multi-agent antibiotic therapy, unroofing surgery, and/or catheter replacement should be performed to prevent peritonitis.

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Association of Maternal Factors with Perinatal Complications in Pregnancies Complicated with Diabetes: A Single-Center Retrospective Analysis.

Endo S, Saisho Y, Miyakoshi K, Ochiai D, Matsumoto T, Kawano Y, Mitsuishi M, Irie J, Tanaka M, Meguro S, Tanaka M, Itoh H

Journal of clinical medicine 7 （ 1 ） 2018年01月

ISSN 2077-0383

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Serum triglycerides predict first cardiovascular events in diabetic patients with hypercholesterolemia and retinopathy

Tada H., Kawashiri M., Nomura A., Yoshimura K., Itoh H., Komuro I., Yamagishi M.

European Journal of Preventive Cardiology （European Journal of Preventive Cardiology） 25 （ 17 ） 1852 - 1860 2018年01月

ISSN 20474873

© The European Society of Cardiology 2018. Aims: Low-density lipoprotein cholesterol predicts cardiovascular events in patients with diabetes. However, it is uncertain whether serum triglycerides level is also associated with an occurrence of future cardiovascular events in diabetic patients. We aimed to test whether serum triglycerides is associated with first cardiovascular events in diabetic patients. Methods and results: We recruited 5042 participants with diabetes mellitus from the standard versus intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY), multicenter, prospective, randomized, open-label, blinded-endpoint study. Median follow-up was three years. We evaluated an association of serum triglycerides with first cardiovascular events in cox-regression hazard models adjusted by age, sex, hypertension, current smoking, low-density lipoprotein cholesterol, and body mass index. Cardiovascular events were defined as (a) major adverse cardiac events including myocardial infarction, stroke, or cardiac death; and (b) cardiovascular diseases including myocardial infarction, unstable angina, ischemic stroke, or large artery disease or peripheral arterial disease. Serum triglycerides were associated with major adverse cardiac events (adjusted hazard ratio: 1.021 per 10 mg/dl; 95% confidence interval: 1.007-1.035; p=0.0025) and cardiovascular diseases (adjusted hazard ratio: 1.023 per 10 mg/dl; 95% confidence interval: 1.013-1.034; p=0.0000077). Comparing the top quintile (>185 mg/dl) with the bottom quintile (<79 mg/dl), the adjusted hazard ratio increased 1.89 (95% confidence interval: 1.03-2.80, p=0.04) for major adverse cardiac events, and 1.90 (95% confidence interval: 1.18-3.07, p=0.007) for cardiovascular diseases. There were no overall interactions of triglycerides and treatment assignment (standard/intensive statins) on both outcomes (p-trend=0.33 for major adverse cardiac events, p-trend=0.62 for cardiovascular diseases). Conclusions: Serum triglycerides were associated with first cardiovascular events among high-risk diabetes patients with hypercholesterolemia and retinopathy.

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Effectiveness of nationwide screening and lifestyle intervention for abdominal obesity and cardiometabolic risks in Japan: The metabolic syndrome and comprehensive lifestyle intervention study on nationwide database in Japan (MetS ACTION-J study)

Nakao Y., Miyamoto Y., Ueshima K., Nakao K., Nakai M., Nishimura K., Yasuno S., Hosoda K., Ogawa Y., Itoh H., Ogawa H., Kangawa K., Nakao K.

PLoS ONE （PLoS ONE） 13 （ 1 ） 2018年01月

© 2018 Nakao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Lifestyle interventions can substantially improve obesity and cardiometabolic risks. However, evidence of long-term benefits of national intervention is sparse. We aimed to evaluate the long-term effectiveness of a nationwide program for abdominal obesity. Methods A retrospective cohort study was performed using a longitudinal nationwide individual data in subjects aged 40–74 years who underwent checkups in fiscal year (FY) 2008. Lifestyle interventions were provided via interview in subjects with abdominal obesity and at least one cardiometabolic risk factor. Subjects who attended the lifestyle intervention (participants) were compared to those who did not attend (non-participants). Outcomes were waist circumferences (WC) and body mass index (BMI) reduction, reversal of metabolic syndrome (MetS), and changes in cardiometabolic risks. We used a three-step process with robust analytic approaches to account for selection bias that included traditional multivariate analysis, propensity-score matching and instrumental variable (IV) analyses. Results Of 19,969,722 subjects, 4,370,042 were eligible for analyses; 111,779 participants and 907,909 non-participants. A higher percentage of participants had 5% reductions in obesity profiles at year 3, compared to non-participants (WC, 21.4% vs 16.1%; BMI, 17.6% vs 13.6%; p<0.001 each). Participants also had higher reversal for MetS (adjusted odds ratio 1.31; 95% confidence interval: 1.29–1.33; p<0.001). Greater reductions in cardiometabolic risks were observed in participants. Those results were confirmed in analyses using a propensity score-matched cohort (n = 75,777, each) and IV analyses. Limitations of this work include the use of non-randomized national data in Japan to assess the effectiveness of the nationwide preventive program. Conclusions In the nationwide lifestyle intervention for abdominal obesity, the at-risk population achieved significant reductions in WC, BMI, and cardiometabolic risks in 3 years. This study provides evidence that the nationwide program effectively achieved long-term improvement in abdominal obesity and cardiometabolic risks.

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Transcription factors as therapeutic targets in chronic kidney disease

Hishikawa A., Hayashi K., Itoh H.

Molecules （Molecules） 23 （ 5 ） 2018年

© 2018 by the authors. The growing number of patients with chronic kidney disease (CKD) is recognized as an emerging problem worldwide. Recent studies have indicated that deregulation of transcription factors is associated with the onset or progression of kidney disease. Several clinical trials indicated that regression of CKD may be feasible via activation of the transcription factor nuclear factor erythroid-2 related factor 2 (Nrf2), which suggests that transcription factors may be potential drug targets for CKD. Agents stabilizing hypoxia-inducible factor (HIF), which may be beneficial for renal anemia and renal protection, are also now under clinical trial. Recently, we have reported that the transcription factor Kruppel-like factor 4 (KLF4) regulates the glomerular podocyte epigenome, and that the antiproteinuric effect of the renin–angiotensin system blockade may be partially mediated by KLF4. KLF4 is one of the Yamanaka factors that induces iPS cells and is reported to be involved in epigenetic remodeling. In this article, we summarize the transcription factors associated with CKD and particularly focus on the possibility of transcription factors being novel drug targets for CKD through epigenetic modulation.

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The Role of Non-Tuberculous Mycobacteria in Peritoneal Dialysis-Related Infections: A Literature Review

Washida N., Itoh H.

Contributions to Nephrology （Contributions to Nephrology） 196 155 - 161 2018年

ISSN 03025144

© 2018 S. Karger AG, Basel. Background: Peritonitis is one of the most frequent reasons for withdrawal of peritoneal dialysis (PD). Although most cases of PD-related peritonitis can be treated with antibiotics, it is occasionally refractory and culture-negative. Summary: The causes of refractory PD-related peritonitis include antibiotic-resistant bacteria, fungal peritonitis, biofilm formation in PD catheters, bacterial translocation from the gastrointestinal tract, and encapsulating peritoneal sclerosis. Among them, culture-negative peritonitis is notable, and non-tuberculous mycobacteria (NTM) can be a cause of culture-negative peritonitis. In the present study, the treatment and outcomes of NTM peritonitis and exit site infections were investigated by collecting data from relevant reviews published during the last 10 years. Catheter removal was required in 92.2% of the patients with NTM peritonitis, and withdrawal of PD was performed in 91.9%. The overall mortality rate (including unrelated deaths) was 12.4% in patients with NTM peritonitis. Among patients with NTM exit site infections, 33.3% developed peritonitis, and catheter removal was required in 50.0%. A lower percentage of patients stopped PD when the catheter was removed without developing peritonitis (37.5%) than when it was removed after the onset of peritonitis (91.9%). Changing the exit site or unroofing was performed in 12.5% of the patients with NTM exit site infections. In addition, these infections resolved with antibiotics alone or without antibiotics in 18.8 and 12.5% of the patients, respectively, while 6.25% of the patients died.

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Significance of computed tomography and serum potassium in predicting subtype diagnosis of primary aldosteronism

Umakoshi H., Tsuiki M., Takeda Y., Kurihara I., Itoh H., Katabami T., Ichijo T., Wada N., Yoshimoto T., Ogawa Y., Kawashima J., Sone M., Inagaki N., Takahashi K., Watanabe M., Matsuda Y., Kobayashi H., Shibata H., Kamemura K., Otsuki M., Fujii Y., Yamamto K., Ogo A., Yanase T., Suzuki T., Naruse M., JPAS Study Group

Journal of Clinical Endocrinology and Metabolism （Journal of Clinical Endocrinology and Metabolism） 103 （ 3 ） 900 - 908 2018年

ISSN 0021972X

Copyright © 2018 Endocrine Society. Context: The number of centers with established adrenal venous sampling (AVS) programs for the subtype diagnosis of primary aldosteronism (PA) is limited. Objective: Aim was to develop an algorithm for AVS based on subtype prediction by computed tomography (CT) and serum potassium. Design: A multi-institutional retrospective cohort study in Japan. Patients: A total of 1591 patients with PA were classified into four groups according to CT findings and potassium status. Subtype diagnosis of PA was determined by AVS. Main Outcome Measure: Prediction value of the combination of CT findings and potassium status for subtype diagnosis. Results: The percentages of unilateral hyperaldosteronism on AVS were higher in patients with unilateral disease on CT than those with bilateral normal results on CT (50.8% vs 14.6%, P, 0.01), and these percentages were higher in those with hypokalemia than those with normokalemia (58.4% vs 11.5%, P, 0.01). The prevalence and odds ratio for unilateral hyperaldosteronism on AVS were as follows: bilateral normal on CT with normokalemia, 6.2% (reference); unilateral disease on CT with normokalemia, 23.8% and 4.8 [95% confidence interval (CI), 3.1 to 7.2]; bilateral normal on CT with hypokalemia, 38.1% and 9.4 (95% CI, 6.2 to 14.1), and unilateral disease on CT with hypokalemia, 70.6% and 36.4 (95% CI, 24.7 to 53.5). Conclusions: Patients with PA with bilateral normal results on CT and normokalemia likely have a low prior probability of a lateralized form of AVS and could be treated medically, whereas those with unilateral disease on CT and hypokalemia have a high probability of a lateralized form of AVS.

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Prevalence of Cardiovascular Disease and Its Risk Factors in Primary Aldosteronism A Multicenter Study in Japan

Ohno Y., Sone M., Inagaki N., Yamasaki T., Ogawa O., Takeda Y., Kurihara I., Itoh H., Umakoshi H., Tsuiki M., Ichijo T., Katabami T., Tanaka Y., Wada N., Shibayama Y., Yoshimoto T., Ogawa Y., Kawashima J., Takahashi K., Fujita M., Watanabe M., Matsuda Y., Kobayashi H., Shibata H., Kamemura K., Otsuki M., Fujii Y., Yamamoto K., Ogo A., Okamura S., Miyauchi S., Fukuoka T., Izawa S., Yoneda T., Hashimoto S., Yanase T., Suzuki T., Kawamura T., Tabara Y., Matsuda F., Naruse M.

Hypertension （Hypertension） 71 （ 3 ） 530 - 537 2018年

ISSN 0194911X

© 2018 American Heart Association, Inc. There have been several clinical studies examining the factors associated with cardiovascular disease (CVD) in patients with primary aldosteronism (PA); however, their results have left it unclear whether CVD is affected by the plasma aldosterone concentration or hypokalemia. We assessed the PA database established by the multicenter JPAS (Japan Primary Aldosteronism Study) and compared the prevalence of CVD among patients with PA with that among age-, sex-, and blood pressure-matched essential hypertension patients and participants with hypertension in a general population cohort. We also performed binary logistic regression analysis to determine which parameters significantly increased the odds ratio for CVD. Of the 2582 patients with PA studied, the prevalence of CVD, including stroke (cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage), ischemic heart disease (myocardial infarction or angina pectoris), and heart failure, was 9.4% (stroke, 7.4%; ischemic heart disease, 2.1%; and heart failure, 0.6%). The prevalence of CVD, especially stroke, was higher among the patients with PA than those with essential hypertension/ hypertension. Hypokalemia (K+ ≤3.5 mEq/L) and the unilateral subtype significantly increased adjusted odds ratios for CVD. Although aldosterone levels were not linearly related to the adjusted odds ratio for CVD, patients with plasma aldosterone concentrations ≥125 pg/mL had significantly higher adjusted odds ratios for CVD than those with plasma aldosterone concentrations <125 pg/mL. Thus, patients with PA seem to be at a higher risk of developing CVD than patients with essential hypertension. Moreover, patients with PA presenting with hypokalemia, the unilateral subtype, or plasma aldosterone concentration ≥125 pg/mL are at a greater risk of CVD and have a greater need for PA-specific treatments than others.

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Lower serum total bilirubin concentration is associated with higher prevalence of gestational diabetes mellitus in Japanese pregnant women

Nishimura T., Tanaka M., Saisho Y., Miyakoshi K., Tanaka M., Itoh H.

Endocrine Journal （Endocrine Journal） 65 （ 12 ） 1199 - 1208 2018年

ISSN 09188959

©The Japan Endocrine Society. We aimed to clarify the pathophysiological significance of total bilirubin (TB) in gestational diabetes mellitus (GDM). This was a cross-sectional study that included 616 pregnant Japanese women (368 normal glucose tolerance [NGT] and 248 GDM). Serum TB concentration, homeostasis model assessment of insulin resistance (HOMA-IR), and other clinical parameters were compared in NGT and GDM women. TB concentration was also compared according to the number of abnormal OGTT values. Logistic regression analysis was used to evaluate the association between TB and GDM prevalence. A multiple linear regression model was used to evaluate the association between TB and HOMA-IR. TB concentrations were significantly lower in GDM women than in NGT women. This result did not change after adjustments for TB sampling timing were made. Out of 248 GDM women, the prevalences of 1-and 2/3-abnormal OGTT values (1-and 2/3-AV) GDM were 72.2% (n = 179) and 27.8% (n = 69), respectively. In the multiple comparisons, TB concentrations were significantly lower in women with 2/3-AV GDM than in women with NGT and 1-AV GDM. Multiple logistic regression analysis showed that TB was a significantly associated factor for 2/3-AV, but not for total GDM. HOMA-IR was significantly higher in GDM women than in NGT women. The univariate, but not multivariate, analysis showed that TB was a significantly associated factor for HOMA-IR. Our findings suggest that hypobilirubinemia may be involved in the pathogenesis of GDM.

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Development and validation of subtype prediction scores for the workup of primary aldosteronism

Kobayashi H., Abe M., Soma M., Takeda Y., Kurihara I., Itoh H., Umakoshi H., Tsuiki M., Katabami T., Ichijo T., Wada N., Yoshimoto T., Ogawa Y., Kawashima J., Sone M., Inagaki N., Takahashi K., Watanabe M., Matsuda Y., Shibata H., Kamemura K., Yanase T., Otsuki M., Fujii Y., Yamamoto K., Ogo A., Nanba K., Tanabe A., Suzuki T., Naruse M.

Journal of Hypertension （Journal of Hypertension） 36 （ 11 ） 2269 - 2276 2018年

ISSN 02636352

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. Objectives: A subtype prediction score for primary aldosteronism has not yet been developed and validated using a large dataset. This study aimed to develop and validate a new subtype prediction score and to compare it with existing scores using a large multicenter database. Methods: In total, 1936 patients with primary aldosteronism were randomly assigned to the development and validation datasets, constituting 1290 and 646 patients, respectively. Three prediction scores were generated with or without confirmatory tests, using logistic regression analysis. In the validation dataset, new and existing prediction scores were compared using receiver operating characteristic curve, net reclassification improvement, and integrated discrimination improvement analyses. Results: The new prediction score is simply calculated using serum potassium levels [>3.9 mmol/l (four points); 3.5-3.9 mmol/l (three points)], the absence of adrenal nodules during computed tomography (three points), a baseline plasma aldosterone concentration of <210.0 pg/ ml (two points), a baseline aldosterone/renin ratio of less than 620 (two points), and female sex (one point). Using the validation dataset, we found that a new subtype prediction score of at least 8 had a positive predictive value of 93.5% for bilateral hyperaldosteronism. The new prediction score for bilateral hyperaldosteronism was better than the existing prediction scores in the receiver operating characteristic curve and net reclassification improvement analyses. Conclusion: The new prediction score has clear advantages over the existing prediction scores in terms of diagnostic accuracy, feasibility, and the potential for generalization in a large population. These data will help healthcare professionals to better select patients who require adrenal venous sampling.

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High Glucose Stimulates Mineralocorticoid Receptor Transcriptional Activity Through the Protein Kinase C beta Signaling

Hayashi, T., Shibata, H., Kurihara, I., Yokota, K., Mitsuishi, Y., Ohashi, K., Murai-Takeda, A., Jo, R., Ohyama, T., Sakamoto, M., Tojo, K., Tajima, N., Utsunomiya, K. and Itoh, H.

Int Heart J 2017年09月

ISSN 1349-2365

Activation of mineralocorticoid receptor (MR) is shown in resistant hypertension including diabetes mellitus. Although protein kinase C (PKC) signaling is involved in the pathogenesis of diabetic complications, an association between PKC and MR is not known. Activation of PKCalpha and PKCbeta by TPA (12-O-Tetradecanoylphorbol 13-acetate) increased MR proteins and its transcriptional activities in HEK293-MR cells. In contrast, a high glucose condition resulted in PKCbeta but not PKCalpha activation, which is associated with elevation of MR protein levels and MR transcriptional activities. Reduction of endogenous PKCbeta by siRNA decreased those levels. Interestingly, high glucose did not affect MR mRNA levels, but rather decreased ubiquitination of MR proteins. In db/db mice kidneys, levels of phosphorylated PKCbeta2, MR and Sgk-1 proteins were elevated, and the administration of PKC inhibitor reversed these changes compared to db/+ mice. These data suggest that high glucose stimulates PKCbeta signaling, which leads to MR stabilization and its transcriptional activities.

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Association between severity of obstructive sleep apnea and glycated hemoglobin level in Japanese individuals with and without diabetes

Kurosawa, H., Saisho, Y., Fukunaga, K., Haraguchi, M., Yamasawa, W., Kurihara, I., Betsuyaku, T. and Itoh, H.

Endocr J 2017年09月

ISSN 0918-8959

Aim of this study was to examine the association between the severity of obstructive sleep apnea (OSA) and dysglycemia in Japanese individuals with and without type 2 diabetes (T2DM). We enrolled 115 individuals diagnosed with OSA with an apnea hypopnea-index (AHI) >/= 20 in whom continuous positive airway pressure (CPAP) therapy was introduced (N = 115, 44 with T2DM, age 62 +/- 11 years, BMI 27.0 +/- 4.4 kg/m2 and AHI median 36.1; interquartile range 27.2-48.1). During admission, the severity of OSA was evaluated by polysomnography, and its association with glycated hemoglobin (HbA1c) level was examined. Continuous glucose monitoring (CGM) was also conducted during the admission in 94 individuals. Apnea-hypopnea index (AHI), non-rapid eye movement (REM) AHI, minimum peripheral capillary oxygen saturation (SpO2) and percentage of sleep time (%TST) with SpO2 < 90% were significantly associated with HbA1c level in total and non-diabetic individuals (all p < 0.05) but not in those with T2DM, the majority of whom were treated with anti-diabetic medications. The associations of the non-REM AHI and %TST with SpO2 < 90% with HbA1c level remained significant after adjustment for age, sex and BMI in non-diabetic and T2DM subjects treated with dietary therapy only. Mean glucose level, but not SD or coefficient of variation of glucose, assessed by CGM was significantly associated with AHI and non-REM AHI in non-diabetic subjects after adjustment for age, sex and BMI. In conclusion, the severity of OSA was associated with increased HbA1c level independently of BMI in Japanese individuals, especially in those without diabetes.

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Pancreas Fat and beta Cell Mass in Humans With and Without Diabetes: An Analysis in the Japanese Population

Murakami, R., Saisho, Y., Watanabe, Y., Inaishi, J., Tsuchiya, T., Kou, K., Sato, S., Kitago, M., Kitagawa, Y., Yamada, T. and Itoh, H.

J Clin Endocrinol Metab 102 （ 9 ） 3251 - 3260 2017年09月

ISSN 0021-972

Context: The mechanisms by which beta cell mass is reduced in patients with type 2 diabetes remain unclear. It has been postulated that ectopic fat deposits in the pancreas induce beta cell apoptosis, leading to the development of diabetes. Objective: The aim of this study was to clarify the effects of intrapancreatic fat on beta and alpha cell mass in humans with and without diabetes. Design and Subjects: Using our tissue database, pancreas sections of 72 Japanese nondiabetic (NDM) autopsy cases and 50 diabetic and 49 age- and body mass index (BMI)-matched NDM patients who underwent pancreatic surgery were analyzed. In addition to histological grading, intrapancreatic fat area (IPFA) was quantified as fractional intralobular, but not interlobular, fat area to the whole pancreas area. Results: Although IPFA was positively correlated with age and BMI, there was no significant difference in IPFA between cases with and without diabetes. Moreover, no association was found between IPFA and either beta or alpha cell area, or glycated hemoglobin. Conclusion: These findings suggest that pancreatic fat deposits have little effect on beta cell mass and the development of diabetes in humans.

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GLP-1 receptor agonist, liraglutide, ameliorates hepatosteatosis induced by anti-CD3 antibody in female mice

Itoh, A., Irie, J., Tagawa, H., Kusumoto, Y., Kato, M., Kobayashi, N., Tanaka, K., Kikuchi, R., Fujita, M., Nakajima, Y., Wu, Y., Yamada, S., Kawai, T., Ridgway, W. M. and Itoh, H.

J Diabetes Complications 31 （ 9 ） 1370 - 1375 2017年09月

ISSN 1056-8727

AIMS: Hepatosteatosis is mainly induced by obesity and metabolic disorders, but various medications also induce hepatosteatosis. The administration of anti-CD3 antibody was shown to induce hepatosteatosis, but changes in lipid and glucose metabolism remain unclear. We investigated the mechanism of hepatosteatosis induced by anti-CD3 antibody and the effects of glucagon-like peptide-1 (GLP-1) receptor agonist that was recently shown to affect immune function in metabolic disorders. METHODS: Anti-CD3 antibody was administered to female BALB/c and C.B-17-scid mice with or without reconstitution by naive CD4-positive splenocytes. Hepatic lipid content, serum lipid profile and glucose tolerance were evaluated. Splenic CD4-positive T lymphocytes were stimulated with the GLP-1R agonist, liraglutide, and cytokine production was measured. The effect of liraglutide on metabolic parameters in vivo was investigated in a T-cell activation-induced hepatosteatosis model. RESULTS: The administration of anti-CD3 antibody induced hepatosteatosis, hyperlipidemia, and glucose intolerance. C.B-17-scid mice reconstituted with CD4-positive T lymphocytes developed hepatosteatosis induced by anti-CD3 antibody. Liraglutide suppressed CD4-positive T lymphocyte cytokine expression in vitro and in vivo, and improved hepatosteatosis, glucose tolerance, and insulin sensitivity. CONCLUSIONS: Liraglutide suppressed the activation of CD4-positive T lymphocytes, and improved hepatosteatosis and metabolic disorders induced by T-cell activation in female mice.

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Nanogel-based nasal ghrelin vaccine prevents obesity.

Azegami T, Yuki Y, Sawada S, Mejima M, Ishige K, Akiyoshi K, Itoh H, Kiyono H

Mucosal immunology 10 （ 5 ） 1351 - 1360 2017年09月

ISSN 1933-0219

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Intranasal vaccination against angiotensin II type 1 receptor and pneumococcal surface protein A attenuates hypertension and pneumococcal infection in rodents

Azegami T., Yuki Y., Hayashi K., Hishikawa A., Sawada S., Ishige K., Akiyoshi K., Kiyono H., Itoh H.

Journal of Hypertension （Journal of Hypertension） 36 （ 2 ） 387 - 394 2017年08月

ISSN 0263-6352

© 2018 Wolters Kluwer Health, Inc. All rights reserved. Objectives: To combat global increases in the prevalence of lifestyle-related diseases and concomitant infectious diseases, we aimed to develop an innovative intranasal vaccine that simultaneously targets both hypertension and pneumonia, is not given by invasive injection, and offers prolonged therapeutic effect and reduced frequency of administration. Methods: Angiotensin II type 1 receptor-pneumococcal surface protein A (AT1R-PspA) vaccine, consisting of a cationic nanometer-sized hydrogel incorporating AT1R partial peptide conjugated with PspA and cyclic diguanylate monophosphate adjuvant, was created and given intranasally to spontaneously hypertensive rats (SHRs). Antigen-specific antibodies and blood pressure were examined to evaluate immune responses and the antihypertensive effect of the vaccine. To examine the protective effect of antibodies induced by vaccination on pneumococcal infection, sera obtained from immunized SHRs were incubated with a lethal dose of Streptococcus pneumoniae and then administered to mice. Results: Five doses of AT1R-PspA nasal-vaccine-induced AT1R-specific serum IgG antibody production and attenuated the development of hypertension in SHRs in the long term. Both in-vitro and in-vivo studies revealed that responses to angiotensin II were suppressed in vaccinated rats. Mice passively immunized with sera obtained from AT1R-PspA-vaccinated SHRs were protected from lethal pneumococcal infection. Conclusion: Intranasal immunization with AT1R-PspA vaccine has the potential to simultaneously attenuate the development of hypertension and protect from lethal pneumococcal infection.

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Investigation of Metabolic Factors Associated with eGFR Decline Over 1 Year in a Japanese Population without CKD

Hayashi, K., Takayama, M., Abe, T., Kanda, T., Hirose, H., Shimizu-Hirota, R., Shiomi, E., Iwao, Y. and Itoh, H.

J Atheroscler Thromb 24 （ 8 ） 863 - 875 2017年08月

ISSN 1340-3478

AIM: Early intervention before the progression of chronic kidney disease (CKD) is essential to prevent end-stage renal disease (ESRD) and cardiovascular complications. This study evaluated the correlation between metabolic and lifestyle-related factors and the decline of estimated glomerular filtration rate (eGFR) over 1 year in a Japanese population without CKD. METHODS: Subjects who received two consecutive annual health checkups from 2013 to 2015 were involved. Factors associated with eGFR decline were identified using multiple regression models. RESULTS: A total of 2531 subjects aged 58.9+/-11.7 years old were included in this study. Baseline levels of HDL-C and ApoA1 correlated with the eGFR decline over 1 year defined as eGFR reduction rate of 15% or more and/or eGFR at the next year 60 ml/min/m2 (odds ratio (OR) 0.87 (per 10 mg/dl); 95% CI, 0.80-0.94; p=0.0012, 0.90 (per 10 mg/dl); 0.86-0.96; p=0.0004, respectively). A U-shaped relationship between the eGFR decline and HDL-C or ApoA1 levels was not observed in non-CKD population of this study. Metabolic syndrome was significantly associated with eGFR decline (OR 1.32; 1.04-1.67; p=0.0205), although obesity-related factors did not show a significant correlation with eGFR decline over 1 year. CONCLUSION: Low HDL-C and ApoA1 levels significantly correlated with eGFR decline in a short period of 1 year. Metabolic syndrome also showed a significant association with eGFR decline. This study suggests the importance of hypertension and low HDL-C in the metabolic syndrome effect on eGFR decline rather than obesity in non-CKD population.

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Association of Kidney Dysfunction With Asymptomatic Cerebrovascular Abnormalities in a Japanese Population With Health Checkups

Hayashi, K., Takayama, M., Kanda, T., Kashiwagi, K., Hishikawa, A., Iwao, Y. and Itoh, H.

Circ J 81 （ 8 ） 1191 - 1197 2017年07月

ISSN 1346-9843

BACKGROUND: Cerebrovascular disease is a major cause of mortality and morbidity. Chronic kidney disease (CKD) is prevalent in stroke patients. This study evaluated the correlation between kidney dysfunction and asymptomatic findings on carotid ultrasonography (US) and brain magnetic resonance imaging (MRI) in a Japanese population with health checkups.Methods and Results:In total, 1,716 subjects aged 40-80 years, who received health checkups from January 1 to December 31, 2015, were included. Common carotid artery intima-media thickness (CCA-IMT) and carotid plaques by US, and the presence of old non-lacunar infarctions, lacunar infarctions, white matter lesions (WMLs), cerebral microbleeds (CMBs), and atrophy by brain MRI were evaluated. After adjusting for cardiovascular risk factors, multiple regression analyses revealed that an eGFR ranging from 15 to 44 mL/min/1.73 m2was independently associated with CCA plaques and hypoechoic or heterogeneous plaques. Proteinuria was associated with CCA or internal carotid artery plaques, the number of carotid plaques, and the presence of old non-lacunar infarctions and CMBs. CONCLUSIONS: Decreased eGFR and proteinuria were independent risk factors for asymptomatic abnormalities on carotid US and brain MRI, which are surrogate markers for cerebrovascular diseases. Evaluation of these abnormalities may be useful for prevention of symptomatic cerebrovascular events in CKD patients.

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Treatment of sarcopenia and glucose intolerance through mitochondrial activation by 5-aminolevulinic acid

Fujii, C., Miyashita, K., Mitsuishi, M., Sato, M., Fujii, K., Inoue, H., Hagiwara, A., Endo, S., Uto, A., Ryuzaki, M., Nakajima, M., Tanaka, T., Tamaki, M., Muraki, A., Kawai, T. and Itoh, H.

Sci Rep 7 （ 1 ） 4013 2017年06月

ISSN 2045-2322

Recently, sarcopenia has attracted attention as therapeutic target because it constitutes a risk factor for metabolic and cardiovascular diseases. We focused 5-aminolevulinic acid (ALA) which act as electron carriers in the mitochondrial electron transport system. The mice that received ALA for 8 weeks gained muscle strength and endurance, and exhibited increased muscle mass and mitochondrial amount. Administration of ALA to sarcopenia mice aged 100 weeks and chronic kidney disease (CKD) model mice also increased muscle mass and improved physical performance. Metabolome analysis revealed increased branched-chain amino acids (BCAAs) levels in the skeletal muscle of ALA-treated mice. Quantitative PCR analysis revealed decreased expression levels in branched-chain amino acid transaminases (BCATs) that degrade BCAAs and other muscle-degrading factors, and increased levels of mitochondria-activating factors. We also studied in cultured myocytes and obtained compatible results. ALA-treated mice tended to increase body weight, but reduced blood glucose level. These suggested that ALA treatment not only activated muscle mitochondria but also enhanced muscle mass through an increase in BCAAs contents, as to improve muscle strength, endurance and glucose tolerance in mice. In these ways, muscle mitochondrial activation with ALA is suggested to be useful for the treatment of sarcopenia and glucose intolerance.

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Clinical significance of 'cardiometabolic memory': a systematic review of randomized controlled trials

Itoh, H., Kurihara, I., Miyashita, K. and Tanaka, M.

Hypertens Res 40 （ 6 ） 526 - 534 2017年06月

ISSN 0916-9636

'Cardiometabolic memory' has been proposed based on clinical evidence to explain how, even after the cessation of a clinical trial, the superiority of one treatment over the outcome persists. To understand the cardiometabolic memory phenomenon, we performed a systematic review of randomized controlled trials (RCTs) using PubMed in August 2016. The search terms 'randomized controlled trial', 'post-trial follow-up' and 'diabetes, hypertension or dyslipidemia' were used, and articles published after the year 2000 were searched. We judged the memory phenomenon to be positive when the cardiovascular outcome at the end of the post-trial follow-up period in the intervention group was significantly superior even though the favorable control of a risk factor (blood glucose, blood pressure or lipid level) during the trial period was lost after the cessation of the intervention. Among 907 articles retrieved in the initial screening, 21 articles were judged as describing a positive memory phenomenon. Eight, six and seven of the articles concerned diabetes, hypertension and dyslipidemia, respectively. Transient intensive glucose lowering rather easily induced memory for the suppression of diabetic microangiopathies, while memory for the suppression of macroangiopathies tended to be first evident in the post-trial follow-up period. Transient intensive blood pressure lowering was generally effective in the formation of memory for the suppression of cardiovascular events and had an especially strong impact on risk reduction of chronic heart failure. Transient intensive LDL cholesterol lowering clearly had a long-term beneficial effect on risk reduction of cardiovascular events. Our systematic review revealed the clinical relevance of cardiometabolic memory.

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Bile acid binding resin prevents fat accumulation through intestinal microbiota in high-fat diet-induced obesity in mice

Kusumoto, Y., Irie, J., Iwabu, K., Tagawa, H., Itoh, A., Kato, M., Kobayashi, N., Tanaka, K., Kikuchi, R., Fujita, M., Nakajima, Y., Morimoto, K., Sugizaki, T., Yamada, S., Kawai, T., Watanabe, M., Oike, Y. and Itoh, H.

Metabolism 71 1 - 6 2017年06月

ISSN 0026-0495

BACKGROUND: Bile acid binding resin (BAR) absorbs intestinal bile acids, and improves obesity and metabolic disorders, but the precise mechanism remains to be clarified. Recent findings reveal that obesity is associated with skewed intestinal microbiota. Thus, we investigated the effect of BAR on intestinal microbiota and the role of microbiota in the prevention of obesity in high-fat diet-induced obesity in mice. PROCEDURES: Male Balb/c mice were fed a low-fat diet (LFD), high-fat diet (HFD), or HFD with BAR (HFD+BAR), and then metabolic parameters, caecal microbiota, and metabolites were investigated. The same interventions were conducted in germ-free and antibiotic-treated mice. MAIN FINDINGS: The frequency of Clostridium leptum subgroup was higher in both HFD-fed and HFD+BAR-fed mice than in LFD-fed mice. The frequency of Bacteroides-Prevotella group was lower in HFD-fed mice than in LFD-fed mice, but the frequency was higher in HFD+BAR-fed mice than in HFD-fed mice. Caecal propionate was lower in HFD-fed mice than in LFD-fed mice, and higher in HFD+BAR-fed mice than in HFD-fed mice. HFD+BAR-fed mice showed lower adiposity than HFD-fed mice, and the reduction was not observed in germ-free or antibiotic-treated mice. Colonized germ-free mice showed a reduction in adiposity by BAR administration. Energy expenditure was lower in HFD-fed mice and higher in HFD+BAR-fed mice, but the increments induced by administration of BAR were not observed in antibiotic-treated mice. CONCLUSIONS: Modulation of intestinal microbiota by BAR could be a novel therapeutic approach for obesity.

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Eggshell membrane powder ameliorates intestinal inflammation by facilitating the restitution of epithelial injury and alleviating microbial dysbiosis.

Jia H, Hanate M, Aw W, Itoh H, Saito K, Kobayashi S, Hachimura S, Fukuda S, Tomita M, Hasebe Y, Kato H

Scientific reports 7 43993 2017年03月

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A case of familial dysalbuminemic hyperthyroxinemia (FDH) in Japan: FDH as a possible differential diagnosis of syndrome of inappropriate secretion of thyroid-stimulating hormone (SITSH)

Kobayashi, S., Yoshimura Noh, J., Shimizu, T., Sato, T., Kurihara, I., Sugino, K., Itoh, H. and Ito, K.

Endocr J 64 （ 2 ） 207 - 212 2017年02月

ISSN 0918-8959

Familial dysalbuminemic hyperthyroxinemia (FDH) is an autosomal dominant condition and is the most commonly inherited euthyroid hyperthyroxinemia in Caucasians. However, it is extremely rare in Asian populations. A 30-year-old Japanese woman, who was incidentally found to have apparent thyroid dysfunction, was admitted to our hospital in 2004. She had extremely elevated serum free thyroxine (FT4), moderately elevated free triiodothyronine (FT3), and normal thyroid-stimulating hormone (TSH). Clinical thyroid examination revealed no abnormalities other than small goiter. Anti-thyroglobulin antibody titer was positive, but titers of other anti-thyroid antibodies, including antithyroid peroxidase antibody, TSH receptor antibodies, and thyroid-stimulating antibody, were negative. Levels of FT3, FT4, and TSH were similar when measured by three different laboratory kits, and FT4 was still high when measured by equilibrium dialysis. By affinity chromatography, FT4, TT4, and albumin were extracted to the same fraction, and the levels of FT4 and TT4 were extremely high. By combination of reversed phase liquid chromatography and mass spectrometry techniques, the amino acid sequence of human serum albumin was determined. The patient was found to be a heterozygote for p.R218P mutation in the gene for human serum albumin and was diagnosed as FDH. This patient, who harbored the p.R218P mutation in the albumin gene, is the fifth case report of FDH in Japan. This condition is characterized by extremely high serum FT4 and moderately high serum FT3 levels. Although rare, FDH should be considered in the differential diagnosis for syndrome of inappropriate secretion of TSH (SITSH) in Japan.

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Temporal trends in renal function and birthweight in Japanese adolescent males (1998-2015)

Kanda T., Takeda A., Hirose H., Abe T., Urai H., Inokuchi M., Wakino S., Tokumura M., Itoh H., Kawabe H.

Nephrology Dialysis Transplantation （Nephrology Dialysis Transplantation） 33 （ 2 ） 304 - 310 2017年01月

ISSN 0931-0509

© 2017 The Author . Published by Oxford University Press on behalf of ERA-EDTA. Background Low birthweight (LBW) is a worldwide public health problem, demonstrating an increasing incidence in developed countries, including Japan. LBW is also a risk factor for later development of chronic kidney disease (CKD). To date, studies have not evaluated the population impacts of increasing LBW rates on renal function. Methods Estimated glomerular filtration rate (EGFR) was evaluated in 3737 Japanese adolescent males (15-16 years old) using annual cross-sectional data over an 18-year period (1998-2015). Results Between the initial (1998-2003) and final (2010-15) periods of the study, the mean birthweight decreased from 3213.4 ± 383.8 to 3116.2 ± 382.3 g and the LBW rate increased from 2.5 to 5.5% (both P ≤ 0.01). Additionally, the mean EGFR decreased from 105.1 ± 15.9 to 97.4 ± 13.8 mL/min/1.73 m 2 and the prevalence of mildly reduced renal function (EGFR ≤ 60-<90 mL/min/1.73 m 2) increased from 16.4 to 30.0% (both P ≤ 0.01), most evident in the LBW group (from 10.3 to 41.7%, P ≤0.01). The prevalence of proteinuria also increased significantly. Mildly reduced renal function was significantly associated with LBW [odds ratio (LBW 3000-3999 g) 1.51; 95% confidence interval 1.00-2.55; P = 0.047]. Conclusions In this population of Japanese adolescents, the frequency of mildly reduced renal function increased as the LBW frequency increased. Our findings may have implications for the broader Japanese population as well as for other populations in which the prevalence of LBW is increasing.

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A case of autoimmune polyendocrine syndrome type I with strong positive GAD antibody titer, followed up with glucose tolerance measured by oral glucose tolerance test

Murakami, R., Kawai, T., Meguro, S., Hayashi, M. and Itoh, H.

Neuro Endocrinol Lett 37 （ 8 ） 540 - 542 2017年01月

ISSN 0172-780X

A 26-year-old Japanese woman presented with adrenal insufficiency, and treatment was started with cortisone and fludrocortisone in 1975. A few years later, she presented with hypoparathyroidism and was diagnosed with autoimmune polyendocrine syndrome type I (APS I), and treatment with calcium and alfacalcidol was started. She was found to have subacute thyroiditis and relative adrenal failure in 2006. Her condition remained stable under treatment with cortisone, fludrocortisone, levothyroxine, calcium lactate, precipitated calcium carbonate and alfacalcidol. While antibodies against pancreatic glutamic acid decarboxylase (GAD) were strongly positive (7,690 U/ml), fasting glucose level was 4.9 mmol/L and HbA1c was 6.3% on admission. As GAD antibody showed a high-titer of >10,000 U/ml and fasting plasma glucose level showed a rising trend, we performed 75-g oral glucose tolerance test (OGTT) 6 years after discharge. Whereas OGTT in 2012 showed impaired glucose tolerance, glucose tolerance had reverted to normal in 2014. A patient with a high-titer GAD antibody does not always have progressive glucose intolerance. GAD antibody positivity is common in not only type 1 diabetes, but also APS I and stiff-person syndrome (SPS). There are differences in recognized epitopes among the three disorders. Epitopes for GAD65 antibody associated with type 1 diabetes are located in the middle region and the COOH-terminal of the GAD65 protein, whereas epitopes associated with SPS reside in the NH2-terminal in addition to the middle region and COOH-terminal. The present case suggests that these differences in epitopes may be related to various pathogenic mechanisms including glucose intolerance.

Ghrelin treatment improves physical decline in sarcopenia model mice through muscular enhancement and mitochondrial activation

Tamaki, M., Miyashita, K., Hagiwara, A., Wakino, S., Inoue, H., Fujii, K., Fujii, C., Endo, S., Uto, A., Mitsuishi, M., Sato, M., Doi, T. and Itoh, H.

Endocr J 64 （ Suppl. ） S47 - s51 2017年

ISSN 0918-8959

Chronic kidney disease (CKD) impairs physical performance in humans, which leads to a risk of all-cause mortality. In our previous study, we demonstrated that a reduction in muscle mitochondria rather than muscle mass was a major cause of physical decline in 5/6 nephrectomized CKD model mice. Because ghrelin administration has been reported to enhance oxygen utilization in skeletal muscle, we examined the usefulness of ghrelin for a recovery of physical decline in 5/6 nephrectomized C57Bl/6 mice, focusing on the epigenetic modification of peroxisome proliferator activated receptor gamma coactivator-1alpha (PGC-1alpha), a master regulator of mitochondrial biogenesis. The mice were intraperitoneally administered acylated ghrelin (0.1 nmol/gBW; three times per week) for a month. Muscle strength and exercise endurance were measured by using a dynamometer and treadmill, respectively. Mitochondrial DNA copy number was determined by quantitative PCR. The methylation levels of the cytosine residue at 260 base pairs upstream of the translation initiation point (C-260) of PGC-1alpha, which has been demonstrated to decrease the expression, was evaluated by methylation-specific PCR and bisulfite genomic sequencing methods after the ghrelin administration. Ghrelin administration improved both muscle strength and exercise endurance in the mice and was associated with an increase in muscle mass and muscle mitochondrial content. Ghrelin administration decreased the methylation ratio of C-260 of PGC-1alpha in the skeletal muscle and increased the expression. Therefore, ghrelin administration effectively reduced the physical decline in 5/6 nephrectomized mice and was accompanied with an increased mitochondrial content through de-methylation of the promoter region of PGC-1alpha in the muscle.

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Treatment of diabetic mice with the SGLT2 inhibitor TA-1887 antagonizes diabetic cachexia and decreases mortality

Sugizaki, T., Zhu, S., Guo, G., Matsumoto, A., Zhao, J., Endo, M., Horiguchi, H., Morinaga, J., Tian, Z., Kadomatsu, T., Miyata, K., Itoh, H. and Oike, Y.

NPJ Aging Mech Dis 3 12 2017年

ISSN 2056-3973

A favorable effect of an inhibitor of the sodium-glucose cotransporter 2 (SGLT2i) on mortality of diabetic patients was recently reported, although mechanisms underlying that effect remained unclear. Here, we examine SGLT2i effects on survival of diabetic mice and assess factors underlying these outcomes. To examine SGLT2i treatment effects in a model of severe diabetes, we fed genetically diabetic db/db mice a high-fat diet and then assessed outcomes including diabetic complications between SGLT2i TA-1887-treated and control mice. We also compare effects of SGLT2i TA-1887 with those of lowering blood glucose levels via insulin treatment. Untreated db/db mice showed remarkable weight loss, or cachexia, while TA-1887-treated mice did not but rather continued to gain weight at later time points and decreased mortality. TA-1887 treatment prevented pancreatic beta cell death, enhanced preservation of beta cell mass and endogenous insulin secretion, and increased insulin sensitivity. Moreover, TA-1887 treatment attenuated inflammation, oxidative stress, and cellular senescence, especially in visceral white adipose tissue, and antagonized endothelial dysfunction. Insulin treatment of db/db mice also prevented weight loss and antagonized inflammation and oxidative stress. However, insulin treatment had less potent effects on survival and prevention of cellular senescence and endothelial dysfunction than did TA-1887 treatment. SGLT2i treatment prevents diabetic cachexia and death by preserving function of beta cells and insulin target organs and attenuating complications. SGLT2i treatment may be a promising therapeutic strategy for type 2 diabetes patients with morbid obesity and severe insulin resistance.

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The short chain fatty acid receptor GPR43 regulates inflammatory signals in adipose tissue M2-type macrophages

Nakajima, A., Nakatani, A., Hasegawa, S., Irie, J., Ozawa, K., Tsujimoto, G., Suganami, T., Itoh, H. and Kimura, I.

PLoS One 12 （ 7 ） e0179696 2017年

ISSN 1932-6203

The regulation of inflammatory responses within adipose tissue by various types of immune cells is closely related to tissue homeostasis and progression of metabolic disorders such as obesity and type 2 diabetes. G-protein-coupled receptor 43 (GPR43), which is activated by short-chain fatty acids (SCFAs), is known to be most abundantly expressed in white adipose tissue and to modulate metabolic processes. Although GPR43 is also expressed in a wide variety of immune cells, whether and how GPR43 in adipose tissue immune cells regulates the inflammatory responses and metabolic homeostasis remains unknown. In this study, we investigated the role of GPR43 in adipose tissue macrophages by using Gpr43-deficient mice and transgenic mice with adipose-tissue-specific overexpression of GPR43. We found that GPR43 activation by SCFA resulted in induction of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) in anti-inflammatory M2-type macrophages within adipose tissue. By contrast, this effect was not noted in inflammatory M1-type macrophages, suggesting that GPR43 plays distinct functions depending on macrophage types. Local TNF-alpha signaling derived from steady-state adipose tissue is associated with proper tissue remodeling as well as suppression of fat accumulation. Thus, GPR43-involving mechanism that we have identified supports maintenance of adipose tissue homeostasis and increase in metabolic activity. This newly identified facet of GPR43 in macrophages may have clinical implications for immune-metabolism related episodes.

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L-Carnitine improves gastrointestinal disorders and altered the intestinal microbiota in hemodialysis patients

Irie, J., Kanno, Y., Kikuchi, R., Yoshida, T., Murai, S., Watanabe, M., Itoh, H. and Hayashi, M.

Biosci Microbiota Food Health 36 （ 1 ） 11 - 16 2017年

ISSN 2186-6953

Patients receiving hemodialysis also manifest gastrointestinal symptoms, such as constipation, caused by restriction of water intake and the loss of body water balance. Because dietary carnitine deficiency is considered to cause smooth muscle dysmotility of the gastrointestinal tract similarly to that in skeletal muscles, carnitine deficiency in hemodialysis patients may be one cause of gastrointestinal discomfort and dysfunctions. We performed a multicenter nonrandomized single-arm prospective clinical trial. Fifteen Japanese patients receiving hemodialysis were administered L-carnitine tablets (900 mg) for 3 months, and clinical and biochemical analyses were performed before and after treatment. The serum total carnitine level was increased significantly by supplementation with L-carnitine for 3 months (from 40.9 +/- 2.6 mumol/l to 172.3 +/- 19.0 mumol/l, p<0.05). The myasthenia score was decreased significantly by the supplementation (from 1.3 +/- 0.3 to 0.8 +/- 0.2, p<0.05). The frequency of passing stool tended to increase with the treatment for 3 months (from 4.2 +/- 0.5 times/week to 4.8 +/- 0.5 times/week). A phyla-level analysis of the microbiota showed that the composition of the individual microbiota was not different between before and after supplementation. A genus-level analysis, however, revealed that the relative abundance of genus Clostridium subcluster 4 was significantly decreased by the supplementation (from 7.7 +/- 1.9% to 4.7 +/- 1.3%, p<0.05). Oral supplementation of L-carnitine to the patients receiving hemodialysis improved not only their muscle discomfort but also their gastrointestinal disorders and microbiota, although its effect on the prognosis of hemodialysis patients should be further investigated.

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[Aging and homeostasis. Age-associated diseases and clinical application of NMN(Nicotinamide Mononucleotide).]

Irie, J. and Itoh, H.

Clin Calcium 27 （ 7 ） 983 - 990 2017年

ISSN 0917-5857

Sirtuins are NAD+-dependent deacetylase and have drawn much attention as important regulators of aging and longevity. Because NAD+ decline during the aging process, the approach to regulating aging using NAD+ precursor such as nicotinamide mononucleotide (NMN) to replenish cellular NAD+ through the activation of sirtuins have been investigated. In various animal models, NMN has been shown to mitigate age-associated physiological changes in liver, adipose tissue, muscle, pancreas, kidney, retina, and central nerve system. In animal models of metabolic diseases, NMN has been demonstrated to improve obesity, insulin resistance, and muscle mitochondrial dysfunction. In this review, recent findings in the NMN research will be summarized, and the potential of NMN on the regulation of age-associated diseases in humans will be discussed.

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Relationships between Composition of Major Fatty Acids and Fat Distribution and Insulin Resistance in Japanese

Fujii, C., Kawai, T., Azuma, K., Oguma, Y., Katsukawa, F., Hirose, H., Tanaka, K., Meguro, S., Matsumoto, H. and Itoh, H.

J Diabetes Res 2017 1567467 2017年

Objective. The aim of this study was to evaluate the relationships between the composition of free fatty acids (FFAs) and metabolic parameters, including body fat distribution, in Japanese. Methods. The study subjects were 111 Japanese patients (54 males, 57 females). Metabolic parameters and visceral and subcutaneous fat areas as determined by CT scanning at the umbilical level were measured. Glucose tolerance test (GTT) was performed by administering 75 g glucose orally. Results. The percentage of linoleic acid (C18:2), the greatest constituent among FFAs, was negatively correlated with visceral fat area (r = -0.411, p < 0.0001), fasting glucose (r = -0.330, p < 0.0001), HbA1c (r = -0.231, p = 0.0146), and systolic blood pressure (r = -0.224, p = 0.0184). Linoleic acid percentage was also significantly negatively correlated with HOMA-IR (r = -0.416, p < 0.0001) by simple correlation. Based on the findings of OGTT, the 111 subjects were classified into three groups: 33 with normal glucose tolerance, 71 with impaired glucose tolerance (IGT), and 7 diabetic subjects. The percentage of serum linoleic acid in diabetic subjects was significantly lower than that in normal subjects. Conclusion. We conclude that serum linoleic acid level is negatively correlated with the accumulation of visceral fat in relation to a reduction of insulin resistance in Japanese subjects.

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One-year eGFR decline rate is a good predictor of prognosis of renal failure in patients with type 2 diabetes.

Nojima J, Meguro S, Ohkawa N, Furukoshi M, Kawai T, Itoh H

Proceedings of the Japan Academy. Series B, Physical and biological sciences 93 （ 9 ） 746 - 754 2017年

ISSN 0386-2208

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Generation of kidney tubular organoids from human pluripotent stem cells

Yamaguchi, S., Morizane, R., Homma, K., Monkawa, T., Suzuki, S., Fujii, S., Koda, M., Hiratsuka, K., Yamashita, M., Yoshida, T., Wakino, S., Hayashi, K., Sasaki, J., Hori, S. and Itoh, H.

Sci Rep 6 38353 2016年12月

ISSN 2045-2322

Recent advances in stem cell research have resulted in methods to generate kidney organoids from human pluripotent stem cells (hPSCs), which contain cells of multiple lineages including nephron epithelial cells. Methods to purify specific types of cells from differentiated hPSCs, however, have not been established well. For bioengineering, cell transplantation, and disease modeling, it would be useful to establish those methods to obtain pure populations of specific types of kidney cells. Here, we report a simple two-step differentiation protocol to generate kidney tubular organoids from hPSCs with direct purification of KSP (kidney specific protein)-positive cells using anti-KSP antibody. We first differentiated hPSCs into mesoderm cells using a glycogen synthase kinase-3beta inhibitor for 3 days, then cultured cells in renal epithelial growth medium to induce KSP+ cells. We purified KSP+ cells using flow cytometry with anti-KSP antibody, which exhibited characteristics of all segments of kidney tubular cells and cultured KSP+ cells in 3D Matrigel, which formed tubular organoids in vitro. The formation of tubular organoids by KSP+ cells induced the acquisition of functional kidney tubules. KSP+ cells also allowed for the generation of chimeric kidney cultures in which human cells self-assembled into 3D tubular structures in combination with mouse embryonic kidney cells.

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Nonalbuminuric Renal Insufficiency: Can It Be a Novel Category of Diabetic Nephropathy?

Tanaka, M. and Itoh, H.

Endocrinol Metab (Seoul) 31 （ 4 ） 533 - 534 2016年12月

ISSN 2093-596X

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Obesity-induced kidney injury is attenuated by amelioration of aberrant PHD2 activation in proximal tubules

Futatsugi, K., Tokuyama, H., Shibata, S., Naitoh, M., Kanda, T., Minakuchi, H., Yamaguchi, S., Hayashi, K., Minamishima, Y. A., Yanagita, M., Wakino, S. and Itoh, H.

Sci Rep 6 36533 2016年11月

ISSN 2045-2322

The involvement of tissue ischemia in obesity-induced kidney injury remains to be elucidated. Compared with low fat diet (LFD)-mice, high fat diet (HFD)-fed mice became obese with tubular enlargement, glomerulomegaly and peritubular capillary rarefaction, and exhibited both tubular and glomerular damages. In HFD-fed mice, despite the increase in renal pimonidazole-positive areas, the expressions of the hypoxia-responsive genes such as Prolyl-hydroxylase PHD2, a dominant oxygen sensor, and VEGFA were unchanged indicating impaired hypoxic response. Tamoxifen inducible proximal tubules (PT)-specific Phd2 knockout (Phd2-cKO) mice and their littermate control mice (Control) were created and fed HFD or LFD. Control mice on HFD (Control HFD) exhibited renal damages and renal ischemia with impaired hypoxic response compared with those on LFD. After tamoxifen treatment, HFD-fed knockout mice (Phd2-cKO HFD) had increased peritubular capillaries and the increased expressions of hypoxia responsive genes compared to Control HFD mice. Phd2-cKO HFD also exhibited the mitigation of tubular damages, albuminuria and glomerulomegaly. In human PT cells, the increased expressions of hypoxia-inducible genes in hypoxic condition were attenuated by free fatty acids. Thus, aberrant hypoxic responses due to dysfunction of PHD2 caused both glomerular and tubular damages in HFD-induced obese mice. Phd2-inactivation provides a novel strategy against obesity-induced kidney injury.

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Corrigendum to "Placental (pro)renin receptor expression and plasma soluble (pro)renin receptor levels in preeclampsia" [YPLAC 37C (2016) 72-78]

Nartita, T., Ichihara, A., Matsuoka, K., Takai, Y., Bokuda, K., Morimoto, S., Itoh, H. and Seki, H.

Placenta 47 130 2016年11月

ISSN 0143-4004

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The role of short-chain fatty acid on blood pressure regulation

Miyamoto, J., Kasubuchi, M., Nakajima, A., Irie, J., Itoh, H. and Kimura, I.

Curr Opin Nephrol Hypertens 25 （ 5 ） 379 - 83 2016年09月

ISSN 1062-4821

PURPOSE OF REVIEW: The gut microbiota and its metabolites have been implicated in the regulation of host physiological functions such as inflammatory and metabolic responses. The short-chain fatty acid (SCFA) receptor is expressed in the kidney and blood vessels as well, and has been reported to function as a regulator of blood pressure (BP). This review highlights the role of SCFAs derived from gut microbial fermentation in the regulation of BP. RECENT FINDINGS: Olfactory receptor 78 (Olfr78) is a member of the G-protein-coupled receptor family, and it plays a key role as a chemosensor in various tissues. Both Olfr78 and G protein-coupled receptor 41 (GPR41) are expressed in smooth muscle cells of blood vessels and they recognize SCFAs. Oral administration of SCFAs was found to change BP in vivo, an effect that was altered in Olfr78 and GPR41-deficient mice. SUMMARY: The regulation of BP via SCFA receptors has provided new insights into the interactions between the gut microbiota and BP control systems. We summarize these interactions and describe their contributions to a novel pathway involved in BP regulation. These recent findings could open new avenues for the development of therapeutic strategies for the treatment of cardiovascular diseases.

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Colonic Pro-inflammatory Macrophages Cause Insulin Resistance in an Intestinal Ccl2/Ccr2-Dependent Manner

Kawano, Y., Nakae, J., Watanabe, N., Kikuchi, T., Tateya, S., Tamori, Y., Kaneko, M., Abe, T., Onodera, M. and Itoh, H.

Cell Metab 24 （ 2 ） 295 - 310 2016年08月

ISSN 1550-4131

High-fat diet (HFD) induces low-grade chronic inflammation and insulin resistance. However, little is known about the mechanism underlying HFD-induced chronic inflammation in peripheral insulin-responsive tissues. Here, we show that colonic pro-inflammatory macrophages regulate insulin sensitivity under HFD conditions. To investigate the pathophysiological role of colonic macrophages, we generated macrophage-specific chemokine (C-C Motif) receptor 2 (Ccr2) knockout (M-Ccr2KO) and intestinal epithelial cell-specific tamoxifen-inducible Ccl2 knockout (Vil-Ccl2KO) mice. Both strains exhibited similar body weight to control under HFD. However, they exhibited decreased infiltration of colonic pro-inflammatory macrophages, decreased intestinal permeability, and inactivation of the colonic inflammasome. Interestingly, they showed significantly improved glucose tolerance and insulin sensitivity with decreased chronic inflammation of adipose tissue. Therefore, inhibition of pro-inflammatory macrophage infiltration prevents HFD-induced insulin resistance and could be a novel therapeutic approach for type 2 diabetes.

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Dysbiosis in the Pathophysiology of Coronary Artery Disease

Irie, J. and Itoh, H.

J Atheroscler Thromb 23 （ 8 ） 901 - 2 2016年08月

ISSN 1340-3478

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Rationale and Design of the Standard Versus Intensive Statin Therapy for Hypercholesterolemic Patients with Diabetic Retinopathy (EMPATHY) Study: a Randomized Controlled Trial

Ueshima, K., Itoh, H., Kanazawa, N., Komuro, I., Nagai, R., Takeuchi, M. and Yamazaki, T.

J Atheroscler Thromb 23 （ 8 ） 976 - 90 2016年08月

ISSN 1340-3478

AIM: Hyperlipidemia and diabetic retinopathy increase the risk of cardiovascular disease (CVD). The standard versus intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) study examines whether intensive lipid-lowering therapy is superior to standard therapy in reducing the incidence of cardiovascular events in patients with hyperlipidemia and diabetic retinopathy, but without a history of coronary artery disease. METHODS: Patients who had elevated low-density lipoprotein cholesterol (LDL-C) and diabetic retinopathy without a history of coronary artery disease were eligible for the study. Patients were randomly assigned in a 1:1 ratio to receive intensive or standard therapy. Patients are being treated with monotherapy with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin) for a maximum of 5.5 years to achieve the following LDL-C target: 70 mg/dL for the intensive therapy group or >/=100 and 120 mg/dL for the standard therapy group. The primary endpoint is a composite of incidence of CVD and death from CVD. RESULTS: Between May 2010 and October 2013, 5,995 patients were assessed for eligibility, and 5,144 were assigned to the study treatment (2,571 and 2,573 in the intensive and standard therapy groups, respectively), and baseline data were analyzed from 5,107 (2,550 in the intensive therapy group and 2,557 in the standard therapy group). CONCLUSIONS: This is the first study assessing the benefits of intensive statin therapy in patients with hypercholesterolemia and diabetic retinopathy in a primary prevention setting. Furthermore, this study evaluates the appropriateness of the treat-to-target approach because all patients are treated to achieve specific LDL-C targets by titrating statin therapy. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000003486.

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Effects of Obesity and Diabetes on alpha- and beta-Cell Mass in Surgically Resected Human Pancreas

Inaishi, J., Saisho, Y., Sato, S., Kou, K., Murakami, R., Watanabe, Y., Kitago, M., Kitagawa, Y., Yamada, T. and Itoh, H.

J Clin Endocrinol Metab 101 （ 7 ） 2874 - 82 2016年07月

ISSN 0021-972

CONTEXT: The ethnic difference in beta-cell regenerative capacity in response to obesity may be attributable to different phenotypes of type 2 diabetes among ethnicities. OBJECTIVE: This study aimed to clarify the effects of diabetes and obesity on beta- (BCM) and alpha-cell mass (ACM) in the Japanese population. DESIGN, SETTING, AND PARTICIPANTS: We obtained the pancreases of 99 individuals who underwent pancreatic surgery and whose resected pancreas sample contained adequate normal pancreas for histological analysis. Questionnaires on a family history of diabetes and history of obesity were conducted in 59 patients. Pancreatic sections were stained for insulin or glucagon, and fractional beta- and alpha-cell area were measured. Islet size and density as well as beta-cell turnover were also quantified. RESULTS: In patients with diabetes, BCM was decreased by 46% compared with age- and body mass index-matched nondiabetic patients (1.48% +/- 1.08% vs 0.80% +/- 0.54%, P < .001), whereas there was no difference in ACM between the groups. There was no effect of obesity or history of obesity on BCM and ACM irrespective of the presence or absence of diabetes. There was a negative correlation between BCM, but not ACM, and glycated hemoglobin before and after pancreatic surgery. In addition, reduced BCM was observed in patients with pancreatic cancer compared with those with other pancreatic tumors. CONCLUSIONS: These findings suggest that the increase in BCM in the face of insulin resistance is extremely limited in the Japanese, and BCM rather than ACM has a major role in regulating blood glucose level in humans.

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Combination of 5-aminolevulinic acid and ferrous ion reduces plasma glucose and hemoglobin A1c levels in Zucker diabetic fatty rats

Hara, T., Koda, A., Nozawa, N., Ota, U., Kondo, H., Nakagawa, H., Kamiya, A., Miyashita, K., Itoh, H., Nakajima, M. and Tanaka, T.

FEBS Open Bio 6 （ 6 ） 515 - 28 2016年06月

ISSN 2211-5463

Mitochondrial dysfunction is associated with type 2 diabetes mellitus (T2DM). 5-Aminolevulinic acid (ALA), a natural amino acid produced only in the mitochondria, is a precursor of heme. Cytochromes that contain heme play an important role in aerobic energy metabolism. Thus, ALA may help reduce T2DM-associated hyperglycemia. In this study, we investigated the effect of ALA combined with sodium ferrous citrate (SFC) on hyperglycemia in Zucker diabetic fatty (ZDF) rats. We found that the gavage administration of ALA combined with SFC (ALA/SFC) for 6 weeks reduced plasma glucose and hemoglobin A1c (HbA1c) levels in rats without affecting plasma insulin levels. The glucose-lowering effect depended on the amount of ALA/SFC administered per day. Furthermore, the glucose tolerance was also significantly improved by ALA/SFC administration. Although food intake was slightly reduced in the rats administered ALA/SFC, there was no effect on their body weight. Importantly, ALA/SFC administration induced heme oxygenase-1 (HO-1) expression in white adipose tissue and liver, and the induced expression levels of HO-1 correlated with the glucose-lowering effects of ALA/SFC. Taken together, these results suggest that ALA combined with ferrous ion is effective in reducing hyperglycemia of T2DM without affecting plasma insulin levels. HO-1 induction may be involved in the mechanisms underlying the glucose-lowering effect of ALA/SFC.

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miR-363 induces transdifferentiation of human kidney tubular cells to mesenchymal phenotype

Morizane, R., Fujii, S., Monkawa, T., Hiratsuka, K., Yamaguchi, S., Homma, K. and Itoh, H.

Clin Exp Nephrol 20 （ 3 ） 394 - 401 2016年06月

ISSN 1342-1751

BACKGROUND: microRNAs (miRNAs) are non-coding small RNAs that regulate embryonic development, cell differentiation and pathological processes via interaction with mRNA. Epithelial-mesenchymal transition (EMT) is pathological process that involves in a variety of diseases such as cancer or fibrosis. METHODS: In this study, we identified miR-363 as a potent inducer of EMT by microarray analysis in human kidney tubular cells, and analyzed the function and mechanisms of miR-363. RESULTS: Overexpression of miR-363 induced mesenchymal phenotypes with loss of epithelial phenotypes in human kidney tubular cells. In addition, in vitro scratch assay demonstrated that miR-363 promotes cell migration of primary culture of human kidney tubular cells. We identified TWIST/canonical WNT pathway as the downstream effecter of miR-363, and inhibition of canonical WNT by small molecule, IWR-1, attenuated EMT induced by miR-363. CONCLUSION: miR-363 induces transdifferentiation of human kidney tubular cells via upregulation of TWIST/canonical WNT pathway.

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The role of adipose tissue asymmetric dimethylarginine/dimethylarginine dimethylaminohydrolase pathway in adipose tissue phenotype and metabolic abnormalities in subtotally nephrectomized rats

Minakuchi, H., Wakino, S., Hosoya, K., Sueyasu, K., Hasegawa, K., Shinozuka, K., Yoshifuji, A., Futatsugi, K., Komatsu, M., Kanda, T., Tokuyama, H., Hayashi, K. and Itoh, H.

Nephrol Dial Transplant 31 （ 3 ） 413 - 23 2016年03月

ISSN 0931-0509

BACKGROUND: The lipodystrophy-like phenotype has been suggested in early chronic kidney disease (CKD). It includes adipose tissue atrophy, systemic insulin resistance (IR), dyslipidemia and ectopic lipid accumulation. To elucidate its pathogenesis, we investigated the role of two uremic toxins that affect insulin sensitivity: an endogenous nitric oxide synthase inhibitor, and asymmetric dimethylarginine (ADMA) and indoxyl sulfate (IS). METHODS: Six-week-old Sprague-Dawley rats were rendered CKD by subtotal nephrectomy (Nx) and compared with sham-operated rats. Cultured 3T3-L1 fibroblasts were differentiated into mature adipocytes with or without ADMA. Transgenic (Tg) mice overexpressing each isoform of ADMA degrading enzyme, dimethylarginine dimethylaminohydrolase 1 (DDAH1) and DDAH2 were subject to Nx and their phenotypes were investigated. RESULTS: In Nx rats, IR was evident and insulin stimulation failed to activate insulin signaling in adipose tissues. Adipose tissue weight, adipocyte size and adipocyte differentiation marker expressions decreased as a consequence of IR in Nx. Tissue lipid content in the liver and muscle increased in Nx rats. Tissue levels of ADMA, IS and oxidative stress increased in the adipose tissue of Nx rats. Both DDAH1 and DDAH2 expressions decreased, and a putative IS receptor, aryl hydrocarbon receptor, expression increased in the adipose tissue of Nx rats. ADMA inhibited adipocyte differentiation, triglyceride accumulation and insulin signaling, which were reversed by pretreatment with cGMP. In each type of Tg mice overexpressing DDAH1 or DDAH2, all lipodystrophy-like phenotypes induced by Nx were reversed. CONCLUSIONS: In mild CKD, dysregulation of the ADMA/DDAH pathway in adipose tissue triggers lipodystrophy-like phenotype changes, including ectopic fat depositions.

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Gut Lactobacillus protects against the progression of renal damage by modulating the gut environment in rats

Yoshifuji, A., Wakino, S., Irie, J., Tajima, T., Hasegawa, K., Kanda, T., Tokuyama, H., Hayashi, K. and Itoh, H.

Nephrol Dial Transplant 31 （ 3 ） 401 - 12 2016年03月

ISSN 0931-0509

BACKGROUND: The role of gut microbiota in the progression of chronic kidney disease (CKD) has not been fully elucidated. METHODS: Renal failure was induced in 6-week-old spontaneously hypertensive rats by 5/6 nephrectomy (Nx). We analyzed the gut microbiota population to identify the relevant species potentially involved in inducing renal damage. Human colon Caco-2 cells were used to delineate the mechanism involved in the molecular changes in the gut of Nx rats. RESULTS: Nx rats showed an increase in Bacteroides (Bact) and a decrease in Lactobacillus (Lact) species compared with sham-operated rats. Lact, but not Bact, populations were significantly associated with urinary protein excretion. Treatment of Nx rats with 1 x 10(10) CFU/kg/day Lact ameliorated increased urinary protein excretion and higher serum levels of the uremic toxins, indoxyl sulfate and p-cresyl sulfate, and serum urea nitrogen levels. Lact also attenuated systemic inflammation in Nx rats, as evaluated by serum lipopolysaccharide, interleukin-6 and C-reactive protein levels. Histologically, renal sclerosis in Nx rats was restored by Lact treatment. A reduction in the expression of tight junction proteins and the Toll-like receptor 2 (TLR2), a putative Lact receptor, in the colons of Nx rats were mitigated by Lact. Treatment of Caco-2 cells with indole downregulated tight junction protein expression, which was abolished by exposure to Lact. The effects of Lact were reversed by treatment with OxPAPC, a TLR inhibitor. Similarly, the increase in the permeability of the Caco-2 cell monolayer was reversed by the administration of Lact. Lact upregulated TLR2 expression in Caco-2 cells. Lact also attenuated the increase in serum indoxyl sulfate and urea levels and urinary protein excretion in Nx rats even in the pseudogerm-free environment. CONCLUSIONS: Lact supplementation mitigated the systemic inflammation and proteinuria associated with renal failure, suggesting that in the gut microbiota, Lact plays a protective role against the progression of CKD.

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Intestinal Bile Acid Composition Modulates Prohormone Convertase 1/3 (PC1/3) Expression and Consequent GLP-1 Production in Male Mice

Morimoto, K., Watanabe, M., Sugizaki, T., Irie, J. and Itoh, H.

Endocrinology 157 （ 3 ） 1071 - 81 2016年03月

ISSN 0013-7227

Besides an established medication for hypercholesterolemia, bile acid binding resins (BABRs) present antidiabetic effects. Although the mechanisms underlying these effects are still enigmatic, glucagon-like peptide-1 (GLP-1) appears to be involved. In addition to a few reported mechanisms, we propose prohormone convertase 1/3 (PC1/3), an essential enzyme of GLP-1 production, as a potent molecule in the GLP-1 release induced by BABRs. In our study, the BABR colestimide leads to a bile acid-specific G protein-coupled receptor TGR5-dependent induction of PC1/3 gene expression. Here, we focused on the alteration of intestinal bile acid composition and consequent increase of total TGR5 agonistic activity to explain the TGR5 activation. Furthermore, we demonstrate that nuclear factor of activated T cells mediates the TGR5-triggered PC1/3 gene expression. Altogether, our data indicate that the TGR5-dependent intestinal PC1/3 gene expression supports the BABR-stimulated GLP-1 release. We also propose a combination of BABR and dipeptidyl peptidase-4 inhibitor in the context of GLP-1-based antidiabetic therapy.

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Placental (pro)renin receptor expression and plasma soluble (pro)renin receptor levels in preeclampsia

Nartita, T., Ichihara, A., Matsuoka, K., Takai, Y., Bokuda, K., Morimoto, S., Itoh, H. and Seki, H.

Placenta 37 72 - 8 2016年01月

ISSN 0143-4004

INTRODUCTION: The prorenin receptor ((P)RR) contributes to the regulation of the tissue renin-angiotensin system (RAS) and the function of V-ATPase, which are essential for Wnt signaling. Thus, (P)RRs may be involved in the control both of feto-placental and maternal circulation during pregnancy. This study was conducted to clarify how placental (P)RR expression and plasma soluble (P)RR [s(P)RR] levels are associated with blood pressure elevations and renal function during pregnancy. METHODS: We conducted a cross-sectional study, conducted at Saitama medical center in 2010-2013. Preeclamptic women (n = 16) diagnosed according to the criteria of Japan Society of Obstetrics and Gynecology and normotensive pregnant women (n = 15) participated in the study. We measured the expression of (P)RR in the placenta, plasma s(P)RR levels, systolic blood pressure (SBP), and estimated glomerular filtration rate (eGFR). RESULTS: Placental expression of (P)RR was significantly higher in preeclamptic women than in normotensive pregnant women. The plasma s(P)RR levels were significantly higher in preeclamptic women than in normotensive pregnant women. Systolic blood pressure (SBP) was positively correlated with placental (P)RR levels (P = 0.0001) and plasma s(P)RR levels (P = 0.005) in all pregnant women. In preeclamptic women, SBP was positively correlated with placental (P)RR levels (P = 0.004), but not with plasma s(P)RR levels (P = 0.15). The eGFR was negatively correlated with placental (P)RR levels (P = 0.02) and plasma s(P)RR levels (P = 0.0002) in all pregnant women. In preeclamptic women, eGFR was negatively correlated with plasma s(P)RR levels (P = 0.006), but not with placental (P)RR levels (P = 0.93). DISCUSSION: Placental (P)RR can be involved in blood pressure regulation via the tissue RAS. On the other hand, plasma s(P)RR may be involved in the pathogenesis of decreased renal function in preeclampsia.

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Time-dependent changes in insulin requirement for maternal glycemic control during antenatal corticosteroid therapy in women with gestational diabetes: a retrospective study

Itoh, A., Saisho, Y., Miyakoshi, K., Fukutake, M., Kasuga, Y., Ochiai, D., Matsumoto, T., Tanaka, M. and Itoh, H.

Endocr J 63 （ 1 ） 101 - 4 2016年

ISSN 0918-8959

Though recommended for pregnant women at risk of preterm birth to improve perinatal outcomes, antenatal corticosteroid (ACS) treatment can cause maternal hyperglycemia, especially in cases of glucose intolerance. A standardized protocol for preventing hyperglycemia during ACS treatment remains to be established. We herein retrospectively investigated the time-dependent changes in insulin dose required for maternal glycemic control during ACS treatment in gestational diabetes (GDM). Twelve singleton pregnant women with GDM who received 12 mg of betamethasone intramuscularly twice 24 hours apart were included in this analysis. Of those, eight also received ritodrine hydrochloride for preterm labor. The blood glucose levels were maintained at 70-120 mg/dL with continuous intravenous infusion of insulin and nothing by mouth for 48 hours after the first betamethasone administration. After the first dose of betamethasone, the insulin dosage needed for glycemic control gradually increased and reached a maximum (6.6 +/- 5.8 units/hr) at 10 hours, then, decreased to 4.1 +/- 1.5 units/hr at 24 hours. Similar changes in the insulin requirement were found after the second betamethasone dose (the maximum insulin dosage: 5.5 +/- 1.6 units/hr at 9 hours following the second administration). Women treated with ritodrine hydrochloride needed more insulin, than those without ritodrine hydrochloride treatment (130.8 +/- 15.0 vs. 76.8 +/- 15.2 units/day, respectively, p < 0.05). Our data indicated that the requirement for insulin is highest 9-10 hours after each dose of betamethasone. When GDM is treated with ACS, levels of blood glucose should be carefully monitored, especially in patients treated with ritodrine hydrochloride.

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Palmitic acid-rich diet suppresses glucose-stimulated insulin secretion (GSIS) and induces endoplasmic reticulum (ER) stress in pancreatic islets in mice

Hirata, T., Kawai, T., Hirose, H., Tanaka, K., Kurosawa, H., Fujii, C., Fujita, H., Seto, Y., Matsumoto, H. and Itoh, H.

Endocr Res 41 （ 1 ） 8 - 15 2016年

ISSN 0743-5800

The objective was to clarify whether dietary palmitic acid supplementation affects glucose-stimulated insulin secretion (GSIS) and the endoplasmic reticulum (ER) stress pathway in pancreatic islets in mice. Eight-week-old male C57BL/6J mice were randomly divided into three treatment diet groups: control diet, palmitic acid-supplemented diet (PAL) and oleic acid-supplemented diet (OLE). After 2 weeks of treatment, intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test were performed. GSIS was assessed by pancreatic perfusion in situ with basal (100 mg/dL) glucose followed by a high (300 mg/dL) glucose concentration. We measured mRNA levels of ER stress markers such as C/EBP homologous protein (CHOP), immunoglobulin heavy-chain binding protein (BIP) and X-box binding protein (XBP)-1 using real-time polymerase chain reaction (PCR) analyses in isolated islets. Immunohistochemical staining was also performed. Mice fed PAL showed significantly decreased glucose tolerance (p < 0.05). In the perfusion study, GSIS was significantly suppressed in the PAL group (p < 0.05). Semi-quantitative RT-PCR revealed that islet CHOP, BIP, and XBP-1 mRNA expression were significantly increased in the PAL group (p < 0.05). TUNEL-positive beta-cells were not detected in all groups. Dietary palmitic acid-supplementation for 2 weeks might suppress GSIS and induce ER stress in pancreatic islets in mice, in the early stage of lipotoxicity.

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DNA Damage and Epigenetic Changes in Kidney Diseases - Focused on Transcription Factors in Podocytes

Hayashi, K., Hishikawa, A. and Itoh, H.

Curr Hypertens Rev 12 （ 2 ） 105 - 11 2016年

ISSN 1573-4021

Recently it has been shown that epigenetic mechanisms are involved in initiation and progression of caridiovascular and metabolic diseases, including diabetes, obesity, atherosclerosis, heart failure, hypertension and kidney diseases. In these chronic diseases, various exogenous and endogenous stresses cause DNA damage, followed by DNA repair process. Accumulation of DNA damages and impaired repair process can lead to epigenetic changes, which may contribute to onset and progression of diseases. Recently we have shown that therapeutic effect of transcription factor KLF4 (Kruppel-like factor 4) in kidney glomerular epithelial cells (podocytes) on proteinuric kidney diseases through epigenetic mechanisms. Our result suggests the possibility of transcription factors as a target of selective epigenetic therapy. Moreover, we have reported that renin-angiotensin system (RAS) blockers, which are widely prescribed for the treatment of cardiovascular diseases, can restore epigenetic changes through KLF4 in part. These results suggest that activation of RAS causes epigenetic changes in disease states, and elucidation of the precise mechanism may lead to establishment of novel therapeutic target of kidney diseases. In this review we focus on DNA damage repair system and epigenetic modulators in disease states, and speculate a candidate for epigenetic therapy of kidney diseases.

Communication from Tubular Epithelial Cells to Podocytes through Sirt1 and Nicotinic Acid Metabolism

Hasegawa, K., Wakino, S., Sakamaki, Y., Muraoka, H., Umino, H., Minakuchi, H., Yoshifuji, A., Naitoh, M., Shinozuka, K., Futatsugi, K., Urai, H., Kanda, T., Tokuyama, H., Hayashi, K. and Itoh, H.

Curr Hypertens Rev 12 （ 2 ） 95 - 104 2016年

ISSN 1573-4021

We have recently published that tubular epithelial cells affect the podocyte epigenome though nicotinic acid metabolism in diabetic nephropathy (DN), and we have named this relationship "proximal tubule-podocyte communication". In this review, we describe this novel mechanism in the early stage of DN, focusing on the function of renal tubular Sirt1 and Sirt1-related nicotinic acid metabolism. Mainly, we discuss the following three findings. First, we described the details of proximal tubule-podocyte communication. Second, we explained how Sirt1 regulates albuminuria via epigenetic mechanisms. This means that repeated high glucose stress triggers the initial changes in proximal tubules, which lead to the epigenetically irreversible glomerular damages. However, proximal tubular Sirt1 overexpression can rescue these changes. Our previous data indicated that the decrease in Sirt1 expression in proximal tubules caused the reduction in glomerular Sirt1 and the subsequent increase in glomerular Claudin-1. It seemed plausible that some humoral mediator is released from proximal tubules, migrates to podocytes and glomeruli, and affects Sirt1 expression in podocytes. Third, we mentioned a mediator connecting this communication, nicotinamide mononucleotide (NMN). We suggest the potential of Sirt1 or NMN as not only a therapeutic target but also as a prognostic marker of very early stage DN.

Adrenal Insufficiency under Standard Dosage of Glucocorticoid Replacement after Unilateral Adrenalectomy for Cushing's Syndrome

Fujii, K., Miyashita, K., Kurihara, I., Hiratsuka, K., Sato, S., Yokota, K., Kobayashi, S., Shibata, H. and Itoh, H.

Case Rep Endocrinol 2016 2347528 2016年

ISSN 2090-6501

Glucocorticoid replacement is needed for patients after adrenal surgery for Cushing's syndrome; however, the adequate dosage is not easily determined. The patient was a 62-year-old woman who has had hypertension for 5 years and presented with heart failure due to hypertrophic cardiomyopathy. She consulted with us because of general fatigue, facial edema, and muscle weakness and was diagnosed with Cushing's syndrome. A laparoscopic left adrenalectomy was performed, standard dosage of postoperative replacement was administered, and she was discharged with 30 mg/day of hydrocortisone (cortisol). However, she suffered from loss of appetite and was transferred to an emergency unit with the symptoms of adrenal insufficiency on postoperative day 15. After initial hydrocortisone replacement with 200 mg/day, the dosage was gradually decreased during hospitalization; however, reduction of hydrocortisone dosage lower than 60 mg/day was difficult because of nausea and fatigue. Her circadian cortisol profile after hydrocortisone administration showed delayed and lowered peaks, which suggested that hydrocortisone absorption in the intestine was impaired. Therefore, complicated heart failure may have led to the adrenal insufficiency in the patient. In such cases, we should consider postoperative administration of more than the standard dosage of hydrocortisone to avoid adrenal insufficiency after surgery for Cushing's syndrome.

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A case of severe osteomalacia caused by Tubulointerstitial nephritis with Fanconi syndrome in asymptomotic primary biliary cirrhosis

Yamaguchi, S., Maruyama, T., Wakino, S., Tokuyama, H., Hashiguchi, A., Tada, S., Homma, K., Monkawa, T., Thomas, J., Miyashita, K., Kurihara, I., Yoshida, T., Konishi, K., Hayashi, K., Hayashi, M. and Itoh, H.

BMC Nephrol 16 187 2015年11月

ISSN 1471-2369

BACKGROUND: Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease, characterized by increased concentrations of serum IgM and the presence of circulating anti-mitochondrial antibodies. Although bone diseases such as osteoporosis or osteodystrophy are commonly associated with PBC, osteomalacia which is caused by abnormal vitamin D metabolism, mineralization defects, and phosphate deficiency has not been recognized as a complication of PBC. CASE PRESENTATION: We report the case of a 49-year-old Japanese woman who complained of multiple fractures. Hypophosphatemic osteomalacia was diagnosed from a low serum phosphorus level, 1,25-dihydroxyvitamin D3 level, high levels of bone specific alkaline phosphatase and the findings of bone scintigraphy, although a bone biopsy was not performed. Twenty four hour urine demonstrated a low renal fractional tubular reabsorption of phosphate, increased fractional excretion of uric acid and generalized aminoaciduria. An intravenous bicarbonate loading test suggested the presence of proximal renal tubular acidosis (RTA). These biochemical data indicated Fanconi syndrome with proximal RTA. A kidney biopsy demonstrated the features of tubulointerstitial nephritis (TIN). The patient was also suspected as having primary biliary cirrhosis (PBC) because of high levels of alkaline phosphatase, IgM and the presence of anti-mitochondrial M2 antibody, though biochemical liver function was normal. Sequential liver biopsy was compatible with PBC and the diagnosis of PBC was definite. After administration of 1,25 dihydroxyvitamin D3, neutral potassium phosphate, sodium bicarbonate for osteomalacia and subsequent predonizolone for TIN, symptoms of fractures were relieved and renal function including Fanconi syndrome was ameliorated. CONCLUSION: In this case, asymptomatic PBC was shown to induce TIN with Fanconi syndrome with dysregulation of electrolytes and vitamin D metabolism, which in turn led to osteomalacia with multiple fractures. Osteomalacia has not been recognized as a result of the renal involvement of PBC. PBC and its rare complication of TIN with Fanconi syndrome should be considered in adult patients with unexplained osteomalacia even in the absence of liver dysfunction.

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Comparison of the effects of low-dose rosuvastatin on plasma levels of cholesterol and oxidized low-density lipoprotein in 3 ultracentrifugally separated low-density lipoprotein subfractions

Homma, K., Homma, Y., Ozawa, H., Shiina, Y., Shibata, T., Yoshida, T., Hasegawa, K., Kanda, T., Tokuyama, H., Wakino, S., Hayashi, K., Itoh, H. and Hori, S.

J Clin Lipidol 9 （ 6 ） 751 - 757 2015年11月

ISSN 1933-2874

BACKGROUND: Plasma-oxidized (ox) low-density lipoprotein (LDL) is an atherogenic lipoprotein. The distribution of ox-LDL in plasma LDL subfractions and the effect of statins on this distribution have not been investigated in detail. OBJECTIVE: We examined the distribution of cholesterol and ox-LDL in 3 ultracentrifugally separated plasma LDL subfractions and investigated the effects of a statin, rosuvastatin, on the levels of these lipoproteins. MATERIALS AND METHODS: Thirty-one polygenic hypercholesterolemic subjects were included in this study. Levels of cholesterol and ox-LDL in 3 plasma LDL subfractions and plasma levels of remnant-like particle cholesterol, ox-LDL, and adiponectin were measured after 0, 3, 6, and 12 months of treatment with rosuvastatin. Sequential ultracentrifugation was performed to subfractionate plasma lipoproteins. RESULTS: The mean daily dose of rosuvastatin over the 12 months of treatment was 2.9 +/- 1.0 mg (mean +/- standard deviation). The cholesterol subfraction distribution was 43 +/- 10% as low-density LDL, 46 +/- 8% as medium-density LDL, and 13 +/- 5% as high-density LDL. Similarly, the distribution of ox-LDL was 31 +/- 10% as low-density LDL, 48 +/- 7% as medium-density LDL, and 22 +/- 8% as high-density LDL. After 12 months of treatment with rosuvastatin, the level of cholesterol was significantly reduced in all 3 subfractions (P < .0001), as was the level of ox-LDL (P < .0001). Furthermore, the plasma cholesterol level in high-density lipoprotein2 increased significantly. CONCLUSIONS: The distribution of ox-LDL in plasma LDL subfractions was more skewed toward the denser subfractions, compared with cholesterol. Rosuvastatin treatment significantly reduced plasma levels of cholesterol and ox-LDL in all LDL subfractions.

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Serum bilirubin concentration is associated with eGFR and urinary albumin excretion in patients with type 1 diabetes mellitus

Nishimura, T., Tanaka, M., Sekioka, R. and Itoh, H.

J Diabetes Complications 29 （ 8 ） 1223 - 7 2015年11月

ISSN 1056-8727

AIMS: Although relationships of serum bilirubin concentration with estimated glomerular filtration rate (eGFR) and urinary albumin excretion (UAE) in patients with type 2 diabetes have been reported, whether such relationships exist in patients with type 1 diabetes is unknown. METHODS: A total of 123 patients with type 1 diabetes were investigated in this cross-sectional study. The relationship between bilirubin (total and indirect) concentrations and log(UAE) as well as eGFR was examined by Pearson's correlation analyses. Multivariate regression analyses were used to assess the association of bilirubin (total and indirect) with eGFR as well as log(UAE). RESULTS: A positive correlation was found between serum bilirubin concentration and eGFR; total bilirubin (r=0.223, p=0.013), indirect bilirubin (r=0.244, p=0.007). A negative correlation was found between serum bilirubin concentration and log(UAE); total bilirubin (r=-0.258, p=0.005), indirect bilirubin (r=-0.271, p=0.003). Multivariate regression analyses showed that indirect bilirubin concentration was an independent determinant of eGFR and log(UAE). CONCLUSIONS: Bilirubin concentration is associated with both eGFR and log(UAE) in patients with type 1 diabetes. Bilirubin might have a protective role in the progression of type 1 diabetic nephropathy.

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Renin-angiotensin blockade resets podocyte epigenome through Kruppel-like Factor 4 and attenuates proteinuria

Hayashi, K., Sasamura, H., Nakamura, M., Sakamaki, Y., Azegami, T., Oguchi, H., Tokuyama, H., Wakino, S., Hayashi, K. and Itoh, H.

Kidney Int 88 （ 4 ） 745 - 53 2015年10月

ISSN 0085-2538

Proteinuria is a central component of chronic kidney disease and an independent risk factor for cardiovascular disease. Kidney podocytes have an essential role as a filtration barrier against proteinuria. Kruppel-like Factor 4 (KLF4) is expressed in podocytes and decreased in glomerular diseases leading to methylation of the nephrin promoter, decreased nephrin expression and proteinuria. Treatment with an angiotensin receptor blocker (ARB) reduced methylation of the nephrin promoter in murine glomeruli of an adriamycin nephropathy model with recovery of KLF4 expression and a decrease in albuminuria. In podocyte-specific KLF4 knockout mice, the effect of ARB on albuminuria and the nephrin promoter methylation was attenuated. In cultured human podocytes, angiotensin II reduced KLF4 expression and caused methylation of the nephrin promoter with decreased nephrin expression. In patients, nephrin promoter methylation was increased in proteinuric kidney diseases with decreased KLF4 and nephrin expression. KLF4 expression in ARB-treated patients was higher in patients with than without ARB treatment. Thus, angiotensin II can modulate epigenetic regulation in podocytes and ARB inhibits these actions in part via KLF4 in proteinuric kidney diseases. This study provides a new concept that renin-angiotensin system blockade can exert therapeutic effects through epigenetic modulation of the kidney gene expression.

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Sirtuin and metabolic kidney disease

Wakino, S., Hasegawa, K. and Itoh, H.

Kidney Int 88 （ 4 ） 691 - 8 2015年10月

ISSN 0085-2538

Sirtuin is a nicotinamide adenine dinucleotide-dependent deacetylase. One of its isoforms, Sirt1, is a key molecule in glucose, lipid, and energy metabolism. The renal protective effects of Sirt1 are found in various models of renal disorders with metabolic impairment, such as diabetic nephropathy. Protective effects include the maintenance of glomerular barrier function, anti-fibrosis effects, anti-oxidative stress effects, and regulation of mitochondria function and energy metabolism. Various target molecules subject to direct deacetylation or epigenetic gene regulation have been identified as effectors of the renal protective function of sirtuin. Recently, it was demonstrated that Sirt1 expression decreases in proximal tubules before albuminuria in a mouse model of diabetic nephropathy, and that albuminuria is suppressed in proximal tubule-specific mice overexpressing Sirt1. These findings suggest that decreased Sirt1 expression in proximal tubular cells causes abnormal nicotine metabolism and reduces the supply of nicotinamide mononucleotide from renal tubules to glomeruli. This further decreases expression of Sirt1 in glomerular podocytes and increases expression of a tight junction protein, claudin-1, which results in albuminuria. Activators of the sirtuin family of proteins, including resveratrol, may be important in the development of new therapeutic strategies for treating metabolic kidney diseases, including diabetic nephropathy.

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Effects of Liraglutide Monotherapy on Beta Cell Function and Pancreatic Enzymes Compared with Metformin in Japanese Overweight/Obese Patients with Type 2 Diabetes Mellitus: A Subpopulation Analysis of the KIND-LM Randomized Trial

Tanaka, K., Saisho, Y., Manesso, E., Tanaka, M., Meguro, S., Irie, J., Sugiura, H., Kawai, T., Jinzaki, M., Cobelli, C. and Itoh, H.

Clin Drug Investig 35 （ 10 ） 675 - 84 2015年10月

ISSN 1173-2563

BACKGROUND AND OBJECTIVE: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are becoming one of the major therapeutic options for the treatment of type 2 diabetes mellitus (T2DM). This study was conducted as an exploratory analysis to clarify the effects of liraglutide, a GLP-1RA, on beta cell function, fat distribution and pancreas volume compared with metformin in Japanese overweight/obese patients with T2DM. METHODS: A subpopulation of the Keio study for Initial treatment of type 2 Diabetes with Liraglutide versus Metformin (KIND-LM) study participants (n = 20, 10 in oral metformin group and 10 in subcutaneous liraglutide group) who were enrolled at Keio University Hospital and underwent frequently sampled mixed meal tolerance test (MTT) and abdominal computed tomography (CT) at weeks 0 and 24 were included in this analysis. The patients were treated with either metformin or liraglutide throughout the 24-week study period. RESULTS: Changes in glycemic parameters such as glycated hemoglobulin (HbA1c), glycated albumin and 1,5-anhydroglucitol at week 24 were comparable between the groups. An oral minimal model based on MTT revealed that static-phase beta cell responsiveness (Phi s) and static-phase disposition index were significantly increased at week 24 in the liraglutide group but not in the metformin group. There was no significant change in fat distribution as well as body weight at week 24 in either group. Serum amylase and lipase levels modestly but significantly increased in the liraglutide group during the study; however, there was no incidence of pancreatitis and pancreas volume was not changed in the liraglutide group. CONCLUSION: Liraglutide monotherapy for 24 weeks improved beta cell responsiveness with no change in either body weight or fat distribution. Further investigation is needed to clarify the mechanism by which liraglutide increases serum pancreatic enzymes. TRIAL REGISTRATION: The University Hospital Medical Information Network (UMIN) Clinical Trials Registry ( http://www.umin.ac.jp/ctr/ ); UMIN000004243.

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Improvement of Physical Decline Through Combined Effects of Muscle Enhancement and Mitochondrial Activation by a Gastric Hormone Ghrelin in Male 5/6Nx CKD Model Mice

Tamaki, M., Hagiwara, A., Miyashita, K., Wakino, S., Inoue, H., Fujii, K., Fujii, C., Sato, M., Mitsuishi, M., Muraki, A., Hayashi, K., Doi, T. and Itoh, H.

Endocrinology 156 （ 10 ） 3638 - 48 2015年10月

ISSN 0013-7227

Because a physical decline correlates with an increased risk of a wide range of disease and morbidity, an improvement of physical performance is expected to bring significant clinical benefits. The primary cause of physical decline in 5/6 nephrectomized (5/6Nx) chronic kidney disease model mice has been regarded as a decrease in muscle mass; however, our recent study showed that a decrease in muscle mitochondria plays a critical role. In the present study, we examined the effects of a gastric hormone ghrelin, which has been reported to promote muscle mitochondrial oxidation, on the physical decline in the chronic kidney disease model mice, focusing on the epigenetic modulations of a mitochondrial activator gene, peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha). Ghrelin treatment improved a decline in exercise endurance of 5/6Nx mice, associated with an increase in both of the muscle mass and mitochondrial amount. The expression level of PGC-1alpha was decreased in the skeletal muscle of 5/6Nx mice, which was associated with an increase in the methylation ratio of the cytosine residue at 260 base pairs upstream of the initiation point. Conversely, ghrelin treatment de-methylated the cytosine residue and increased the expression of PGC-1alpha. A representative muscle anabolic factor, IGF-1, did not affect the expression of PGC-1alpha and muscle mitochondrial amount, although it increased muscle mass. As a result, IGF-1 treatment in 5/6Nx mice did not increase the decreased exercise endurance as effectively as ghrelin treatment did. These findings indicate an advantage of ghrelin treatment for a recovery of physical decline.

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A large-scale prospective registration study of the safety and efficacy of sorafenib tosylate in unresectable or metastatic renal cell carcinoma in Japan: results of over 3200 consecutive cases in post-marketing all-patient surveillance.

Akaza H, Oya M, Iijima M, Hyodo I, Gemma A, Itoh H, Adachi M, Okayama Y, Sunaya T, Inuyama L

Japanese journal of clinical oncology 45 （ 10 ） 953 - 62 2015年10月

ISSN 0368-2811

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Impact of Switching From Darbepoetin Alfa to Epoetin Beta Pegol on Iron Utilization and Blood Pressure in Peritoneal Dialysis Patients.

Washida N, Inoue S, Kasai T, Shinozuka K, Hosoya K, Morimoto K, Wakino S, Hayashi K, Itoh H

ISSN 1744-9979

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Relationships among different glycemic variability indices obtained by continuous glucose monitoring

Saisho, Y., Tanaka, C., Tanaka, K., Roberts, R., Abe, T., Tanaka, M., Meguro, S., Irie, J., Kawai, T. and Itoh, H.

Prim Care Diabetes 9 （ 4 ） 290 - 6 2015年08月

ISSN 1878-0210

The aim of this study was to assess the relationships among indices of glycemic variability obtained by continuous glucose monitoring (CGM). CGM was performed in 88 patients with diabetes (20 type 1 and 68 type 2 diabetes, age 59 +/- 15 years) admitted to our hospital (Keio University Hospital, Tokyo, Japan) between 2010 and 2012. Mean glucose, glucose standard deviation (SDglu) and other glycemic indices such as index of glycemic control (ICG), J-index, mean of daily differences (MODD), continuous overlapping net glycemic action 1 (CONGA1), mean amplitude of glycemic excursions (MAGE) and M value were calculated from CGM data, and the correlations among these indices were assessed. There were strong correlations between SDglu and the indices MAGE, CONGA1, MODD and M value (all r > 0.8, P < 0.05). On the other hand, mean glucose was strongly correlated with J index and M value (both r > 0.8, P < 0.05). SDglu and other glycemic variability indices were more strongly correlated with hypoglycemia than was mean glucose, and the combination of mean glucose and SDglu was useful for predicting hypoglycemia in patients with diabetes. In this study, we demonstrated the characteristics of various glycemic variability indices in relation to mean glucose and SDglu. This information will help physicians to understand the characteristics of various glycemic variability indices and to select an appropriate index for their purpose. Our results also underpin the importance of glycemic variability in relation to risk of hypoglycemia in patients with diabetes.

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Effects of Glucocorticoid Treatment on beta- and alpha-Cell Mass in Japanese Adults With and Without Diabetes

Sato, S., Saisho, Y., Inaishi, J., Kou, K., Murakami, R., Yamada, T. and Itoh, H.

Diabetes 64 （ 8 ） 2915 - 27 2015年08月

ISSN 0012-1797

The aim of this study was 1) to clarify beta-cell regenerative capacity in the face of glucocorticoid (GC)-induced insulin resistance and 2) to clarify the change in beta- and alpha-cell mass in GC-induced diabetes in humans. We obtained the pancreases from 100 Japanese autopsy case subjects. The case subjects were classified according to whether or not they had received GC therapy before death and the presence or absence of diabetes. Fractional beta-cell area (%BCA) and alpha-cell area (%ACA) were quantified, and the relationship with GC therapy was evaluated. As a result, in case subjects without diabetes, there was no significant difference in %BCA between case subjects with and without GC therapy (1.66 +/- 1.05% vs. 1.21 +/- 0.59%, P = 0.13). %ACA was also not significantly different between the two groups. In case subjects with type 2 diabetes, %BCA and %ACA were both significantly reduced compared with control subjects without diabetes; however, neither %BCA nor %ACA was significantly decreased in case subjects with GC-induced diabetes. There was a significant negative correlation between %BCA and HbA1c measured before death; however, this relationship was attenuated in case subjects with GC therapy. In conclusion, the current study suggests that beta- and alpha-cell mass remain largely unchanged in the face of GC-induced insulin resistance in Japanese individuals, implying limited capacity of beta-cell regeneration in adult humans. The absence of apparent beta-cell deficit in case subjects with GC-induced diabetes suggests that GC-induced diabetes is mainly caused by insulin resistance and/or beta-cell dysfunction, but not necessarily a deficit of beta-cell mass.

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Bile acid binding resin improves hepatic insulin sensitivity by reducing cholesterol but not triglyceride levels in the liver

Tagawa, H., Irie, J., Itoh, A., Kusumoto, Y., Kato, M., Kobayashi, N., Tanaka, K., Morinaga, R., Fujita, M., Nakajima, Y., Morimoto, K., Sugizaki, T., Kawano, Y., Yamada, S., Kawai, T., Watanabe, M. and Itoh, H.

Diabetes Res Clin Pract 109 （ 1 ） 85 - 94 2015年07月

ISSN 0168-8227

AIMS: Bile acid binding resin (BAR) improves glycaemic control in patients with type 2 diabetes. Although the mechanism is hypothesised to involve the clearance of excess hepatic triglyceride, this hypothesis has not been examined in appropriately designed studies. Therefore, we investigated whether reduced hepatic triglyceride deposition is involved in BAR-mediated improvements in glycaemic control in spontaneous fatty liver diabetic mice without dietary interventions. METHODS: Male 6-week-old fatty liver Shionogi (FLS) mice were fed a standard diet without or with 1.5% BAR (colestilan) for 6 weeks. Glucose tolerance, insulin sensitivity, hepatic lipid content, and gene expression were assessed. A liver X receptor (LXR) agonist was also administered to activate the LXR pathway. We also retrospectively analysed the medical records of 21 outpatients with type 2 diabetes who were treated with colestilan for >/=6 months. RESULTS: BAR enhanced glucose tolerance and insulin sensitivity in FLS mice without altering fat mass. BAR improved hepatic insulin sensitivity, increased IRS2 expression, and decreased SREBP expression. BAR reduced hepatic cholesterol levels but not hepatic triglyceride levels. BAR also reduced the expression of LXR target genes, and LXR activation abolished the BAR-mediated improvements in glycaemic control. Colestilan significantly lowered serum cholesterol levels and improved glycaemic control in patients with type 2 diabetes. CONCLUSIONS: BAR improved hepatic insulin resistance in FLS mice by reducing hepatic cholesterol without affecting hepatic triglyceride levels or body fat distribution. Our study revealed that BAR improves glycaemic control at least in part by downregulating the hepatic cholesterol-LXR-IRS2 pathway.

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Transcription factors and epigenetic modulation: its therapeutic implication in chronic kidney disease

Hayashi, K. and Itoh, H.

Arch Immunol Ther Exp (Warsz) 63 （ 3 ） 193 - 6 2015年06月

ISSN 0004-069

Recently emerging evidence has shown that epigenetic mechanisms are involved in initiation and progression of various diseases, including kidney diseases. In the present article, we review the current data regarding the role of epigenetic modulation in chronic kidney disease (CKD) and kidney fibrosis, including DNA methylation and histone modification. Especially we focused on the role of transcription factors in epigenetic modulation and the possibility of therapeutic target of CKD. We have recently reported that transcription factor Kruppel-like factor 4 (also known as gut-enriched Kruppel-like factor) is expressed in kidney podocytes (visceral epithelial cells) and modulates podocyte phenotype by gene-selective epigenetic control. Targeting transcription factors for epigenetic modification may be a good candidate for remission and regression of CKD. It is necessary for the therapy of CKD with an epigenetic-based approach to investigate organ-, tissue-, or gene-specific treatment methods for reduction of side effects.

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CT during Arteriography to Visualize the Right Adrenal Vein for Adrenal Venous Sampling

Oguro, S., Nakatsuka, S., Yashiro, H., Hashimoto, S., Miyashita, K., Kurihara, I., Itoh, H. and Jinzaki, M.

J Vasc Interv Radiol 26 （ 6 ） 910 - 4 2015年06月

ISSN 1051-0443

The present report describes 6 cases of adrenal venous sampling (AVS) in patients who underwent computed tomography (CT) during arteriography because cannulation of right adrenal veins was otherwise difficult. CT was performed during arteriography to obtain information on the location and direction of the right adrenal vein. Two right adrenal veins were visualized in 1 case. The right central adrenal vein was not visualized in 1 case owing to an injury from a previous unsuccessful AVS procedure, but the right renal capsular vein was well visualized. CT during arteriography could contribute to a high AVS success rate.

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C-peptide immunoreactivity index is associated with improvement of HbA1c: 2-Year follow-up of sitagliptin use in patients with type 2 diabetes

Nishimura, T., Meguro, S., Sekioka, R., Tanaka, K., Saisho, Y., Irie, J., Tanaka, M., Kawai, T. and Itoh, H.

Diabetes Res Clin Pract 108 （ 3 ） 441 - 7 2015年06月

ISSN 0168-8227

AIMS: This retrospective study aimed to determine the hypoglycaemic effect of 2 years of sitagliptin administration in terms of changes in HbA1c and C-peptide immunoreactivity (CPR) index (plasma CPR [ng/mL]/glucose [mg/dL]x100). METHODS: The inclusion criteria for DPP-4 inhibitor-naive outpatients with type 2 diabetes (n=285) were: continuation of sitagliptin for >/=700 days from initial administration and measurement of HbA1c, serum CPR, and plasma glucose levels at 0, 3, 6, 12, 18, and 24 months after sitagliptin initiation. Logistic regression analyses determined the factors contributing to the response to sitagliptin, based on responder (DeltaHbA1c </=-0.4% [</=-4 mmol/mol]) and non-responder (DeltaHbA1c >-0.4% [>-4 mmol/mol]) groups. RESULTS: The HbA1c level decreased and CPR index increased from baseline to 3, 6, 12, 18, and 24 months after the start of sitagliptin administration (HbA1c: 7.4 +/- 0.8% [57 +/- 9 mmol/mol], 7.3 +/- 0.9% [57 +/- 9 mmol/mol], 7.4 +/- 0.9% [58 +/- 10 mmol/mol], 7.1 +/- 0.8% [55 +/- 9 mmol/mol], and 7.3 +/- 0.9% [57 +/- 10 mmol/mol], respectively, all P<0.001 vs. baseline [8.0 +/- 1.0%, 64 +/- 11 mmol/mol] and CPR index: 1.69 +/- 0.96, 1.71 +/- 1.10, 1.62 +/- 0.96, 1.64 +/- 0.92, and 1.66 +/- 0.96, respectively, all P<0.05 vs. baseline [1.47 +/- 0.81]). Higher baseline HbA1c level, shorter diabetes duration, and greater CPR index increase after sitagliptin administration were associated with the response to sitagliptin. CONCLUSIONS: Our results suggest that sitagliptin improves glycaemic control via an improved intrinsic insulin response.

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Insulin resistance in chronic kidney disease is ameliorated by spironolactone in rats and humans

Hosoya, K., Minakuchi, H., Wakino, S., Fujimura, K., Hasegawa, K., Komatsu, M., Yoshifuji, A., Futatsugi, K., Shinozuka, K., Washida, N., Kanda, T., Tokuyama, H., Hayashi, K. and Itoh, H.

Kidney Int 87 （ 4 ） 749 - 60 2015年04月

ISSN 0085-2538

In this study, we examined the association between chronic kidney disease (CKD) and insulin resistance. In a patient cohort with nondiabetic stages 2-5 CKD, estimated glomerular filtration rate (eGFR) was negatively correlated and the plasma aldosterone concentration was independently associated with the homeostasis model assessment of insulin resistance. Treatment with the mineralocorticoid receptor blocker spironolactone ameliorated insulin resistance in patients, and impaired glucose tolerance was partially reversed in fifth/sixth nephrectomized rats. In these rats, insulin-induced signal transduction was attenuated, especially in the adipose tissue. In the adipose tissue of nephrectomized rats, nuclear mineralocorticoid receptor expression, expression of the mineralocorticoid receptor target molecule SGK-1, tissue aldosterone content, and expression of the aldosterone-producing enzyme CYP11B2 increased. Mineralocorticoid receptor activation in the adipose tissue was reversed by spironolactone. In the adipose tissue of nephrectomized rats, asymmetric dimethylarginine (ADMA; an uremic substance linking uremia and insulin resistance) increased, the expression of the ADMA-degrading enzymes DDAH1 and DDAH2 decreased, and the oxidative stress increased. All of these changes were reversed by spironolactone. In mature adipocytes, aldosterone downregulated both DDAH1 and DDAH2 expression, and ADMA inhibited the insulin-induced cellular signaling. Thus, activation of mineralocorticoid receptor and resultant ADMA accumulation in adipose tissue has, in part, a relevant role in the development of insulin resistance in CKD.

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Changes in ultracentrifugally separated plasma lipoprotein subfractions in patients with polygenic hypercholesterolemia, familial combined hyperlipoproteinemia, and familial hypercholesterolemia after treatment with atorvastatin

Homma, K., Homma, Y., Yoshida, T., Ozawa, H., Shiina, Y., Wakino, S., Hayashi, K., Itoh, H. and Hori, S.

J Clin Lipidol 9 （ 2 ） 210 - 6 2015年03月

ISSN 1933-2874

BACKGROUND: Plasma levels of low-density lipoproteins (LDLs) are decreased through stimulation of their hepatic uptake by statins via an LDL receptor. However, it is unclear whether statins equally stimulate the hepatic uptake of all LDL subfractions. OBJECTIVE: We compared the effects of atorvastatin on 3 LDL subfractions, and their associations with LDL-receptor activities, in Japanese patients with polygenic hypercholesterolemia (PHC), familial combined hyperlipoproteinemia (FCHL), and familial hypercholesterolemia (FH). MATERIALS AND METHODS: Atorvastatin was administered to patients with PHC (n = 11), FCHL (n = 16), and FH (n = 13). We measured plasma levels of lipids, remnant-like particle cholesterol, apoproteins, and cholesterol in lipoprotein fractions. Sequential ultracentrifugation was performed to subfractionate the plasma lipoproteins, and lymphocyte LDL-receptor activities were estimated using flow cytometry. RESULTS: The average daily dosage of atorvastatin was 10, 27, and 40 mg in patients with PHC, FCHL, and FH, respectively; after 12 months of atorvastatin treatment, LDL cholesterol (LDL-C) plasma levels decreased by 44%, 50%, and 53%, respectively (all, P < .0001). Atorvastatin reduced low-density LDL-C plasma levels in patients with PHC (48% reduction), FCHL (53%), and FH (46%) (all, P < .0001). Plasma levels of medium-density and high-density LDL-C were also significantly reduced in the 3 patient groups (all, P </= .0147). LDL-receptor activity was negatively correlated with baseline levels of medium-density LDL-C and with the decreases in plasma md-LDL-C levels. CONCLUSION: Atorvastatin decreased the levels of the 3 LDL fractions. The md-LDL decrease appeared to be mainly because of stimulation of LDL-receptor activity.

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Serum total bilirubin concentration is negatively associated with increasing severity of retinopathy in patients with type 2 diabetes mellitus

Sekioka, R., Tanaka, M., Nishimura, T. and Itoh, H.

J Diabetes Complications 29 （ 2 ） 218 - 21 2015年03月

ISSN 1056-8727

AIMS: Serum bilirubin concentration is associated with diabetic retinopathy in patients with type 2 diabetes. This study investigated the relationships between serum bilirubin concentration and the severity of diabetic retinopathy. In addition, the importance of bilirubin was compared with factors that were previously shown to be associated with the incidence of diabetic retinopathy. METHODS: A total of 674 patients with type 2 diabetes were investigated in this cross-sectional study. Serum total bilirubin concentration was compared between patients with and without diabetic retinopathy, and according to the severity of retinopathy. Univariate and multivariate analyses were performed to evaluate the association of retinopathy with total bilirubin concentration, duration of diabetes, body mass index, systolic blood pressure, and haemoglobin A1c. RESULTS: Serum total bilirubin concentration was significantly lower in patients with retinopathy than in those without. Patients with severer retinopathy showed lower total bilirubin concentration, longer diabetes duration, and higher systolic blood pressure. These three parameters were independent explanatory factors for diabetic retinopathy. CONCLUSIONS: Total bilirubin concentration is lower in patients with type 2 diabetes complicated with severer retinopathy. Thus, bilirubin might protect against retinopathy in patients with type 2 diabetes.

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Impact of Peritoneal Dialysis Catheter Insertion by a Nephrologist: Results of a Questionnaire Survey of Patients and Nurses

Washida, N., Aikawa, K., Inoue, S., Kasai, T., Shinozuka, K., Morimoto, K., Hosoya, K., Hayashi, K. and Itoh, H.

Adv Perit Dial 31 59 - 68 2015年

ISSN 1197-8554

Peritoneal dialysis (PD) is an excellent dialysis mo- dality, but it is underutilized in the United States and Japan. In the present study, we evaluated the impact of interventional nephrology in PD on the impres- sions held by patients and nurses about selection of a renal replacement therapy and the complications associated with PD therapy. Over aperiod of 7 years, PD catheter insertion in 120 patients with end-stage renal disease (age: 63.0 +/- 13.3 years) was performed by nephrologists at Keio University Hospital or Saitama Medical Center. A questionnaire survey evaluating the advantages and disadvantages of this interventional nephrology approach in PD was distributed to 72 PD patients and to 53 nurses in charge of those patients. After interventional nephrology in PD was adopted, the number of patients selecting PD therapy increased. The incidence of peritonitis was relatively low (1 episode in 101.1 patient-months). Responses to the questionnaire survey showed that neither patients nor nurses were concerned about catheter insertion by physicians, and no communication problems between the patients, nurses, and physicians were reported. Approximately 60% of the nurses specializing in PD therapy showed higher motivation with interventional nephrology, which might have a favorable effect on the selection of PD therapy, on the incidence of peritonitis, and on the tripartite communication between patients, nurses, and physicians.

Efficacy and safety of liraglutide monotherapy compared with metformin in Japanese overweight/obese patients with type 2 diabetes

Tanaka, K., Saisho, Y., Kawai, T., Tanaka, M., Meguro, S., Irie, J., Imai, T., Shigihara, T., Morimoto, J., Yajima, K., Atsumi, Y., Takei, I. and Itoh, H.

Endocr J 62 （ 5 ） 399 - 409 2015年

ISSN 0918-8959

There is little information on direct comparison between metformin and glucagon-like peptide-1 (GLP-1) receptor agonists in the Asian population. This study examined the efficacy and safety of liraglutide monotherapy compared with metformin monotherapy in overweight/obese Japanese patients with type 2 diabetes (T2DM). The study was a 24-week, open-labeled, randomized controlled study. Overweight or obese patients with T2DM aged 20-75 years with suboptimal glycemic control were randomized to liraglutide or metformin monotherapy. The primary endpoint was change in HbA1c at week 24. Secondary endpoints included changes in daily glycemic profile, body weight, incidence of hypoglycemia and other adverse events. The study, which was originally planned to enroll 50 subjects in each group, was ended with insufficient recruitment. A total of 46 subjects completed the study, and analysis was conducted in this cohort. Reduction in HbA1c at week 24 was comparable between the metformin (n = 24) and liraglutide (n = 22) groups (-0.95 +/- 0.80% vs. -0.80 +/- 0.88%, p = 0.77), while the liraglutide group reached maximal reduction more rapidly than did the metformin group. There was no significant difference in weight gain or incidence of hypoglycemia between the groups. Diarrhea was more frequent in the metformin group, while constipation was more frequent in the liraglutide group. There was no significant difference in treatment satisfaction between the groups. In conclusion, liraglutide and metformin monotherapy showed similar reduction in HbA1c during 24 weeks, with no difference in weight gain or incidence of hypoglycemia in overweight or obese Japanese patients with T2DM.

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Efficacy and safety of sitagliptin added to insulin in Japanese patients with type 2 diabetes: the EDIT randomized trial

Sato, S., Saisho, Y., Kou, K., Meguro, S., Tanaka, M., Irie, J., Kawai, T. and Itoh, H.

PLoS One 10 （ 3 ） e0121988 2015年

ISSN 1932-6203

AIMS: To clarify the efficacy and safety of adding sitagliptin to insulin therapy in Japanese patients with suboptimally controlled type 2 diabetes (T2DM). STUDY DESIGN AND METHODS: This was a 24-week, prospective, randomized, open-labeled, controlled trial. Patients with T2DM who were suboptimally controlled despite receiving at least twice daily injection of insulin were enrolled in the study. The patients were randomized to continuation of insulin treatment (Insulin group) or addition of sitagliptin 50 to 100 mg daily to insulin treatment (Ins+Sita group). The primary outcome was change in HbA1c at week 24. RESULTS: Adding sitagliptin to insulin significantly reduced HbA1c from 7.9 +/- 1.0% at baseline to 7.0 +/- 0.8% at week 24 (P <0.0001), while there was no significant change in HbA1c in the Insulin group (7.8 +/- 0.7% vs. 7.8 +/- 1.1%, P = 0.32). The difference in HbA1c reduction between the groups was 0.9% (95% confidence interval, 0.4 to 1.5, P = 0.01). There was no significant weight gain in either group. Incidence of hypoglycemia was significantly reduced in the Ins+Sita group compared with the Insulin group. Treatment satisfaction was improved in the Ins+Sita group. Baseline HbA1c level and beta cell function were associated with the magnitude of reduction in HbA1c in the Ins+Sita group. CONCLUSION: Adding sitagliptin to insulin reduced HbA1c without weight gain or increase in hypoglycemia, and improved treatment satisfaction in Japanese patients with T2DM who were suboptimally controlled despite at least twice daily injection of insulin. TRIAL REGISTRATION: The University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000004678.

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A Reduction of HbA1c after 3 Months Predicts 2-year Responsiveness to Sitagliptin Treatment

Nishimura, T., Meguro, S., Sekioka, R., Tanaka, K., Saisho, Y., Irie, J., Tanaka, M., Kawai, T. and Itoh, H.

Intern Med 54 （ 23 ） 2981 - 9 2015年

ISSN 0918-2918

OBJECTIVE: This retrospective study evaluated the long-term efficacy of sitagliptin and the factors contributing to its glucose-lowering effect. METHODS: Six hundred and sixteen dipeptidyl peptidase-4 inhibitor-naive outpatients with type 2 diabetes who began sitagliptin treatment between December 1, 2009 and December 31, 2011 were included in this study. The inclusion criteria were that the patient had regularly visited our hospital for a period of >/=700 days from the initiation of sitagliptin treatment and the measurement of hemoglobin A1c (HbA1c) had been performed at 0, 3, 6, 12, 18, and 24 months after the initiation of treatment. From the population of 616 patients, 447 and 169 had received sitagliptin for >/=700 and <700 days, respectively. The primary endpoint was DeltaHbA1c at 24 months. The factors associated with the hypoglycemic effect of sitagliptin were also investigated. RESULTS: Sitagliptin treatment significantly decreased the level of HbA1c, and the hypoglycemic effect was sustained for at least 2 years. The baseline HbA1c level, duration of diabetes, Deltabody weight value, and DeltaHbA1c value at 3 months were independently associated with the hypoglycemic effect of sitagliptin. CONCLUSION: Sitagliptin has a long-term hypoglycemic effect in type 2 diabetes patients. A patient's DeltaHbA1c at 3 months may be a predictor of their DeltaHbA1c at 24 months.

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Role of endogenous ACTH on circadian aldosterone rhythm in patients with primary aldosteronism

Sonoyama, T., Sone, M., Tamura, N., Honda, K., Taura, D., Kojima, K., Fukuda, Y., Kanamoto, N., Miura, M., Yasoda, A., Arai, H., Itoh, H. and Nakao, K.

Endocr Connect 3 （ 4 ） 173 - 9 2014年12月

ISSN 2049-3614

We recently reported that stimulation with high-dose ACTH caused different responses in terms of aldosterone secretion in aldosterone-producing adenomas (APAs) and idiopathic hyperaldosteronism (IHA) in patients with primary aldosteronism (PA). However, the role of endogenous ACTH in aldosterone secretion in PA has not been systematically evaluated. In this study, we examined diurnal changes in plasma aldosterone concentration (PAC), and changes in PAC after dexamethasone administration in patients with suspected PA, in order to evaluate the effect of endogenous ACTH on aldosterone secretion. Seventy-three patients admitted to Kyoto University Hospital with suspected PA were included. The patients were classified into non-PA, IHA, and APA groups according to the results of captopril challenge test and adrenal venous sampling. PAC at 0900 h (PAC0900), 2300 h (PAC2300), and after 1-mg dexamethasone suppression test (PACdex) was measured and compared among the three groups. The PAC2300/PAC0900 and PACdex/PAC0900 ratios were also analyzed. PAC2300 and PACdex were lower than PAC0900 in all three groups. There were no significant differences in PAC2300/PAC0900 among the three groups. However, PACdex/PAC0900 was significantly lower in the APA group compared with the non-PA and IHA groups. The results of this study indicate that aldosterone secretion in APA patients is more strongly dependent on endogenous ACTH than in IHA and non-PA patients. The results also suggest that factors other than ACTH, such as clock genes, may cause diurnal changes in aldosterone secretion in IHA and non-PA patients.

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Effects of cilnidipine on sympathetic nerve activity and cardiorenal function in hypertensive patients with type 2 diabetes mellitus: association with BNP and aldosterone levels

Tanaka, M., Sekioka, R., Nishimura, T., Ichihara, A. and Itoh, H.

Diabetes Res Clin Pract 106 （ 3 ） 504 - 10 2014年12月

ISSN 0168-8227

AIMS: Hypertension stimulates the sympathetic nervous system and this phenomenon is exacerbated by diabetes mellitus. We investigated the effects of cilnidipine, an N/L-type calcium channel blocker, on aspects of this system in patients with type 2 diabetes mellitus. METHODS: In 33 hypertensive patients with type 2 diabetes mellitus treated with a calcium channel blocker other than cilnidipine, we evaluated the influence of switching to cilnidipine on blood pressure, heart rate, catecholamine, plasma renin and aldosterone concentration, brain natriuretic peptide, urine liver-type fatty acid binding protein, and urinary albumin excretion ratio in the same patients by a cross-over design. Other biochemical parameters were also evaluated. RESULTS: Switching to cilnidipine did not change blood pressure but caused reduction in catecholamine concentrations in blood and urine and plasma aldosterone concentration, accompanied by significant reduction in brain natriuretic peptide, urine liver-type fatty acid binding protein, and albumin excretion ratio. These parameters other than brain natriuretic peptide were significantly increased after cilnidipine was changed to the original calcium channel blocker. CONCLUSIONS: In 33 hypertensive patients with type 2 diabetes mellitus, compared to other calcium channel blockers, cilnidipine suppressed sympathetic nerve activity and aldosterone, and significantly improved markers of cardiorenal disorders. Therefore, cilnidipine may be an important calcium channel blocker for use in combination with renin-angiotensin-aldosterone system inhibitors when dealing with hypertension complicated with diabetes mellitus.

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Relationship between body mass index and pancreas volume in Japanese people

Kou, K., Saisho, Y., Jinzaki, M. and Itoh, H.

Jop 15 （ 6 ） 626 - 7 2014年11月

ISSN 1590-8577

CONTEXT: The volume of the pancreas increases with obesity. OBJECTIVE: This study was aimed to explore the relationship between body mass index (BMI) and pancreas volume in Japanese. METHODS: The pancreas volume was examined in a total of 103 (60 men and 43 women) Japanese adults who had undergone abdominal computed tomography (CT) scan. The pancreas was outlined by hand in each CT image and the pancreas volume was computed by summing the product of pancreas area of each image and the CT section thickness. RESULTS: There was a significant positive correlation between BMI and pancreas volume (r = 0.41, P <0.001). This relationship was expressed by the following equation: y = 23.8 + 2.48x, where y is pancreas volume (cm3) and x is BMI. CONCLUSIONS: There is a positive correlation between BMI and pancreas volume in Japanese and this relationship is similar to that in Caucasians. This information will be useful to estimate the impact of obesity on pancreas volume in Japanese and for comparison among different ethnicities.

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Improvement in karyomegalic interstitial nephritis three years after ifosfamide and cisplatin therapy by corticosteroid

Matsuura, T., Wakino, S., Yoshifuji, A., Nakamura, T., Tokuyama, H., Hashiguchi, A., Konishi, K., Iwasa, T., Shoji, M., Hosono, A., Ohashi, K., Chuman, H. and Itoh, H.

CEN Case Rep 3 （ 2 ） 226 - 231 2014年11月

ISSN 2192-4449

Long-term nephrotoxicity of ifosfamide is occasionally progressive, and, in such case, there has been no specific treatment to prevent progression. It has been reported that the presence of karyomegalic interstitial nephritis, which is rare type of interstitial nephritis, may be related to ifosfamide-induced nephropathy with poor prognosis and resistant to the immunosuppressive therapy. A 15-year-old boy presented with progressive nephrotoxicity 3 years after systemic chemotherapy with ifosfamide and cisplatin for the treatment of osteosarcoma. Renal biopsy revealed the severe tubulointerstitial nephritis with tubular atrophy and focal global and segmental glomerular sclerosis. It also showed tubular epithelial cells with variably sized nuclei, some of which were massively enlarged, abnormal hyperchromatic, irregular shaped, and bizarre-appearing. These morphological changes were suggestive of the histology of karyomegalic interstitial nephritis. Corticosteroid retarded the progression of nephrotoxicity. The present case is the first report, suggesting that corticosteroid was effective against the late-onset renal toxicity by ifosfamide therapy. Our case also suggests that karyomegalic interstitial nephritis may be the result of long-term nephrotoxicity of ifosfamide. Since concurrent treatment with cisplatin is one of the risk factors for ifosfamide nephrotoxicity, there is a possibility that cisplatin may have a synergetic effect with ifosfamide for producing karyomegalic interstitial nephritis.

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Renal arteriolar injury by salt intake contributes to salt memory for the development of hypertension

Oguchi, H., Sasamura, H., Shinoda, K., Morita, S., Kono, H., Nakagawa, K., Ishiguro, K., Hayashi, K., Nakamura, M., Azegami, T., Oya, M. and Itoh, H.

Hypertension 64 （ 4 ） 784 - 91 2014年10月

ISSN 0194-911

The role of salt intake in the development of hypertension is prominent, but its mechanism has not been fully elucidated. Our aim was to examine the effect of transient salt intake during the prehypertensive period in hypertensive model animals. Dahl salt-sensitive rats and spontaneously hypertensive rats were fed from 6 to 14 weeks with low-salt (0.12% NaCl), normal-salt (0.8% NaCl), high-salt (7% NaCl), or high-sodium/normal-chloride diet and returned to normal-salt diet for 3 months. Rats in the high-salt group saw elevations in blood pressure (BP) not only during the treatment period but also for the 3 months after returning to normal-salt diet. We named this phenomenon salt memory. Renal arteriolar injury was found in the high-salt group at the end of experiment. Dahl salt-sensitive rats were fed from 6 to 14 weeks with high-salt diet with angiotensin receptor blocker, vasodilator, calcium channel blocker, and calcium channel blocker+angiotensin receptor blocker and returned to normal-salt diet. Although BP was suppressed to control levels by vasodilator or calcium channel blocker, elevated renal angiotensin II and renal arteriolar injury were observed, and salt memory did not disappear because of sustained renal arteriolar injury. Calcium channel blocker+angiotensin receptor blocker suppressed renal arteriolar injury, resulting in the disappearance of salt memory. Cross-transplantation of kidneys from Dahl salt-sensitive rats on high salt to control rats caused increase of BP, whereas control kidneys caused reduction in BP of hypertensive rats, inducing the central role of the kidney. These results suggest that renal arteriolar injury through BP and renal angiotensin II elevation plays important roles in the development of salt memory for hypertension.

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Significant roles of the (pro)renin receptor in integrity of vascular smooth muscle cells

Kurauchi-Mito, A., Ichihara, A., Bokuda, K., Sakoda, M., Kinouchi, K., Yaguchi, T., Yamada, T., Sun-Wada, G. H., Wada, Y. and Itoh, H.

Hypertens Res 37 （ 9 ） 830 - 5 2014年09月

ISSN 0916-9636

The (pro)renin receptor ((P)RR) is known to play an important role in the pathogenesis of vascular complications in diabetes mellitus and hypertension through its function in activating the local renin-angiotensin system. Recent studies have shown that the (P)RR is an accessory protein of the vacuolar H(+)-ATPase, suggesting a more fundamental and developmental function. In this study, smooth muscle cell-specific (P)RR/Atp6ap2 conditional knockout mice were generated. Smooth muscle cell-specific ablation of the (P)RR resulted in nonatherogenic sclerosis in the abdominal aorta. The deletion of the (P)RR did not affect ambulatory blood pressure levels. In cultured murine vascular smooth muscle cells (VSMCs), ablation of the (P)RR suppressed the expression of the Vo subunit c of the vacuolar H(+)-ATPase and impaired the cell recycling system, leading to autophagic cell death. In addition, loss of the (P)RR in VSMCs induced the expression of monocyte chemotactic protein-1 and interleukin-6 mRNAs. These results suggest that the (P)RR is essential for cell survival and downregulation of vascular inflammation in murine VSMCs through maintaining normal function of the vacuolar H(+)-ATPase.

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Serum creatinine and albumin decline predict the contraction of nosocomial aspiration pneumonia in patients undergoing hemodialysis

Minakuchi, H., Wakino, S., Hayashi, K., Inamoto, H. and Itoh, H.

Ther Apher Dial 18 （ 4 ） 326 - 33 2014年08月

ISSN 1744-9979

Aspiration pneumonia (AP) is prevalent in older adults and the hemodialysis (HD) population has been getting older. Therefore, it is speculated that increasing number of HD patients would suffer from AP. However, the clinical aspects of AP in HD patients have not been elucidated. Consecutive HD patients with nosocomial AP hospitalized in our university hospital from April 2007 to December 2008 were recruited. Their clinical characteristics, risk factors for contraction, and the fatality of AP and treatment options were described. Nineteen out of 356 hospitalized HD patients had AP and 8 out of 19 AP patients died, indicating the incidence rate and fatality rate were 5.34% and 42.1%, respectively. Multiple regression analysis revealed that the risk factors for contracting AP included age, body mass index, serum creatinine levels (Cre) and the monthly decline rate of Cre. It also revealed that serum albumin (Alb) and basal total cholesterol levels, the decline rate of Alb and Cre levels, and the duration of AP were independent risk factors for fatality. Survivors were most often treated with tube feeding. Both contraction rate and fatality of nosocomial AP were high among HD patients. Both the malnutrition as well as the decline rate for nutrition and muscle volume indicated by falls in Alb and Cre, respectively, had clinical relevance in AP. Maintaining nutritional state by tube feeding and muscle volume seems to be the mainstay for the prevention and the treatment of AP in HD patients.

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The Niemann-Pick C1 like 1 (NPC1L1) inhibitor ezetimibe improves metabolic disease via decreased liver X receptor (LXR) activity in liver of obese male mice

Sugizaki, T., Watanabe, M., Horai, Y., Kaneko-Iwasaki, N., Arita, E., Miyazaki, T., Morimoto, K., Honda, A., Irie, J. and Itoh, H.

Endocrinology 155 （ 8 ） 2810 - 9 2014年08月

ISSN 0013-7227

Dyslipidemic patients with diabetes mellitus, including metabolic syndrome, are at increased risk of coronary heart disease. It has been reported that ezetimibe, a cholesterol absorption inhibitor, improves metabolic diseases in mice and humans. However, the underlying mechanism has been unclear. Here we explored the effects of ezetimibe on lipid and glucose homeostasis. Male KK-A(y) mice were fed a high-fat diet, which is the mouse model of metabolic syndrome, with or without ezetimibe for 14 weeks. Ezetimibe improved dyslipidemia, steatosis, and insulin resistance. Ezetimibe decreased hepatic oxysterols, which are endogenous agonists of liver X receptor (LXR), to decrease hepatic lipogenic gene expressions, especially in stearoyl-CoA desaturase-1 (SCD1), leading to a remarkable reduction of hepatic oleate content that would contribute to the improvement of steatosis by reducing triglycerides and cholesterol esters. Simultaneously, hepatic beta-oxidation, NADPH oxidase and cytochrome P450 2E1 (CYP2E1) were reduced, and thus reactive oxygen species (ROS) and inflammatory cytokines were also decreased. Consistent with these changes, ezetimibe diminished c-Jun N-terminal kinase (JNK) phosphorylation and improved insulin signaling in the liver. In vitro study using primary hepatocytes obtained from male SD rats, treated with oleate and LXR agonist, showed excess lipid accumulation, increased oxidative stress and impaired insulin signaling. Therefore, in obese subjects, ezetimibe reduces hepatic LXR activity by reducing hepatic oxysterols to lower hepatic oleate content. This improves steatosis and reduces oxidative stress, and this reduction improves insulin signaling in the liver. These results provide insight into pathogenesis and strategies for treatment of the metabolic syndrome.

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Chronic kidney disease reduces muscle mitochondria and exercise endurance and its exacerbation by dietary protein through inactivation of pyruvate dehydrogenase

Tamaki, M., Miyashita, K., Wakino, S., Mitsuishi, M., Hayashi, K. and Itoh, H.

Kidney Int 85 （ 6 ） 1330 - 9 2014年06月

ISSN 0085-2538

Chronic kidney disease impairs physical performance. Here the time course and mechanism of muscle insufficiency in renal failure and the influence of dietary protein were studied using 5/6 nephrectomized C57Bl/6 mice, focusing on muscle mass and mitochondria. A decrease in muscle mitochondria and running distance was found in young (16-20 weeks) 5/6 nephrectomized mice, despite the preservation of muscle volume and power. However, a decrease in muscle volume, associated with a reduction in muscle power, was found in aged (48-52 weeks) 5/6 nephrectomized mice. A high-protein diet feeding from 8 weeks increased muscle volume and power in the mice; but this further decreased running distance. Activation of pyruvate dehydrogenase by dichloroacetate effectively recovered running distance that was decreased by dietary protein. These findings indicate the mechanism of muscle insufficiency in renal failure and suggest that activation of muscle mitochondria would serve as a potential strategy for improving the physical performance of the patients with chronic kidney disease.

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Islet number rather than islet size is a major determinant of beta- and alpha-cell mass in humans

Kou, K., Saisho, Y., Sato, S., Yamada, T. and Itoh, H.

J Clin Endocrinol Metab 99 （ 5 ） 1733 - 40 2014年05月

ISSN 0021-972

OBJECTIVE: The objective of the study was to clarify the relative contribution of islet number and islet size to beta- and alpha-cell mass in humans. RESEARCH DESIGN AND METHODS: We obtained the pancreas at autopsy from 72 Japanese adults with no history of diabetes or pancreatitis (aged 47 +/- 12 years, body mass index 24.1 +/- 5.0 kg/m(2)). Pancreatic sections were stained for insulin or glucagon, and fractional beta-cell area (%BCA) and alpha-cell area (%ACA) were measured. Islet number and islet size as well as beta-cell turnover were also quantified. Glycosylated hemoglobin measured within 1 year prior to death was obtained in 38 individuals. RESULTS: There was considerable interindividual variation in islet density and mean islet size, with a significant negative correlation between the two (r = -0.25, P = .03). There were significant positive correlations between islet density and %BCA or %ACA (r = 0.63, P < .001, and r = 0.41, P = .001), whereas mean islet size correlated with neither of them. Islet density as well as %BCA, but not mean islet size, was negatively correlated with glycosylated hemoglobin (r = -0.37, P = .02, and r = -0.36, P = .03). CONCLUSION: The present study suggests that islet number rather than islet size is a major determinant of beta- and alpha-cell mass in humans. Interindividual difference in islet number may contribute to susceptibility to development of glucose intolerance.

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miR-34c attenuates epithelial-mesenchymal transition and kidney fibrosis with ureteral obstruction

Morizane, R., Fujii, S., Monkawa, T., Hiratsuka, K., Yamaguchi, S., Homma, K. and Itoh, H.

Sci Rep 4 4578 2014年04月

ISSN 2045-2322

micro RNAs (miRNAs) are small non-coding RNAs that act as posttranscriptional repressors by binding to the 3'-UTR of target mRNAs. On the other hand, mesenchymal-epithelial transition (EMT) and kidney fibrosis is a pathological process of chronic kidney disease (CKD), and its relationship to miRNAs is becoming recognized as a potential target for CKD therapies. To find new miRNAs involved in EMT, we examined miRNA expression in experimental models of EMT and renal epithelialization using microarray, and found that miR-34c attenuates EMT induced by TGF-beta in a mouse tubular cell line. To confirm the effects of miR-34c in vivo, we administered the precursor of miR-34c to mice with unilateral ureteral obstruction, and miR-34c decreased kidney fibrosis area and the expression of connective tissue growth factor, alpha-SMA, collagen type 1, collagen type 3 and fibronectin. In conclusion, our study showed miR-34c attenuates EMT and kidney fibrosis of mice with ureteral obstruction.

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Association between plasma triglycerides and high-density lipoprotein cholesterol and microvascular kidney disease and retinopathy in type 2 diabetes mellitus: a global case-control study in 13 countries

Sacks, F. M., Hermans, M. P., Fioretto, P., Valensi, P., Davis, T., Horton, E., Wanner, C., Al-Rubeaan, K., Aronson, R., Barzon, I., Bishop, L., Bonora, E., Bunnag, P., Chuang, L. M., Deerochanawong, C., Goldenberg, R., Harshfield, B., Hernandez, C., Herzlinger-Botein, S., Itoh, H., Jia, W., Jiang, Y. D., Kadowaki, T., Laranjo, N., Leiter, L., Miwa, T., Odawara, M., Ohashi, K., Ohno, A., Pan, C., Pan, J., Pedro-Botet, J., Reiner, Z., Rotella, C. M., Simo, R., Tanaka, M., Tedeschi-Reiner, E., Twum-Barima, D., Zoppini, G. and Carey, V. J.

Circulation 129 （ 9 ） 999 - 1008 2014年03月

ISSN 0009-7322

BACKGROUND: Microvascular renal and retinal diseases are common major complications of type 2 diabetes mellitus. The relation between plasma lipids and microvascular disease is not well established. METHODS AND RESULTS: The case subjects were 2535 patients with type 2 diabetes mellitus with an average duration of 14 years, 1891 of whom had kidney disease and 1218 with retinopathy. The case subjects were matched for diabetes mellitus duration, age, sex, and low-density lipoprotein cholesterol to 3683 control subjects with type 2 diabetes mellitus who did not have kidney disease or retinopathy. The study was conducted in 24 sites in 13 countries. The primary analysis included kidney disease and retinopathy cases. Matched analysis was performed by use of site-specific conditional logistic regression in multivariable models that adjusted for hemoglobin A1c, hypertension, and statin treatment. Mean low-density lipoprotein cholesterol concentration was 2.3 mmol/L. The microvascular disease odds ratio increased by a factor of 1.16 (95% confidence interval, 1.11-1.22) for every 0.5 mmol/L ( approximately 1 quintile) increase in triglycerides or decreased by a factor of 0.92 (0.88-0.96) for every 0.2 mmol/L ( approximately 1 quintile) increase in high-density lipoprotein cholesterol. For kidney disease, the odds ratio increased by 1.23 (1.16-1.31) with triglycerides and decreased by 0.86 (0.82-0.91) with high-density lipoprotein cholesterol. Retinopathy was associated with triglycerides and high-density lipoprotein cholesterol in matched analysis but not significantly after additional adjustment. CONCLUSIONS: Diabetic kidney disease is associated worldwide with higher levels of plasma triglycerides and lower levels of high-density lipoprotein cholesterol among patients with good control of low-density lipoprotein cholesterol. Retinopathy was less robustly associated with these lipids. These results strengthen the rationale for studying dyslipidemia treatment to prevent diabetic microvascular disease.

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Effect of single tablet of fixed-dose amlodipine and atorvastatin on blood pressure/lipid control, oxidative stress, and medication adherence in type 2 diabetic patients

Tanaka, M., Nishimura, R., Nishimura, T., Kawai, T., Meguro, S., Irie, J., Saisho, Y. and Itoh, H.

Diabetol Metab Syndr 6 56 2014年

ISSN 1758-5996

BACKGROUND: Oxidized low-density lipoprotein (LDL) plays central roles in the formation and progression of atherosclerotic lesions. Malondialdehyde (MDA)-modified LDL (MDA-LDL) is speculated to be generated as a result of oxidative stress in the human body. Because both amlodipine and atorvastatin have been reported to reduce oxidative stress, it is expected that both drugs would have a favorable influence to reduce oxidative stress. OBJECTIVE: The objective of this study was to investigate the effects of a single pill of amlodipine (5 mg)/atorvastatin (10 mg) on oxidative stress, blood pressure/lipid control and adherence to medication in patients with type 2 diabetes. METHODS: This combination tablet was administered to 29 patients (16 male), and MDA-LDL, blood pressure, lipid profile, renal/liver function, CPK, hs-CRP, adiponectin, BNP, and HbA1c were measured at baseline, 6, and 12 months, and baPWV and mean IMT were measured at baseline and 12 months. Medication adherence was examined using a questionnaire at 6 months. RESULTS: MDA-LDL was decreased significantly. LDL-C, TG, and Cr were significantly decreased at 6 and 12 months compared with baseline. eGFR was increased at 6 months, and urinary albumin/creatinine ratio was decreased at 12 months. BNP was decreased at 6 and 12 months, and adiponectin was increased at 12 months. Both mean IMT and baPWV were significantly decreased. The results of the questionnaire showed that 93% of patients were satisfied with this medication. No severe adverse event was observed. CONCLUSION: This combination tablet controlled both hypertension and dyslipidemia well in type 2 diabetic patients. The deceases in mean IMT and baPWV might suggest the improvement of atherosclerosis by this medication, which could be caused by the reduction of oxidative stress measured by MDA-LDL. In addition, this medication is expected to improve medication adherence.

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Lower beta cell function relates to sustained higher glycated albumin to glycated hemoglobin ratio in Japanese patients with type 2 diabetes

Saisho, Y., Tanaka, K., Abe, T., Kawai, T. and Itoh, H.

Endocr J 61 （ 2 ） 149 - 57 2014年

ISSN 0918-8959

The aim of this study was to clarify the relationship between baseline beta cell function and future glycated albumin (GA) to glycated hemoglobin ratio (GA/HbA1c) in patients with type 2 diabetes. In our retrospective cohort, 210 type 2 diabetic patients who had been admitted to our hospital and in whom HbA1c and GA had been measured at baseline and 2 years after admission were included in this study. Baseline beta cell function was assessed by postprandial C-peptide immunoreactivity index (PCPRI) during admission. With intensification of treatment during admission, HbA1c and GA were significantly decreased 1 year and 2 years after admission. While baseline HbA1c was not significantly correlated with HbA1c after 2 years, baseline GA/HbA1c was strongly correlated with GA/HbA1c after 2 years (r = 0.575, P <0.001). When the patients were divided into two groups according to median PCPRI, patients with low PCPRI showed higher GA/HbA1c both at baseline and after 2 years compared to those with high PCPRI. There was a significant negative correlation between PCPRI and GA/HbA1c after 2 years (r = -0.379, P <0.001). Multiple regression analysis revealed that PCPRI was an independent predictor of GA/HbA1c after 2 years. In conclusion, our findings suggest that lower beta cell function is associated with sustained higher GA/HbA1c ratio in patients with type 2 diabetes.

Effects of 16-week high-intensity interval training using upper and lower body ergometers on aerobic fitness and morphological changes in healthy men: a preliminary study

Osawa, Y., Azuma, K., Tabata, S., Katsukawa, F., Ishida, H., Oguma, Y., Kawai, T., Itoh, H., Okuda, S. and Matsumoto, H.

Open Access J Sports Med 5 257 - 65 2014年

ISSN 1179-1543

It is unclear whether combined leg and arm high-intensity interval training (HIIT) improves fitness and morphological characteristics equal to those of leg-based HIIT programs. The aim of this study was to compare the effects of HIIT using leg-cycling (LC) and arm-cranking (AC) ergometers with an HIIT program using only LC. Effects on aerobic capacity and skeletal muscle were analyzed. Twelve healthy male subjects were assigned into two groups. One performed LC-HIIT (n=7) and the other LC- and AC-HIIT (n=5) twice weekly for 16 weeks. The training programs consisted of eight to 12 sets of >90% VO2 (the oxygen uptake that can be utilized in one minute) peak for 60 seconds with a 60-second active rest period. VO2 peak, watt peak, and heart rate were measured during an LC incremental exercise test. The cross-sectional area (CSA) of trunk and thigh muscles as well as bone-free lean body mass were measured using magnetic resonance imaging and dual-energy X-ray absorptiometry. The watt peak increased from baseline in both the LC (23%+/-38%; P<0.05) and the LC-AC groups (11%+/-9%; P<0.05). The CSA of the quadriceps femoris muscles also increased from baseline in both the LC (11%+/-4%; P<0.05) and the LC-AC groups (5%+/-5%; P<0.05). In contrast, increases were observed in the CSA of musculus psoas major (9%+/-11%) and musculus anterolateral abdominal (7%+/-4%) only in the LC-AC group. These results suggest that a combined LC- and AC-HIIT program improves aerobic capacity and muscle hypertrophy in both leg and trunk muscles.

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Kidney specific protein-positive cells derived from embryonic stem cells reproduce tubular structures in vitro and differentiate into renal tubular cells

Morizane, R., Monkawa, T., Fujii, S., Yamaguchi, S., Homma, K., Matsuzaki, Y., Okano, H. and Itoh, H.

PLoS One 8 （ 6 ） e64843 2014年

ISSN 1932-6203

Embryonic stem cells and induced pluripotent stem cells have the ability to differentiate into various organs and tissues, and are regarded as new tools for the elucidation of disease mechanisms as well as sources for regenerative therapies. However, a method of inducing organ-specific cells from pluripotent stem cells is urgently needed. Although many scientists have been developing methods to induce various organ-specific cells from pluripotent stem cells, renal lineage cells have yet to be induced in vitro because of the complexity of kidney structures and the diversity of kidney-component cells. Here, we describe a method of inducing renal tubular cells from mouse embryonic stem cells via the cell purification of kidney specific protein (KSP)-positive cells using an anti-KSP antibody. The global gene expression profiles of KSP-positive cells derived from ES cells exhibited characteristics similar to those of cells in the developing kidney, and KSP-positive cells had the capacity to form tubular structures resembling renal tubular cells when grown in a 3D culture in Matrigel. Moreover, our results indicated that KSP-positive cells acquired the characteristics of each segment of renal tubular cells through tubular formation when stimulated with Wnt4. This method is an important step toward kidney disease research using pluripotent stem cells, and the development of kidney regeneration therapies.

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Plasma Antimicrobial Peptide LL-37 Level Is Inversely Associated with HDL Cholesterol Level in Patients with Type 2 Diabetes Mellitus

Meguro, S., Tomita, M., Katsuki, T., Kato, K., Oh, H., Ainai, A., Ito, R., Kawai, T., Itoh, H. and Hasegawa, H.

Int J Endocrinol 2014 703696 2014年

ISSN 1687-8337

Introduction. Relation between atherosclerosis and innate immunity has attracted attention. As the antimicrobial peptide, LL-37, could have an important role in atherosclerosis, we supposed that there could be a meaningful association of plasma LL-37 level with risk factors for cardiovascular disease in subjects with type 2 diabetes mellitus. Materials and Methods. We evaluated plasma LL-37 level and other clinical markers in Japanese subjects with type 2 diabetes mellitus (n = 133, 115 men and 18 women; age 64.7 +/- 11.5 years; HbA1c 8.1 +/- 1.6%). Plasma level of LL-37 was measured by ELISA. Results. Mean plasma LL-37 level was 71.2 +/- 22.3 ng/mL. Plasma LL-37 level showed significant correlations with HDL cholesterol (r = -0.450, P < 0.01), triglyceride (r = 0.445, P < 0.01), and high sensitive C-reactive protein (r = 0.316, P < 0.01) but no significant correlation with age, body mass index, HbA1c, estimated glomerular filtration rate, 25-hydroxyvitamin D, or vitamin D binding protein. Multiple linear regression analysis showed significant correlations of plasma LL-37 level with HDL cholesterol (beta = -0.411, P < 0.01) and high sensitive C-reactive protein (beta = 0.193, P < 0.05). Conclusion. Plasma LL-37 level was positively correlated with inflammatory markers and negatively correlated with HDL cholesterol in patients with type 2 diabetes mellitus.

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Basal-Supported Oral Therapy with Sitagliptin Counteracts Rebound Hyperglycemia Caused by GLP-1 Tachyphylaxis

Meguro, S., Kawai, T., Matsuhashi, T., Sano, M., Fukuda, K., Itoh, H. and Suzuki, Y.

Int J Endocrinol 2014 927317 2014年

ISSN 1687-8337

Introduction. Treatment with a glucagon-like peptide 1 (GLP-1) analog fails in some patients due to rebound hyperglycemia caused by tachyphylaxis (GLP-1 tachyphylaxis). We investigated the efficacy of basal-supported oral therapy (BOT) with insulin glargine and sitagliptin for counteracting GLP-1 tachyphylaxis. Materials and Methods. The subjects were 12 men and 3 women aged 59.9 +/- 10.0 years who had been treated with GLP-1 analogs. All of them had developed rebound hyperglycemia caused by GLP-1 tachyphylaxis. Their GLP-1 analog-based therapy was switched to BOT with insulin glargine plus sitagliptin and other medications. The primary outcomes were whether switching of therapy was associated with a change of hemoglobin A1c (HbA1c) and whether weight gain occurred. Results. Baseline HbA1c was 8.0 +/- 0.9%. It decreased to 7.3 +/- 0.9% at 3 months after switching (P < 0.01) and to 7.2 +/- 0.9% at 4 months (P < 0.05). Weight gain was 1.1 kg after 1 month (P < 0.01) and 2.3 kg after 5 months (P < 0.01). Conclusion. Switching to BOT with insulin glargine and sitagliptin improved glycemic control. The significant decrease of HbA1c demonstrated that this combination can counteract deterioration of glycemic control due to rebound hyperglycemia secondary to GLP-1 tachyphylaxis. However, weight gain remains a problem.

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Rho-kinase contributes to pressure-induced constriction of renal microvessels

Homma, K., Hayashi, K., Wakino, S., Tokuyama, H., Kanda, T., Tatematsu, S., Hasegawa, K., Fujishima, S., Hori, S., Saruta, T. and Itoh, H.

Keio J Med 63 （ 1 ） 1 - 12 2014年

ISSN 0022-9717

Renal afferent arterioles (AFF) regulate glomerular capillary pressure through two main mechanisms: the myogenic response (MYO) and tubuloglomerular feedback (TGF). Because Rho-kinase and nitric oxide synthase (NOS) are established factors that modulate vascular tone, we examined the role of these factors in pressure-induced AFF tone in Wistar-Kyoto rats and in spontaneously hypertensive rats (SHR) using an intravital CCD camera. Elevated renal perfusion pressure elicited marked AFF constriction that was partially inhibited by gadolinium, furosemide and fasudil, which inhibit MYO, TGF and Rho-kinase, respectively; however, this AFF constriction was completely blocked by combined treatment with fasudil+gadolinium or fasudil+furosemide. S-methyl-L-thiocitrulline (SMTC) partially reversed the fasudil-induced inhibition of TGF-mediated, but not that of MYO-mediated, AFF constriction. In SHR, the pressure-induced AFF response was enhanced, and MYO- and TGF-induced constriction were exaggerated. In the presence of gadolinium, SMTC partially mitigated the fasudil-induced inhibition of TGF-mediated AFF constriction. Immunoblot analyses demonstrated that both Rho-kinase activity and neuronal NOS were augmented in SHR kidneys. In conclusion, Rho-kinase contributes to MYO- and TGF-mediated AFF responses, and these responses are enhanced in SHR. Furthermore, neuronal NOS-induced nitric oxide modulates the TGF mechanism. This mechanism constitutes a target for Rho-kinase in TGF-mediated AFF constriction.

Ghrelin protects against renal damages induced by angiotensin-II via an antioxidative stress mechanism in mice

Fujimura, K., Wakino, S., Minakuchi, H., Hasegawa, K., Hosoya, K., Komatsu, M., Kaneko, Y., Shinozuka, K., Washida, N., Kanda, T., Tokuyama, H., Hayashi, K. and Itoh, H.

PLoS One 9 （ 4 ） e94373 2014年

ISSN 1932-6203

We explored the renal protective effects by a gut peptide, Ghrelin. Daily peritoneal injection with Ghrelin ameliorated renal damages in continuously angiotensin II (AngII)-infused C57BL/6 mice as assessed by urinary excretion of protein and renal tubular markers. AngII-induced increase in reactive oxygen species (ROS) levels and senescent changes were attenuated by Ghrelin. Ghrelin also inhibited AngII-induced upregulations of transforming growth factor-beta (TGF-beta) and plasminogen activator inhibitor-1 (PAI-1), ameliorating renal fibrotic changes. These effects were accompanied by concomitant increase in mitochondria uncoupling protein, UCP2 as well as in a key regulator of mitochondria biosynthesis, PGC1alpha. In renal proximal cell line, HK-2 cells, Ghrelin reduced mitochondria membrane potential and mitochondria-derived ROS. The transfection of UCP2 siRNA abolished the decrease in mitochondria-derived ROS by Ghrelin. Ghrelin ameliorated AngII-induced renal tubular cell senescent changes and AngII-induced TGF-beta and PAI-1 expressions. Finally, Ghrelin receptor, growth hormone secretagogue receptor (GHSR)-null mice exhibited an increase in tubular damages, renal ROS levels, renal senescent changes and fibrosis complicated with renal dysfunction. GHSR-null mice harbored elongated mitochondria in the proximal tubules. In conclusion, Ghrelin suppressed AngII-induced renal damages through its UCP2 dependent anti-oxidative stress effect and mitochondria maintenance. Ghrelin/GHSR pathway played an important role in the maintenance of ROS levels in the kidney.

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Postprandial serum C-peptide to plasma glucose ratio predicts future insulin therapy in Japanese patients with type 2 diabetes

Saisho, Y., Kou, K., Tanaka, K., Abe, T., Shimada, A., Kawai, T. and Itoh, H.

Acta Diabetol 50 （ 6 ） 987 - 8 2013年12月

ISSN 0940-5429

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Feasibility of regression of hypertension using contemporary antihypertensive agents

Sasamura, H., Nakaya, H., Julius, S., Tomotsugu, N., Sato, Y., Takahashi, F., Takeuchi, M., Murakami, M., Ryuzaki, M. and Itoh, H.

Am J Hypertens 26 （ 12 ） 1381 - 8 2013年12月

ISSN 0895-7061

BACKGROUND: Recently, we reported that transient treatment of genetically hypertensive rats with high-dose angiotensin receptor blocker (ARB) causes regression of established hypertension. In this study, we investigated whether treatment with candesartan or nifedipine controlled-release (CR) resulted in a sustained regression of hypertension in humans. METHODS: Patients aged 30 to 59 years with untreated stage 1 essential hypertension and a family history of hypertension were treated with the antihypertensive agents candesartan (n = 124) or nifedipine CR (n = 120). After 1 year of treatment (phase 1), the medications were tapered and discontinued (phase 2). During phase 2, home and office blood pressures were monitored for another year to assess posttreatment reoccurrence of stage 1 hypertension. RESULTS: In phase 1, after 1 year of treatment a similarly substantial BP decrease was seen in the candesartan (-24.5/16.1 mm Hg) and nifedipine (-26.8/18.0 mm Hg) groups. In phase 2 there was a substantial reoccurrence of hypertension; at the study end, only 1 patient was able to continue without antihypertensive medication. However, a Kaplan-Meier analysis revealed a significant delay of reoccurrence of hyper tension (P = 0.0001) in the candesartan group. CONCLUSIONS: One year of treatment with candesartan or nifedipine CR was not associated with marked regression of hypertension in humans at the standard doses used in this trial. However, withdrawal of candesartan was associated with a slightly longer delay before restarting medications. Further studies with larger doses of candesartan given over a longer time are required to determine whether such a regimen may induce sustainable and clinically relevant reversal of hypertension and alteration in its natural history.

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Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes

Hasegawa, K., Wakino, S., Simic, P., Sakamaki, Y., Minakuchi, H., Fujimura, K., Hosoya, K., Komatsu, M., Kaneko, Y., Kanda, T., Kubota, E., Tokuyama, H., Hayashi, K., Guarente, L. and Itoh, H.

Nat Med 19 （ 11 ） 1496 - 504 2013年11月

ISSN 1078-8956

Sirtuin 1 (Sirt1), a NAD(+)-regulated deacetylase with numerous known positive effects on cellular and whole-body metabolism, is expressed in the renal cortex and medulla. It is known to have protective effects against age-related disease, including diabetes. Here we investigated the protective role of Sirt1 in diabetic renal damage. We found that Sirt1 in proximal tubules (PTs) was downregulated before albuminuria occurred in streptozotocin-induced or obese (db/db) diabetic mice. PT-specific SIRT1 transgenic and Sirt1 knockout mice showed prevention and aggravation of the glomerular changes that occur in diabetes, respectively, and nondiabetic knockout mice exhibited albuminuria, suggesting that Sirt1 in PTs affects glomerular function. Downregulation of Sirt1 and upregulation of the tight junction protein Claudin-1 by SIRT1-mediated epigenetic regulation in podocytes contributed to albuminuria. We did not observe these phenomena in 5/6 nephrectomized mice. We also demonstrated retrograde interplay from PTs to glomeruli using nicotinamide mononucleotide (NMN) from conditioned medium, measurement of the autofluorescence of photoactivatable NMN and injection of fluorescence-labeled NMN. In human subjects with diabetes, the levels of SIRT1 and Claudin-1 were correlated with proteinuria levels. These results suggest that Sirt1 in PTs protects against albuminuria in diabetes by maintaining NMN concentrations around glomeruli, thus influencing podocyte function.

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Dietary protein decreases exercise endurance through rapamycin-sensitive suppression of muscle mitochondria

Mitsuishi, M., Miyashita, K., Muraki, A., Tamaki, M., Tanaka, K. and Itoh, H.

Am J Physiol Endocrinol Metab 305 （ 7 ） E776 - 84 2013年10月

ISSN 0193-1849

Loss of physical performance is linked not only to decreased activity in daily life but also to increased onset of cardiovascular diseases and mortality. A high-protein diet is recommended for aged individuals in order to preserve muscle mass; however, the regulation of muscle mitochondria by dietary protein has not been clarified. We investigated the long-term effects of a high-protein diet on muscle properties, focusing especially on muscle mitochondria. Mice were fed a high-protein diet from the age of 8 wk and examined for mitochondrial properties and exercise endurance at the ages of 20 and 50 wk. Compared with normal chow, a high-protein diet significantly decreased the amount of muscle mitochondria, mitochondrial activity, and running distance at 50 wk, although it increased muscle mass and grip power. Inhibition of TORC1-dependent signal pathways by rapamycin from 8 wk suppressed the decline in mitochondria and exercise endurance observed when mice were fed the high-protein diet in association with preserved AMPK activity. Collectively, these findings suggest a role for dietary protein as a suppressor of muscle mitochondria and indicate that the age-associated decline in exercise endurance might be accelerated by excessive dietary protein through rapamycin-sensitive suppression of muscle mitochondria.

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Change in beta-cell mass in Japanese nondiabetic obese individuals

Kou, K., Saisho, Y., Satoh, S., Yamada, T. and Itoh, H.

J Clin Endocrinol Metab 98 （ 9 ） 3724 - 30 2013年09月

ISSN 0021-972

AIM: The aim of this study was to clarify the change in beta-cell mass in Japanese obese individuals. METHODS: We obtained the pancreas at autopsy from 39 lean and 33 obese Japanese nondiabetic individuals (aged 47 +/- 13 vs 47 +/- 12 y, P = .83, body mass index 20.4 +/- 1.6 vs 28.5 +/- 3.9 kg/m(2), P < .01). Pancreatic sections were stained for insulin, and beta-cell area (%BCA) was measured as the fraction of the beta-cell area to the total pancreas area. beta-Cell mass was then calculated as the product of %BCA and estimated pancreas weight. beta-Cell replication and apoptosis were assessed by double staining for insulin and Ki67 and insulin and single-stranded DNA, respectively. The frequencies of insulin-positive duct cells and scattered beta-cells were assessed as the surrogate markers of beta-cell neogenesis. The alpha-cell area (%ACA) was also measured, and the %ACA to %BCA ratio was determined. RESULTS: There was no increase in beta-cell mass in obese individuals compared with lean individuals (0.6 +/- 0.4 vs 0.7 +/- 0.4 g, P = .12). beta-Cell replication, beta-cell neogenesis, and beta-cell apoptosis were not significantly increased in the presence of obesity. There was no significant difference in %ACA to %BCA ratio between obese and lean individuals (0.91 +/- 1.09 vs 0.75 +/- 0.51, P = .47). CONCLUSION: There was no increase in beta-cell mass and no detectable change in beta-cell turnover in Japanese obese individuals.

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Renal microcirculation and calcium channel subtypes

Homma, K., Hayashi, K., Yamaguchi, S., Fujishima, S., Hori, S. and Itoh, H.

Curr Hypertens Rev 9 （ 3 ） 182 - 6 2013年08月

ISSN 1573-4021

It has recently been reported that voltage-dependent Ca channel subtypes, e.g., L-, T-, N-, and P/Q-type, are expressed in renal arterioles and renal tubules, and the inhibition of these channels exerts various effects on renal microcirculation. For example, selective blockade of L-type Ca channels with nifedipine preferentially dilates the afferent arteriole and potentially induces glomerular hypertension. On the other hand, recently developed Ca channel blockers (CCBs) such as mibefradil and efonidipine block both T-type and L-type Ca channels and consequently dilate both afferent and efferent arterioles, leading to lowering of intraglomerular pressure. Interestingly, aldosterone has recently been recognized as a factor exacerbating renal diseases, and its secretion from adrenal gland is mediated by T-type Ca channels. Furthermore, T-type CCBs were shown to ameliorate renal dysfunction by suppressing inflammatory processes and renin secretion. On the basis of histological evaluations, N-type Ca channels are present in peripheral nerve terminals innervating both afferent and efferent arterioles. Further, it was suggested that N-type CCBs such as cilnidipine suppress renal arteriolar constriction induced by enhanced sympathetic nerve activity, thereby lowering intraglomerular pressure. Taken together, various Ca channel subtypes are present in the kidney and blockade of selective channels with distinct CCBs exerts diverse effects on renal microcirculation. Inhibition of T-type and N-type Ca channels with CCBs is anticipated to exert pleiotropic effects that would retard the progression of chronic kidney disease through modulation of renal hemodynamic and non-hemodynamic processes.

Effects of mitiglinide, a short-acting insulin secretagogue, on daily glycemic variability and oxidative stress markers in Japanese patients with type 2 diabetes mellitus

Kodani, N., Saisho, Y., Tanaka, K., Kawai, T. and Itoh, H.

Clin Drug Investig 33 （ 8 ） 563 - 70 2013年08月

ISSN 1173-2563

BACKGROUND AND OBJECTIVE: The objective of this study was to clarify the effects of mitiglinide on daily glycemic variability and oxidative stress markers in outpatients with type 2 diabetes mellitus that is insufficiently controlled by diet and/or non-insulin secretagogues. METHODS: We enrolled 24 patients with type 2 diabetes whose glycemic control had been suboptimal [i.e. glycosylated hemoglobin (HbA(1c)) >/= 6.9 %]. The patients were treated with mitiglinide 10 mg three times daily for 16 weeks. If their glycemic control was not improved at week 8, the dose of mitiglinide was increased to 20 mg three times daily. Daily glycemic variability was assessed by 7-point self-monitoring of blood glucose for 2 days, and standard deviation (SD), M value, and mean of daily differences(MODD) were calculated. Oxidative stress was assessed by oxidized low-density lipoprotein, pentosidine,urinary 8-iso-prostaglandin F2 alpha, and urinary 8-hydroxydeoxy guanosine. RESULTS: After 16 weeks of mitiglinide treatment, the HbA(1c) level was significantly decreased (mean +/- SD,7.4 +/- 0.7 to 6.8 +/- 0.5 %, P < 0.0001). Postprandial glucose excursion and glycemic variability were also significantly improved after mitiglinide treatment (all P < 0.05). The reductions in SD, M value, and MODD were 17, 50,and 48 %, respectively. There was a significant positive correlation between the change in HbA(1c) and change in SD during the study (r = 0.454, P = 0.03). There were no significant changes in oxidative stress markers. CONCLUSIONS: The present study supports the notion that mitiglinide improves postprandial glucose excursion and HbA(1c) level in patients with type 2 diabetes. In addition,we demonstrated that mitiglinide also effectively improves daily glycemic variability. The effect of mitiglinide on oxidative stress needs further investigation.

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The hydrolase DDAH2 enhances pancreatic insulin secretion by transcriptional regulation of secretagogin through a Sirt1-dependent mechanism in mice

Hasegawa, K., Wakino, S., Kimoto, M., Minakuchi, H., Fujimura, K., Hosoya, K., Komatsu, M., Kaneko, Y., Kanda, T., Tokuyama, H., Hayashi, K. and Itoh, H.

Faseb j 27 （ 6 ） 2301 - 15 2013年06月

ISSN 0892-6638

The role of dimethylarginine dimethylaminohydrolase 2 (DDAH2) in glucose metabolism is unknown. Here, we generated DDAH2 transgenic (Tg) mice. These mice had lower plasma glucose levels (60 min: 298+/-32 vs. 418+/-35 mg/dl; 120 min: 205+/-15 vs. 284+/-20 mg/dl) and higher insulin levels (15 min: 2.1+/-0.2 vs. 1.5+/-0.1 ng/ml; 30 min: 1.8+/-0.1 vs. 1.5+/-0.1 ng/ml) during intraperitoneal glucose tolerance tests when fed a high-fat diet (HFD) compared with HFD-fed wild-type (WT) mice. Glucose-stimulated insulin secretion (GSIS) was increased in Tg islets by 33%. Pancreatic asymmetrical dimethylarginine, nitric oxide, and oxidative stress levels were not correlated with improvements in insulin secretion in Tg mice. Secretagogin, an insulin vesicle docking protein, was up-regulated by 2.7-fold in Tg mice and in pancreatic MIN-6 cells overexpressing DDAH2. GSIS in MIN-6 cells was dependent on DDAH2-induced secretagogin expression. Pancreatic Sirt1, DDAH2, and secretagogin were down-regulated in HFD-fed WT mice by 70, 75, and 85%, respectively. Overexpression of Sirt1 overexpression by 3.9-fold increased DDAH2 and secretagogin expression in MIN-6 cells by 3.2- and 2.5-fold, respectively. DDAH2 overexpression improved GSIS in pancreas-specific Sirt1-deficient mice. In summary, the Sirt1/DDAH2/secretagogin pathway is a novel regulator of GSIS.

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Sema3A regulates bone-mass accrual through sensory innervations

Fukuda, T., Takeda, S., Xu, R., Ochi, H., Sunamura, S., Sato, T., Shibata, S., Yoshida, Y., Gu, Z., Kimura, A., Ma, C., Xu, C., Bando, W., Fujita, K., Shinomiya, K., Hirai, T., Asou, Y., Enomoto, M., Okano, H., Okawa, A. and Itoh, H.

Nature 497 （ 7450 ） 490 - 3 2013年05月

ISSN 0028-0836

Semaphorin 3A (Sema3A) is a diffusible axonal chemorepellent that has an important role in axon guidance. Previous studies have demonstrated that Sema3a(-/-) mice have multiple developmental defects due to abnormal neuronal innervations. Here we show in mice that Sema3A is abundantly expressed in bone, and cell-based assays showed that Sema3A affected osteoblast differentiation in a cell-autonomous fashion. Accordingly, Sema3a(-/-) mice had a low bone mass due to decreased bone formation. However, osteoblast-specific Sema3A-deficient mice (Sema3acol1(-/-) and Sema3aosx(-/-) mice) had normal bone mass, even though the expression of Sema3A in bone was substantially decreased. In contrast, mice lacking Sema3A in neurons (Sema3asynapsin(-/-) and Sema3anestin(-/-) mice) had low bone mass, similar to Sema3a(-/-) mice, indicating that neuron-derived Sema3A is responsible for the observed bone abnormalities independent of the local effect of Sema3A in bone. Indeed, the number of sensory innervations of trabecular bone was significantly decreased in Sema3asynapsin(-/-) mice, whereas sympathetic innervations of trabecular bone were unchanged. Moreover, ablating sensory nerves decreased bone mass in wild-type mice, whereas it did not reduce the low bone mass in Sema3anestin(-/-) mice further, supporting the essential role of the sensory nervous system in normal bone homeostasis. Finally, neuronal abnormalities in Sema3a(-/-) mice, such as olfactory development, were identified in Sema3asynasin(-/-) mice, demonstrating that neuron-derived Sema3A contributes to the abnormal neural development seen in Sema3a(-/-) mice, and indicating that Sema3A produced in neurons regulates neural development in an autocrine manner. This study demonstrates that Sema3A regulates bone remodelling indirectly by modulating sensory nerve development, but not directly by acting on osteoblasts.

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CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion

Nakamura, Y., Kanai, T., Saeki, K., Takabe, M., Irie, J., Miyoshi, J., Mikami, Y., Teratani, T., Suzuki, T., Miyata, N., Hisamatsu, T., Nakamoto, N., Yamagishi, Y., Higuchi, H., Ebinuma, H., Hozawa, S., Saito, H., Itoh, H. and Hibi, T.

Am J Physiol Gastrointest Liver Physiol 304 （ 8 ） G700 - 7 2013年04月

ISSN 0193-1857

Glucagon-like peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b(+)Gr-1(low) macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b(+)/Gr-1(-) and CD11b(+)/Gr-1(high) cells, but not CD11b(+)/Gr-1(low) cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic cerulein-administered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b(+)-cell migration to the pancreas is critically involved in chronic pancreatitis-mediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.

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[Diabetes mellitus related common medical disorders : recent progress in diagnosis and treatment. Topics: I. Pathophysiology, diagnosis and treatment: 3. Primary aldosteronism, resistant hypertension and diabetes mellitus]

Shibata, H. and Itoh, H.

Nihon Naika Gakkai Zasshi 102 （ 4 ） 850 - 5 2013年04月

ISSN 0021-5384

Relationship between Stage of Diabetic Retinopathy and Pulse Wave Velocity in Japanese Patients with Type 2 Diabetes

Tanaka, K., Kawai, T., Saisho, Y., Meguro, S., Harada, K., Satoh, Y., Kobayashi, K., Mizushima, K., Abe, T. and Itoh, H.

J Diabetes Res 2013 193514 2013年

ISSN 2314-6745

Objectives. We investigated the relationship between the stage of diabetic retinopathy and pulse wave velocity (PWV). Methods. This was a cross-sectional study of 689 patients (406 men and 283 women) with type 2 diabetes who were admitted to our hospital from 2004 to 2007. Brachial-ankle pulse wave velocity (baPWV) was measured by an arterial pressure measurement device as PWV/ABI. Diagnosis of diabetic retinopathy was made by ophthalmologists based on the Davis classification: no diabetic retinopathy (NDR), simple retinopathy (SDR), pre-proliferative retinopathy (pre-PDR), and proliferative retinopathy (PDR). Results. There was a significant difference in PWV between patients without diabetic retinopathy (1657.0 +/- 417.9 m/s (mean +/- SD)) and with diabetic retinopathy (1847.1 +/- 423.9 m/s) (P < 0.001). In addition, the stage of diabetic retinopathy was associated with aortic PWV (1657.0 +/- 417.9 m/s in NDR (n = 420), 1819.4 +/- 430.3 m/s in SDR (n = 152), 1862.1 +/- 394.0 m/s in pre-PDR (n = 54), and 1901.1 +/- 433.5 m/s in PDR (n = 63) (P < 0.001)). Conclusions. In patients with diabetic retinopathy, even in those with SDR, PWV was higher than that in patients without diabetic retinopathy. Physicians should therefore pay attention to the value of PWV and macroangiopathy regardless of the stage of diabetic retinopathy.

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Marked decline in beta cell function during pregnancy leads to the development of glucose intolerance in Japanese women

Saisho, Y., Miyakoshi, K., Ikenoue, S., Kasuga, Y., Matsumoto, T., Minegishi, K., Yoshimura, Y. and Itoh, H.

Endocr J 60 （ 4 ） 533 - 9 2013年

ISSN 0918-8959

The aim of this study is to investigate glucose metabolism longitudinally during pregnancy to explore mechanisms underlying gestational diabetes mellitus (GDM). We reviewed a total of 62 pregnant Japanese women who underwent a 75g oral glucose tolerance test (OGTT) twice during pregnancy (median: early, 13; late, 28 weeks' gestation) because of positive GDM screening. All showed normal OGTT results in early pregnancy. Based on late OGTT, 15 had GDM (late-onset GDM) and 47 normal glucose tolerance (NGT). In early pregnancy, there were no significant differences in insulin sensitivity (insulin sensitivity index derived from OGTT [IS(OGTT)] and homeostasis model assessment for insulin resistance [HOMA-IR]) and insulin secretion (a ratio of the total area-under-the-insulin-curve to the total area-under-the-glucose-curve [AUC(ins/glu)] and insulinogenic index [IGI]) between the NGT and late-onset GDM groups. In each group, insulin sensitivity significantly decreased from early to late pregnancy, most in the late-onset GDM group (each p < 0.05). The insulin secretion showed no significant changes with advancing pregnancy in both of the groups, although late-onset GDM showed significantly lower IGI compared with NGT in late OGTT (p < 0.05). When assessed beta cell function by OGTT-derived disposition index (i.e. Insulin Secretion-Sensitivity Index-2 and IGI/fasting insulin), the indices significantly decreased from early to late pregnancy in the both groups (each p < 0.05). Women with late-onset GDM showed significantly lower indices compared with NGT (each p < 0.05). The failure of beta cell to compensate for decreased insulin sensitivity could contribute to the development of the late-onset GDM.

Association between beta cell function and future glycemic control in patients with type 2 diabetes

Saisho, Y., Kou, K., Tanaka, K., Abe, T., Shimada, A., Kawai, T. and Itoh, H.

Endocr J 60 （ 4 ） 517 - 23 2013年

ISSN 0918-8959

The aim of this study was to clarify the association between C-peptide immunoreactivity (CPR), a marker of beta cell function, and future glycemic control in patients with type 2 diabetes. We conducted a retrospective analysis of 513 consecutive patients with type 2 diabetes who were admitted to our hospital between 2000 and 2007 and followed up for 2 years. Serum and urinary CPR levels were measured during admission, and CPR index was calculated as the ratio of CPR to plasma glucose. The associations between these markers at baseline and glycemic control after 2 years were assessed by means of logistic regression models. After 2 years, 167 patients (32.6%) showed good glycemic control (HbA1c <6.9%). Baseline serum and urinary CPR indices were significantly associated with good glycemic control after 2 years, and the postprandial CPR to plasma glucose ratio (postprandial CPR index) showed the strongest association (odds ratio (OR) 1.29, 95% confidence interval (CI) 1.12-1.50, P = 0.001) among CPR indices. Multivariate analyses showed consistent results (OR 1.23, 95%CI 1.03-1.48, P = 0.021). In conclusion, preserved beta cell function at baseline was associated with better glycemic control thereafter in patients with type 2 diabetes.

C-reactive protein, high-molecular-weight adiponectin and development of metabolic syndrome in the Japanese general population: a longitudinal cohort study

Saisho, Y., Hirose, H., Roberts, R., Abe, T., Kawabe, H. and Itoh, H.

PLoS One 8 （ 9 ） e73430 2013年

ISSN 1932-6203

AIMS: To clarify predictive values of C-reactive protein (CRP) and high-molecular-weight (HMW) adiponectin for development of metabolic syndrome. RESEARCH DESIGN AND METHODS: We conducted a prospective cohort study of Japanese workers who had participated in an annual health checkup in 2007 and 2011. A total of 750 subjects (558 men and 192 women, age 46+/-8 years) who had not met the criteria of metabolic syndrome and whose CRP and HMW-adiponectin levels had been measured in 2007 were enrolled in this study. Associations between CRP, HMW-adiponectin and development of metabolic syndrome after 4 years were assessed by logistic regression analysis and their predictive values were compared by receiver operating characteristic analysis. RESULTS: Among 750 subjects, 61 (8.1%) developed metabolic syndrome defined by modified National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria and 53 (7.1%) developed metabolic syndrome defined by Japan Society for the Study of Obesity (JASSO) in 2011. Although CRP and HMW-adiponectin were both significantly correlated with development of metabolic syndrome, multivariate logistic regression analysis revealed that HMW-adiponectin but not CRP was associated with metabolic syndrome independently of BMI or waist circumference. Adding these biomarkers to BMI or waist circumference did not improve the predictive value for metabolic syndrome. CONCLUSION: Our findings indicate that the traditional markers of adiposity such as BMI or waist circumference remain superior markers for predicting metabolic syndrome compared to CRP, HMW-adiponectin, or the combination of both among the Japanese population.

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Past Obesity as well as Present Body Weight Status Is a Risk Factor for Diabetic Nephropathy

Meguro, S., Kabeya, Y., Tanaka, K., Kawai, T., Tomita, M., Katsuki, T., Oikawa, Y., Atsumi, Y., Shimada, A., Tanaka, M., Irie, J., Saisho, Y. and Itoh, H.

Int J Endocrinol 2013 590569 2013年

ISSN 1687-8337

Aims. We analyzed the prevalence of nephropathy according to past body weight status in Japanese subjects with type 2 diabetes because the influence of past obesity on diabetic complications is not certain. Methods. We examined the prevalence of nephropathy in 2927 subjects with type 2 diabetes mellitus according to current BMI and maximum BMI in the past. We defined "current obesity" as BMI on hospitalization of 25 or more, "previous obesity" as BMI on hospitalization of less than 25 and self-reported maximum BMI in the past of 25 or more, and "continuously lean" as maximum BMI of less than 25. Results. The prevalence of nephropathy was significantly higher in subjects with current obesity (40.6%) or previous obesity (35.6%) than in those who were continuously lean (24.3%) (P < 0.017). In logistic regression analysis, previous obesity, as well as current obesity, was a significant risk factor for nephropathy, independent of sex, age, disease duration, hypertension, dyslipidemia, HbA1c, and diabetic retinopathy. Conclusions. Obesity in the past, as well as the present body weight status, was a risk factor for diabetic nephropathy.

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The role of individual domains and the significance of shedding of ATP6AP2/(pro)renin receptor in vacuolar H(+)-ATPase biogenesis

Kinouchi, K., Ichihara, A., Sano, M., Sun-Wada, G. H., Wada, Y., Ochi, H., Fukuda, T., Bokuda, K., Kurosawa, H., Yoshida, N., Takeda, S., Fukuda, K. and Itoh, H.

PLoS One 8 （ 11 ） e78603 2013年

ISSN 1932-6203

The ATPase 6 accessory protein 2 (ATP6AP2)/(pro)renin receptor (PRR) is essential for the biogenesis of active vacuolar H(+)-ATPase (V-ATPase). Genetic deletion of ATP6AP2/PRR causes V-ATPase dysfunction and compromises vesicular acidification. Here, we characterized the domains of ATP6AP2/PRR involved in active V-ATPase biogenesis. Three forms of ATP6AP2/PRR were found intracellularly: full-length protein and the N- and C-terminal fragments of furin cleavage products, with the N-terminal fragment secreted extracellularly. Genetic deletion of ATP6AP2/PRR did not affect the protein stability of V-ATPase subunits. The extracellular domain (ECD) and transmembrane domain (TM) of ATP6AP2/PRR were indispensable for the biogenesis of active V-ATPase. A deletion mutant of ATP6AP2/PRR, which lacks exon 4-encoded amino acids inside the ECD (Delta4M) and causes X-linked mental retardation Hedera type (MRXSH) and X-linked parkinsonism with spasticity (XPDS) in humans, was defective as a V-ATPase-associated protein. Prorenin had no effect on the biogenesis of active V-ATPase. The cleavage of ATP6AP2/PRR by furin seemed also dispensable for the biogenesis of active V-ATPase. We conclude that the N-terminal ECD of ATP6AP2/PRR, which is also involved in binding to prorenin or renin, is required for the biogenesis of active V-ATPase. The V-ATPase assembly occurs prior to its delivery to the trans-Golgi network and hence shedding of ATP6AP2/PRR would not affect the biogenesis of active V-ATPase.

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Effects of adding ezetimibe to fluvastatin on kidney function in patients with hypercholesterolemia: a randomized control trial

Kinouchi, K., Ichihara, A., Bokuda, K., Morimoto, S. and Itoh, H.

J Atheroscler Thromb 20 （ 3 ） 245 - 56 2013年

ISSN 1340-3478

AIMS: Statins not only reduce low-density lipoprotein (LDL) cholesterol, but also prevent the progression of kidney dysfunction. Ezetimibe, a cholesterol-absorption inhibitor, also lowers LDL cholesterol levels when added to statins; however, the effect of add-on ezetimibe on kidney function has had conflicting results. METHODS: We conducted an open-labeled, randomized, 12-month trial, comparing the effects of daily therapy with 20 mg fluvastatin either with or without 10 mg ezetimibe in 54 patients with dyslipidemia. The prespecified primary outcome was the percent change from baseline in kidney function, which was defined by the estimated glomerular filtration rate. The secondary outcomes were the changes in surrogate atherosclerotic markers. All analyses were by intention to treat. RESULTS: The primary outcome, the percent change from baseline (+/-SE) of the estimated glomerular filtration rate, was -5.5+/-1.9% in the fluvastatin-only group and 6.6+/-1.9% in the fluvastatin-plus-ezetimibe (combined-therapy) group (p=0.0002). Secondary outcomes, consisting of the cardioankle vascular index, augmentation index, ankle-brachial index, and maximum intima-media thickness of the carotid arteries, did not differ significantly between the two groups. At the end of the study, the mean (+/-SD) LDL cholesterol was 122+/-23 mg per deciliter in the fluvastatin group and 111+/-29 mg per deciliter in the combined-therapy group (a between-group difference of 9.2%, p= 0.036). Side-effect and safety profiles were similar in the two groups. CONCLUSION: Combined therapy with fluvastatin 20 mg plus ezetimibe 10 mg daily resulted in a significant improvement in changes in the estimated glomerular filtration rate.

Skew of plasma low- and high-density lipoprotein distributions to less dense subfractions in normotriglyceridemic chronic kidney disease patients on maintenance hemodialysis treatment

Homma, K., Homma, Y., Shiina, Y., Wakino, S., Suzuki, M., Fujishima, S., Hayashi, K., Hori, S. and Itoh, H.

Nephron Clin Pract 123 （ 1-2 ） 41 - 5 2013年

ISSN 1660-2110

BACKGROUND: Plasma levels of small, dense low-density lipoprotein (LDL) were reported to increase in chronic kidney disease (CKD) patients on hemodialysis (HD), but most of these patients were hypertriglyceridemic. Plasma levels of small, dense LDL are known to increase in hypertriglyceridemic subjects. Therefore, to investigate the direct effect of CKD on the distribution of LDL subfractions, we investigated the distribution of LDL subfractions in normotriglyceridemic CKD patients on HD. METHODS: The levels of plasma lipoprotein subfractions and lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP), which markedly influence the distributions of plasma LDL and high-density lipoprotein (HDL) subfractions, were compared between 40 HD patients and 40 normolipidemic controls. Plasma lipoproteins were subfractionated into seven subfractions by ultracentrifugation. RESULTS: Plasma levels of cholesterol (C) in remnant-like particle, which is equivalent to the triglyceride (TG)-rich lipoprotein remnant, were twice as high in HD patients as those in controls with matched TG levels. Plasma levels of C and TG in VLDL and IDL (intermediate density lipoprotein) were slightly higher in HD patients than in controls. The C/TG ratio of VLDL was significantly higher in HD patients than in controls. In comparison with the corresponding values in controls, the C and TG levels in low-density LDL and HDL2 in HD patients were high, whereas those in medium-density LDL, high-density LDL, and HDL3 were low. Plasma LCAT activity and CETP mass were lower in HD patients than in controls. CONCLUSION: Distribution of LDL and HDL skewed toward less dense fractions in normotriglyceridemic CKD patients on HD. A decrease in reverse C transport likely played an important role in these changes in the patients.

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Effect of Telmisartan or Losartan for Treatment of Nonalcoholic Fatty Liver Disease: Fatty Liver Protection Trial by Telmisartan or Losartan Study (FANTASY)

Hirata, T., Tomita, K., Kawai, T., Yokoyama, H., Shimada, A., Kikuchi, M., Hirose, H., Ebinuma, H., Irie, J., Ojiro, K., Oikawa, Y., Saito, H., Itoh, H. and Hibi, T.

Int J Endocrinol 2013 587140 2013年

ISSN 1687-8337

AIM: This study compared the effects of telmisartan and losartan on nonalcoholic fatty liver disease (NAFLD) and biochemical markers of insulin resistance in hypertensive NAFLD patients with type 2 diabetes mellitus. METHODS: This was a randomized, open-label, parallel-group comparison of therapy with telmisartan or losartan. Nineteen hypertensive NAFLD patients with type 2 diabetes were randomly assigned to receive telmisartan at a dose of 40 mg once a day (n = 12) [DOSAGE ERROR CORRECTED] or losartan at a dose of 50 mg once a day (n = 7) for 12 months. RESULTS: The telmisartan group showed a significant decline in serum free fatty acid (FFA) level (from 0.87 +/- 0.26 to 0.59 +/- 0.22 mEq/L (mean +/- SD), P = 0.005) and a significant increase in L/S ratio (P = 0.049) evaluated by CT scan, while these parameters were not changed in the losartan group. CONCLUSION: Although there was no significant difference in improvement in liver enzymes with telmisartan and losartan treatment in hypertensive NAFLD patients with type 2 diabetes after 12 months, it is suggested that telmisartan may exert beneficial effects by improving fatty liver.

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A large coronary aneurysm and its probable precursor lesions in a patient with autosomal dominant polycystic kidney disease: an implication for the process of aneurysmogenesis

Ohara, K., Kimura, T., Karasawa, T., Tokuyama, H., Wakino, S., Hayashi, K., Itoh, H. and Okada, Y.

Pathol Int 62 （ 11 ） 758 - 62 2012年11月

ISSN 1320-5463

Coronary artery aneurysms are rare complications of autosomal dominant polycystic kidney disease (ADPKD), and their pathogenesis remains poorly understood. We report an autopsy case of a 64-year-old ADPKD patient with an asymptomatic, large (4 cm in diameter) saccular aneurysm arising from the left circumflex (LCX) branch of the coronary artery with only mild atherosclerotic changes. Autopsy also revealed small, focal defects of media with or without microaneurysm formation in the LCX, mesenteric and renal arteries, and a fibromuscular dysplasia-like lesion with microaneurysm in the common iliac artery. Since polycystin-1 and -2 are expressed in arterial smooth-muscle cells, these findings imply that abnormal polycystin expression in ADPKD initially causes the focal medial defects, some of which might later progress to microaneurysms and then overt aneurysms. To the best of our knowledge, this is the first description of the pathologic findings of an ADPKD-associated coronary aneurysm and its probable precursor lesions in arteries.

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[The ACE2/Ang(1-7)/Mas receptor axis in cardiovascular and renal diseases]

Kanda, T. and Itoh, H.

Nihon Rinsho 70 （ 9 ） 1487 - 91 2012年09月

ISSN 0047-1852

The renin-angiotensin-aldosterone system(RAAS) plays a crucial role in the regulation of physiological homeostasis and diseases such as hypertension, coronary artery disease and chronic renal failure. In this cascade, the ACE/Ang II/AT1 receptor axis induces pathological effects, such as vasoconstriction, cell proliferation and fibrosis. Recently the ACE2/Ang(1-7)/Mas receptor axis has been recognized as a negative regulator of the RAAS. ACE2 metabolizes Ang II into Ang(1-7), which has opposite properties of Ang II through Mas receptor activation. Both animal and human studies provide strong evidence that the ACE2/Ang(1-7)/Mas receptor axis is protective for end-organ damage. Therefore, the ACE2/Ang(1-7)/Mas receptor axis could be a therapeutic target for coronary artery disease and chronic renal failure.

[Current status of vaccination therapy for hypertension]

Sasamura, H., Azegami, T. and Itoh, H.

Nihon Rinsho 70 （ 9 ） 1627 - 32 2012年09月

ISSN 0047-1852

The renin-angiotensin system (RAS) plays a central role in the control of systemic blood pressure. Since the 1950s, both laboratory and clinical studies have been performed to test the efficacy of vaccines against the RAS for the management of hypertension. Although initial studies using renin vaccines and angiotensin I vaccines were unsuccessful, a recent phase IIa study has shown that vaccination against angiotensin II is effective for the treatment of patients with essential hypertension. Results from animal studies have also suggested that vaccination against the AT1 receptor may be effective not only for lowering blood pressure, but also for the prevention of hypertensive end-organ damage. In the future, the RAS may be an important target for the development of vaccines not only for the treatment, but also for the prevention of hypertension and hypertensive complications.

Loss of Pdk1-Foxo1 signaling in myeloid cells predisposes to adipose tissue inflammation and insulin resistance

Kawano, Y., Nakae, J., Watanabe, N., Fujisaka, S., Iskandar, K., Sekioka, R., Hayashi, Y., Tobe, K., Kasuga, M., Noda, T., Yoshimura, A., Onodera, M. and Itoh, H.

Diabetes 61 （ 8 ） 1935 - 48 2012年08月

ISSN 0012-1797

Chronic inflammation in adipose tissue contributes to obesity-related insulin resistance. The 3-phosphoinositide-dependent protein kinase 1 (Pdk1)/forkhead transcription factor (Foxo1) pathway is important in regulating glucose and energy homeostasis, but little is known about this pathway in adipose tissue macrophages (ATMs). To investigate this, we generated transgenic mice that carried macrophage/granulocyte-specific mutations, including a Pdk1 knockout (LysMPdk1(-/-)), a Pdk1 knockout with transactivation-defective Foxo1 (Delta256LysMPdk1(-/-)), a constitutively active nuclear (CN) Foxo1 (CNFoxo1(LysM)), or a transactivation-defective Foxo1 (Delta256Foxo1(LysM)). We analyzed glucose metabolism and gene expression in ATM populations isolated with fluorescence-activated cell sorting. The LysMPdk1(-/-) mice exhibited elevated M1 macrophages in adipose tissue and insulin resistance. Overexpression of transactivation-defective Foxo1 rescued these phenotypes. CNFoxo1(LysM) promoted transcription of the C-C motif chemokine receptor 2 (Ccr2) in ATMs and increased M1 macrophages in adipose tissue. On a high-fat diet, CNFoxo1(LysM) mice exhibited insulin resistance. Pdk1 deletion or Foxo1 activation in bone marrow-derived macrophages abolished insulin and interleukin-4 induction of genes involved in alternative macrophage activation. Thus, Pdk1 regulated macrophage infiltration by inhibiting Foxo1-induced Ccr2 expression. This shows that the macrophage Pdk1/Foxo1 pathway is important in regulating insulin sensitivity in vivo.

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A case of hypoglycemic hemiparesis and literature review

Yoshino, T., Meguro, S., Soeda, Y., Itoh, A., Kawai, T. and Itoh, H.

Ups J Med Sci 117 （ 3 ） 347 - 51 2012年08月

ISSN 0300-9734

An 89-year-old man with diabetes treated with metformin 500 mg/day and glimepiride 4 mg/day was hospitalized because of hypoglycemic right hemiparesis and dysarthria (casual glucose value 1.8 mmol/L), which resolved quickly following administration of 40 mL of 40% dextrose. Hemiparesis is a rare symptom (4.2%) of hypoglycemia. There are about 200 case reports of hypoglycemic hemiparesis. The average glucose level at which hemiparesis developed was 1.8 mmol/L. Right-sided hemiparesis predominated (R 66%; L 34%). On imaging studies, abnormal findings were frequently observed in the internal capsule or splenium of the corpus callosum. The mechanism of hemiparesis is not fully understood. The existence of cases in which hypoglycemia cannot be distinguished from stroke on imaging studies suggests the importance of measurement of the blood glucose level when the symptoms of stroke are first recognized.

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Coenzyme Q10 reverses mitochondrial dysfunction in atorvastatin-treated mice and increases exercise endurance

Muraki, A., Miyashita, K., Mitsuishi, M., Tamaki, M., Tanaka, K. and Itoh, H.

J Appl Physiol (1985) 113 （ 3 ） 479 - 86 2012年08月

ISSN 0161-7567

Statins are cholesterol-lowering drugs widely used in the prevention of cardiovascular diseases; however, they are associated with various types of myopathies. Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and thus decrease biosynthesis of low-density lipoprotein cholesterol and may also reduce ubiquinones, essential coenzymes of a mitochondrial electron transport chain, which contain isoprenoid residues, synthesized through an HMG-CoA reductase-dependent pathway. Therefore, we hypothesized that statin treatment might influence physical performance through muscular mitochondrial dysfunction due to ubiquinone deficiency. The effect of two statins, atorvastatin and pravastatin, on ubiquinone content, mitochondrial function, and physical performance was examined by using statin-treated mice. Changes in energy metabolism in association with statin treatment were studied by using cultured myocytes. We found that atorvastatin-treated mice developed muscular mitochondrial dysfunction due to ubiquinone deficiency and a decrease in exercise endurance without affecting muscle mass and strength. Meanwhile, pravastatin at ten times higher dose of atorvastatin had no such effects. In cultured myocytes, atorvastatin-related decrease in mitochondrial activity led to a decrease in oxygen utilization and an increase in lactate production. Conversely, coenzyme Q(10) treatment in atorvastatin-treated mice reversed atorvastatin-related mitochondrial dysfunction and a decrease in oxygen utilization, and thus improved exercise endurance. Atorvastatin decreased exercise endurance in mice through mitochondrial dysfunction due to ubiquinone deficiency. Ubiquinone supplementation with coenzyme Q(10) could reverse atorvastatin-related mitochondrial dysfunction and decrease in exercise tolerance.

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MPO-ANCA associated crescentic glomerulonephritis with numerous immune complexes: case report

Morizane, R., Konishi, K., Hashiguchi, A., Tokuyama, H., Wakino, S., Kawabe, H., Hayashi, M., Hayashi, K. and Itoh, H.

BMC Nephrol 13 32 2012年06月

ISSN 1471-2369

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis (CGN) is a major cause of rapidly progressive glomerulonephritis (RPGN). ANCA-associated CGN is generally classified into pauci-immune RPGN, in which there are few or no immune complexes. CASE PRESENTATION: A 78-year-old man presented with RPGN after a 7-year course of chronic proteinuria and hematuria with stable renal function. A blood examination showed a high titer of myeloperoxidase (MPO)-ANCA. A renal biopsy showed crescentic glomerulonephritis with abundant subepithelial, intramenbranous and subendothelial deposits by electron microscopy, leading to the diagnosis of ANCA-associated CGN superimposed on type 3 membranoproliferative glomerulonephritis (MPGN). CONCLUSIONS: This case is unique in that type 3 MPGN and MPO-ANCA-associated CGN coexisted, and no similar case has been reported to date. Because ANCA-associated CGN has a predilection for elderly individuals and primary type 3 MPGN is rarely seen in this age group, coincidental existence appears less likely. This case may confer valuable information regarding the link between immune complex and ANCA-associated CGN.

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Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway

Ichikawa, R., Takayama, T., Yoneno, K., Kamada, N., Kitazume, M. T., Higuchi, H., Matsuoka, K., Watanabe, M., Itoh, H., Kanai, T., Hisamatsu, T. and Hibi, T.

Immunology 136 （ 2 ） 153 - 62 2012年06月

ISSN 0019-2805

Dendritic cells (DCs) are known as antigen-presenting cells and play a central role in both innate and acquired immunity. Peripheral blood monocytes give rise to resident and recruited DCs in lymph nodes and non-lymphoid tissues. The ligands of nuclear hormone receptors can modulate DC differentiation and so influence various biological functions of DCs. The role of bile acids (BAs) as signalling molecules has recently become apparent, but the functional role of BAs in DC differentiation has not yet been elucidated. We show that DCs derived from human peripheral blood monocytes cultured with a BA produce lower levels of interleukin-12 (IL-12) and tumour necrosis factor-alpha in response to stimulation with commensal bacterial antigens. Stimulation through the nuclear receptor farnesoid X (FXR) did not affect the differentiation of DCs. However, DCs differentiated with the specific agonist for TGR5, a transmembrane BA receptor, showed an IL-12 hypo-producing phenotype. Expression of TGR5 could only be identified in monocytes and was rapidly down-regulated during monocyte differentiation to DCs. Stimulation with 8-bromoadenosine-cyclic AMP (8-Br-cAMP), which acts downstream of TGR5 signalling, also promoted differentiation into IL-12 hypo-producing DCs. These results indicate that BAs induce the differentiation of IL-12 hypo-producing DCs from monocytes via the TGR5-cAMP pathway.

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Novel repressor regulates insulin sensitivity through interaction with Foxo1

Nakae, J., Cao, Y., Hakuno, F., Takemori, H., Kawano, Y., Sekioka, R., Abe, T., Kiyonari, H., Tanaka, T., Sakai, J., Takahashi, S. and Itoh, H.

Embo j 31 （ 10 ） 2275 - 95 2012年05月

ISSN 0261-4189

Forkhead box-containing protein o (Foxo) 1 is a key transcription factor in insulin and glucose metabolism. We identified a Foxo1-CoRepressor (FCoR) protein in mouse adipose tissue that inhibits Foxo1's activity by enhancing acetylation via impairment of the interaction between Foxo1 and the deacetylase Sirt1 and via direct acetylation. FCoR is phosphorylated at Threonine 93 by catalytic subunit of protein kinase A and is translocated into nucleus, making it possible to bind to Foxo1 in both cytosol and nucleus. Knockdown of FCoR in 3T3-F442A cells enhanced expression of Foxo target and inhibited adipocyte differentiation. Overexpression of FCoR in white adipose tissue decreased expression of Foxo-target genes and adipocyte size and increased insulin sensitivity in Lepr(db/db) mice and in mice fed a high-fat diet. In contrast, Fcor knockout mice were lean, glucose intolerant, and had decreased insulin sensitivity that was accompanied by increased expression levels of Foxo-target genes and enlarged adipocytes. Taken together, these data suggest that FCoR is a novel repressor that regulates insulin sensitivity and energy metabolism in adipose tissue by acting to fine-tune Foxo1 activity.

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Vaccination against the angiotensin type 1 receptor for the prevention of L-NAME-induced nephropathy

Azegami, T., Sasamura, H., Hayashi, K. and Itoh, H.

Hypertens Res 35 （ 5 ） 492 - 9 2012年05月

ISSN 0916-9636

Previous studies have shown that renin-angiotensin (Ang) system vaccines may be effective for the treatment of hypertension, but their efficacy for the prevention of renal disease is unclear. The aim of this study was to compare the effects of an Ang II type 1 (AT1) receptor vaccine with an Ang II receptor blocker (ARB) and a vasodilator on blood pressure (BP) and renal injury in the L-NAME nephropathy model. Male spontaneously hypertensive rats (SHRs) were divided into six groups and treated transiently with three injections of vehicle or AT1 receptor vaccine (0.1 mg) at age 4, 6 and 8 weeks, or continuously with candesartan cilexetil (0.1 mg kg(-1) per day) or hydralazine hydrochloride (5 mg kg(-1) per day), then administered NG-nitro-L-arginine methyl ester (L-NAME) from age 18 to 21 weeks to induce renal injury. Vaccination against the AT1 receptor caused a significant increase in AT1 receptor titers, and a sustained decrease in BP. L-NAME treatment resulted in a marked increase in proteinuria in the control groups, which was completely suppressed in the AT1 vaccine-treated group, and glomerular injury scores were also significantly decreased. Real-time RT-PCR and immunofluorescence studies revealed increased renin mRNA, and increased glomerular expression of nephrin. Comparable results were seen in rats treated continuously with the ARB candesartan, but not with hydralazine. These results suggest that transient AT1 vaccination is as effective as continuous treatment with ARB, not only for the attenuation of hypertension, but also for the prevention of L-NAME-induced nephropathy in SHR.

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Mineralocorticoid receptor-associated hypertension and its organ damage: clinical relevance for resistant hypertension

Shibata, H. and Itoh, H.

Am J Hypertens 25 （ 5 ） 514 - 23 2012年05月

ISSN 0895-7061

The role of aldosterone in the pathogenesis of hypertension and cardiovascular diseases has been clearly shown in congestive heart failure and endocrine hypertension due to primary aldosteronism. In resistant hypertension, defined as a failure of concomitant use of three or more different classes of antihypertensive agents to control blood pressure (BP), add-on therapy with mineralocorticoid receptor (MR) antagonists is frequently effective, which we designate as "MR-associated hypertension". The MR-associated hypertension is classified into two subtypes, that with elevated plasma aldosterone levels and that with normal plasma aldosterone levels. The former subtype includes primary aldosteronism (PA), aldosterone-associated hypertension which exhibited elevated aldosterone-to-renin ratio and plasma aldosterone levels, but no PA, aldosterone breakthrough phenomenon elicited when angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB) is continued to be given, and obstructive sleep apnea. In contrast, the latter subtype includes obesity, diabetes mellitus, chronic kidney disease (CKD), and polycystic ovary syndrome (PCOS). The pathogenesis of MR-associated hypertension with normal plasma aldosterone levels is considered to be mediated by MR activation by pathways other than high aldosterone levels, such as increased MR levels, increased MR sensitivity, and MR overstimulation by other factors such as Rac1. For resistant hypertension with high plasma aldosterone levels, MR antagonist should be given as a first-line therapy, whereas for resistant hypertension with normal aldosterone levels, ARB or ACE-I should be given as a first-line therapy and MR antagonist would be given as an add-on agent.

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[The 39th scientific meeting: perspectives of internal medicine; the cutting edge of treatment of medical disorders encountered in clinical practice; 10. Summary]

Itoh, H.

Nihon Naika Gakkai Zasshi 101 （ 3 ） 654 - 5 2012年03月

ISSN 0021-5384

'Memory' and 'legacy' in hypertension and lifestyle-related diseases

Sasamura, H. and Itoh, H.

Hypertens Res 35 （ 3 ） 272 - 3 2012年03月

ISSN 0916-9636

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Bile acid binding resin improves metabolic control through the induction of energy expenditure

Watanabe, M., Morimoto, K., Houten, S. M., Kaneko-Iwasaki, N., Sugizaki, T., Horai, Y., Mataki, C., Sato, H., Murahashi, K., Arita, E., Schoonjans, K., Suzuki, T., Itoh, H. and Auwerx, J.

PLoS One 7 （ 8 ） e38286 2012年

ISSN 1932-6203

BACKGROUND: Besides well-established roles of bile acids (BA) in dietary lipid absorption and cholesterol homeostasis, it has recently become clear that BA is also a biological signaling molecule. We have shown that strategies aimed at activating TGR5 by increasing the BA pool size with BA administration may constitute a significant therapeutic advance to combat the metabolic syndrome and suggest that such strategies are worth testing in a clinical setting. Bile acid binding resin (BABR) is known not only to reduce serum cholesterol levels but also to improve glucose tolerance and insulin resistance in animal models and humans. However, the mechanisms by which BABR affects glucose homeostasis have not been established. We investigated how BABR affects glycemic control in diet-induced obesity models. METHODS AND FINDINGS: We evaluated the metabolic effect of BABR by administrating colestimide to animal models for the metabolic syndrome. Administration of BABR increased energy expenditure, translating into significant weight reduction and insulin sensitization. The metabolic effects of BABR coincide with activation of cholesterol and BA synthesis in liver and thermogenesis in brown adipose tissue. Interestingly, these effects of BABR occur despite normal food intake and triglyceride absorption. Administration of BABR and BA had similar effects on BA composition and thermogenesis, suggesting that they both are mediated via TGR5 activation. CONCLUSION: Our data hence suggest that BABR could be useful for the management of the impaired glucose tolerance of the metabolic syndrome, since they not only lower cholesterol levels, but also reduce obesity and improve insulin resistance.

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Effect of obesity on declining beta cell function after diagnosis of type 2 diabetes: a possible link suggested by cross-sectional analysis

Saisho, Y., Tanaka, K., Abe, T., Shimada, A., Kawai, T. and Itoh, H.

Endocr J 59 （ 3 ） 187 - 95 2012年

ISSN 0918-8959

It has been reported that beta cell function progressively declines in patients with type 2 diabetes. The objective of this study was to assess the effect of obesity on declining beta cell function after diagnosis of type 2 diabetes. We conducted a cross-sectional study of 689 consecutive subjects with type 2 diabetes who were admitted to our hospital from 2000 to 2007. Fasting and postprandial serum C-peptide immunoreactivity (CPR) and urinary CPR levels had been measured during admission. The subjects were stratified according to BMI and time since diagnosis. CPR index was calculated as CPR (ng/mL) / plasma glucose (mg/dL) x 100. All CPR measurements were significantly higher in the 263 obese (BMI >/=25) subjects compared to the 426 lean subjects (BMI <25). There was a significant negative correlation between CPR indices and duration of diabetes, suggesting a progressive decline in beta cell function after diagnosis of type 2 diabetes. However, this decline was more apparent in obese subjects (postprandial CPR index 0.059/year) compared to lean subjects (0.025/year). The significant difference in serum CPR indices between the lean and obese subjects was lost in subjects more than 10 years after diagnosis. In conclusion, our observations suggest that beta cell function shows a greater progressive decline in obese subjects than in lean subjects with type 2 diabetes. Treatment of obesity may be an important strategy to preserve beta cell function in patients with type 2 diabetes.

Factors Associated with the Decline of Kidney Function Differ among eGFR Strata in Subjects with Type 2 Diabetes Mellitus

Meguro, S., Tomita, M., Kabeya, Y., Katsuki, T., Oikawa, Y., Shimada, A., Kawai, T., Itoh, H. and Atsumi, Y.

Int J Endocrinol 2012 687867 2012年

ISSN 1687-8337

Introduction. There is no report about risk factors for renal deterioration according to the clinical stage, divided by the estimated glomerular filtration rate (eGFR) in type 2 diabetes. Materials and Methods. We evaluated the factors correlated with the annual eGFR decline in 1303 subjects with type 2 diabetes whose eGFR was >/=30 mL/min/1.73 m(2). eGFR strata were defined by baseline eGFR value as follows: stratum 1: >/=90, stratum 2: >/=60, <90, and stratum 3: >/=30, <60. Results. The annual eGFR decline was 2.3 +/- 5.4 mL/min/1.73 m(2) in overall subjects. Multiple linear regression analysis demonstrated that age, male sex, systolic blood pressure, logarithmically transformed albumin excretion rate (AER), eGFR strata, and hemoglobin concentration were significantly correlated with the annual eGFR decline. When stratified by eGFR, the factors that showed a significant correlation were different among eGFR strata. AER was significantly correlated with annual eGFR decline in all eGFR strata. Hemoglobin concentration showed a significant correlation only in the advanced eGFR stratum. Conclusion. The factors correlated with the annual eGFR decline were different among eGFR strata in type 2 diabetes mellitus, and hemoglobin concentration and AER were important factors for renal deterioration, especially in the advanced eGFR stratum.

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A new preventive strategy for hypoglycemia incorporating added food diet in patients with type 2 diabetes who received sitagliptin therapy

Meguro, S., Sano, M., Kawai, T., Matsuhashi, T., Mogi, S., Fukuda, K., Itoh, H. and Suzuki, Y.

Endocr Res 37 （ 4 ） 175 - 81 2012年

ISSN 0743-5800

There has been concern as to whether dipeptidyl peptidase-4 (DPP-4) inhibitors can be used safely in patients with relatively good glycemic control. This study, approved by the institutional review board of Hanzoumon Diabetes City Atlas Clinic, examined whether DPP-4 inhibitor sitagliptin could safely achieve good glycemic control without severe hypoglycemia by employing the "added food" concept. The subjects were 60 patients (46 men and 14 women) with type 2 diabetes who started sitagliptin therapy during a 1-month period from December 15, 2009 to January 15, 2010. They were recommended to have added food between meals to prevent hypoglycemia, while maintaining the same daily calorie intake. HbA(1c) decreased from 7.1 +/- 1.2% to 6.5 +/- 0.6% after 6 months of sitagliptin treatment (p < 0.001). In patients with a baseline HbA(1c) <7%, it decreased from 6.5 +/- 0.3% to 6.1 +/- 0.4% (p < 0.001). Systolic blood pressure was significantly reduced from 127.7 +/- 17.0 to 122.7 +/- 17.9 mmHg in the patients with a baseline HbA(1c) < 7% (p = 0.018). However, body weight increased by approximately 900 g and high-density lipoprotein cholesterol decreased significantly from 1.57 +/- 0.46 to 1.43 +/- 0.35 mmol/L (p < 0.01) in the patients concomitantly receiving sulfonylureas with sitagliptin. Excellent glycemic control was achieved by sitagliptin treatment together with the added food concept. However, combined use of sitagliptin with sulfonylureas requires attention to weight gain and the lipid profile. Further clinical studies will elucidate whether sitagliptin can decrease cardiovascular events as well as normalizing blood glucose and lowering the blood pressure.

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Regression of atherosclerosis in apolipoprotein E-deficient mice is feasible using high-dose angiotensin receptor blocker, candesartan

Hayashi, K., Sasamura, H., Azegami, T. and Itoh, H.

J Atheroscler Thromb 19 （ 8 ） 736 - 46 2012年

ISSN 1340-3478

AIM: Clinical studies have suggested that renin-angiotensin inhibitors are effective for the prevention of atherosclerosis progression, but the results for the regression of established lesions are equivocal. The aim of this study was to examine the effects of different doses of the angiotensin receptor blocker (ARB) candesartan on the regression of atherosclerosis and lipid-induced nephropathy in apolipoprotein E (apoE)-deficient spontaneously hyperlipidemic (SHL) mice. METHODS AND RESULTS: Male SHL were given an atherogenic diet together with salt loading to induce atherosclerosis. The mice were then treated with various doses of candesartan (0-50 mg/kg/d) for 12 weeks. Treatment with high-dose candesartan caused clear regression of atherosclerotic plaques in the aorta, which was not observed with normal-dose candesartan. Biglycan and ACAT1 expression were significantly decreased, and aortic free cholesterol: cholesterol ester ratios were increased in these mice. Treatment of cultured THP-1 macrophages in vitro with candesartan resulted in a similar decrease in ACAT1 expression. In the kidney, glomerular lipid accumulation, mesangial expansion, and albuminuria were significantly regressed after treatment with high-dose candesartan, while biglycan and ACAT1 expressions were decreased. CONCLUSION: These results suggest that regression of established atherosclerosis lesions in ApoE-deficient mice is feasible using high-dose candesartan, by mechanisms involving (i) a decrease in the lipid-retaining proteoglycan biglycan, and (ii) suppression of ACAT1 expression resulting in increased free cholesterol for lipid release.

Prorenin receptor is essential for normal podocyte structure and function

Oshima, Y., Kinouchi, K., Ichihara, A., Sakoda, M., Kurauchi-Mito, A., Bokuda, K., Narita, T., Kurosawa, H., Sun-Wada, G. H., Wada, Y., Yamada, T., Takemoto, M., Saleem, M. A., Quaggin, S. E. and Itoh, H.

J Am Soc Nephrol 22 （ 12 ） 2203 - 12 2011年12月

ISSN 1046-6673

The prorenin receptor is an accessory subunit of the vacuolar H(+)-ATPase, suggesting that it has fundamental functions beyond activation of the local renin-angiotensin system. Podocytes express the prorenin receptor, but its function in these cells is unknown. Here, podocyte-specific, conditional, prorenin receptor-knockout mice died of kidney failure and severe proteinuria within 4 weeks of birth. The podocytes of these mice exhibited foot process effacement with reduced and altered localization of the slit-diaphragm proteins nephrin and podocin. Furthermore, the podocytes contained numerous autophagic vacuoles, confirmed by enhanced accumulation of microtubule-associated protein 1 light chain 3-positive intracellular vesicles. Ablation of the prorenin receptor selectively suppressed expression of the V(0) c-subunit of the vacuolar H(+)-ATPase in podocytes, resulting in deacidification of intracellular vesicles. In conclusion, the prorenin receptor is important for the maintenance of normal podocyte structure and function.

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The role of microRNA-145 in human embryonic stem cell differentiation into vascular cells

Yamaguchi, S., Yamahara, K., Homma, K., Suzuki, S., Fujii, S., Morizane, R., Monkawa, T., Matsuzaki, Y., Kangawa, K. and Itoh, H.

Atherosclerosis 219 （ 2 ） 468 - 74 2011年12月

ISSN 0021-9150

BACKGROUND: Recent studies have reported that microRNA-145 (miR-145) is a critical mediator in the regulation of proliferation, differentiation, and phenotype expression of smooth muscle cells (SMCs). Previously, we established a system for differentiating human ESCs into vascular cells including endothelial cells (ECs) and vascular smooth muscle cells (SMCs). In the present study, we investigated the role of miR-145 in the differentiation process from human ESCs into ECs and SMCs. METHODS AND RESULTS: Undifferentiated human ESCs were induced to differentiate into vascular lineage according to our established method. Quantitative RT-PCR analysis revealed that human ESC-derived precursor of SMCs (ES-pre-SMCs), similar to human aortic SMCs, expressed a significant amount of miR-145 as well as smooth muscle-specific proteins, compared to undifferentiated human ESCs, adult ECs, or ESC-derived ECs (ES-ECs). However, morphological analysis revealed that human ES-pre-SMCs appeared round and flattened in shape, though human aortic SMCs exhibited the typical spindle-like morphology of SMCs. In addition, Kruppel-like factor 4 and 5 (KLF4 and 5), direct targets of miR-145 and suppressors of smooth muscle differentiation, were upregulated in ES-pre-SMCs compared to aortic SMCs, indicating ES-pre-SMCs were not fully differentiated SMCs. Overexpression of miR-145 in ES-pre-SMCs upregulated the expression of smooth muscle markers, repressed KLF4 and 5 expressions, and changed their morphology into a differentiated spindle-like shape. Furthermore, by introduction of miR-145, ES-pre-SMC proliferation was significantly inhibited and carbachol-stimulated contraction of ES-pre-SMCs was significantly increased. In contrast, downregulation of miR-145 in ES-pre-SMCs upregulated KLF4 and 5 expressions, suppressed the expression of smooth muscle markers, and left unchanged their proliferation and contractility. In ES-ECs, miR-145 overexpression did not induce the synthesis of smooth muscle-related proteins nor suppress the expression of endothelial nitric oxide synthase. CONCLUSION: We showed that miR-145 can regulate the fate and phenotype of human ES-pre-SMCs as they become fully differentiated SMCs. Overexpression of miR-145 on human ES-pre-SMCs is a promising method to obtain functional mature SMCs from human ESCs, which are required for reliable experimental research in the fields of atherosclerosis, hypertension and other vascular diseases.

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A mimic of viral double-stranded RNA triggers fulminant type 1 diabetes-like syndrome in regulatory T cell-deficient autoimmune diabetic mouse

Tada, A., Shimada, A., Yamada, T., Oikawa, Y., Yamada, Y., Okubo, Y., Irie, J., Bluestone, J. A. and Itoh, H.

J Immunol 187 （ 10 ） 4947 - 53 2011年11月

ISSN 0022-1767

Human fulminant type 1 diabetes (FT1D) is an extremely aggressive disease. The delay of proper diagnosis results in high mortality. However, the pathophysiology of this disease remains unclear. We took advantage of CD28-deficient NOD (CD28(-/-) NOD) mice, which have limited numbers of regulatory T cells and develop aggressive autoimmune diabetes, to create a FT1D model that mimicked the disease in humans. Young CD28(-/-) NOD mice were injected with polyinosinic-polycytidylic acid to activate innate immunity in an effort to induce diabetes onset. In this model, innate immune cell activation precedes the onset of diabetes similar to approximately 70% of FT1D patients. Eighty-three percent of CD28(-/-) NOD mice developed diabetes within 1-6 d after injection of polyinosinic-polycytidylic acid. Moreover, T cells infiltrated the pancreatic exocrine tissue and destroyed alpha cells, an observation characteristic of human FT1D. We conclude that an FT1D-like phenotype can be induced in the background of autoimmune diabetes by a mimic of viral dsRNA, and this model is useful for understanding human FT1D.

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Renal amyloidosis caused by apolipoprotein A-II without a genetic mutation in the coding sequence

Morizane, R., Monkawa, T., Konishi, K., Hashiguchi, A., Ueda, M., Ando, Y., Tokuyama, H., Hayashi, K., Hayashi, M. and Itoh, H.

Clin Exp Nephrol 15 （ 5 ） 774 - 9 2011年10月

ISSN 1342-1751

Although the majority of renal amyloidosis is caused by either acquired monoclonal immunoglobulin light-chain amyloidosis or reactive systemic amyloid A, some cases are caused by hereditary amyloidosis. Apolipoprotein A-II (apoAII) amyloidosis is a rare form of hereditary amyloidosis and cannot be diagnosed by a routine examination. Thus, the prevalence and etiology of apoAII amyloidosis are uncertain. In humans, a genetic mutation in the stop codon of apoAII is considered to be a cause of amyloid fibril formation. We report on a 68-year-old man who presented with proteinuria by apoAII amyloidosis without family history. His proteinuria gradually increased to 6 g/day within 1 year. A renal biopsy showed amyloid deposition in the glomeruli, however, acquired monoclonal immunoglobulin light-chain amyloidosis and reactive systemic amyloid A were ruled out. Immunohistochemistry revealed apoAII deposition in the glomeruli, but DNA sequencing did not identify any genetic mutation in the coding sequence of apoAII. Here, we report a case of apoAII amyloidosis without a genetic mutation in the coding sequence and discuss the etiology of apoAII amyloidosis.

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[Obesity: visceral fat]

Mitsuishi, M., Miyashita, K. and Itoh, H.

Nihon Rinsho 69 Suppl 7 568 - 72 2011年09月

ISSN 0047-1852

Rho-kinase inhibition ameliorates peritoneal fibrosis and angiogenesis in a rat model of peritoneal sclerosis

Washida, N., Wakino, S., Tonozuka, Y., Homma, K., Tokuyama, H., Hara, Y., Hasegawa, K., Minakuchi, H., Fujimura, K., Hosoya, K., Hayashi, K. and Itoh, H.

Nephrol Dial Transplant 26 （ 9 ） 2770 - 9 2011年09月

ISSN 0931-0509

BACKGROUND: Peritoneal fibrosis (PF) and angiogenesis are typical morphological changes, leading to loss of peritoneal functions in patients undergoing peritoneal dialysis. The small G protein, Rho, and its downstream effector Rho-kinase have been shown to be involved in the tissue fibrosis process. This study was undertaken to investigate the role of Rho-kinase in the pathogenesis of these alterations. METHODS: PF was induced by intraperitoneal administration of chlorhexidine (CHX) in male rats (CHX group). These rats were treated with a Rho-kinase inhibitor, fasudil (Fas group). Human pleural mesothelial cells, MeT-5A cells, were stimulated by glucose with or without another Rho-kinase inhibitor, Y-27632. RESULTS: Peritoneal damage including peritoneal thickening, fibrous changes, macrophage migration and angiogenesis were evident in the CHX group and were ameliorated in the Fas group. The expression of markers of tissue fibrosis, such as transforming growth factor (TGF)-beta, fibronectin and alpha-smooth muscle cell actin, were increased in the CHX group and were downregulated by fasudil. Similar results were also seen with an inducer of angiogenesis, vascular endothelial growth factor (VEGF). Rho-kinase was activated in the peritoneum of the CHX group, which was inhibited by fasudil. In MeT-5A cells, high glucose increased TGF-beta expression and VEGF secretion, which were blocked by Y-27632. CONCLUSIONS: The activation of Rho-kinase is involved in peritoneal damage at multiple stages including tissue fibrosis and angiogenesis. The inhibition of Rho-kinase constitutes a novel strategy for the treatment of PF.

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Significance of adrenocorticotropin stimulation test in the diagnosis of an aldosterone-producing adenoma

Sonoyama, T., Sone, M., Miyashita, K., Tamura, N., Yamahara, K., Park, K., Oyamada, N., Taura, D., Inuzuka, M., Kojima, K., Honda, K., Fukunaga, Y., Kanamoto, N., Miura, M., Yasoda, A., Arai, H., Itoh, H. and Nakao, K.

J Clin Endocrinol Metab 96 （ 9 ） 2771 - 8 2011年09月

ISSN 0021-972

CONTEXT: Adrenal venous sampling is the "gold standard" test in the diagnosis of an aldosterone-producing adenoma (APA) among patients with primary aldosteronism (PA) but is available only in specialized medical centers. Meanwhile, an APA is reported to be generally more sensitive to ACTH than idiopathic hyperaldosteronism. OBJECTIVE: The aim was to evaluate the diagnostic accuracy of the ACTH stimulation test in the diagnosis of an APA among those with suspicion of PA. PATIENTS AND SETTING: Fifty-nine patients admitted to Kyoto University Hospital on suspicion of PA were included in the study. INTERVENTIONS: ACTH stimulation tests with 1-mg dexamethasone suppression were performed. MAIN OUTCOME MEASURE: Plasma aldosterone concentrations (PAC) were examined every 30 min after ACTH stimulation. Receiver-operated characteristics curve analysis was used to evaluate the diagnostic accuracy. RESULTS: PAC after ACTH stimulations were significantly higher in patients with an APA than in patients with idiopathic hyperaldosteronism or non-PA. Receiver-operated characteristics curve analyses showed that the PAC after ACTH stimulation was effective for the diagnosis of an APA among patients suspected of PA. The diagnostic accuracy was highest at 90 min after ACTH injection, with the optimal cutoff value greater than 37.9 ng/dl corresponding with sensitivity and specificity of 91.3 and 80.6% for the diagnosis of an APA. CONCLUSIONS: Our study indicates that the ACTH stimulation test is useful in the diagnosis of an APA among patients suspected of PA. This test can be used to select patients who are highly suspected of an APA and definitely require adrenal venous sampling.

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[Angiotensin receptor vaccines]

Sasamura, H., Azegami, T. and Itoh, H.

Nihon Rinsho 69 （ 9 ） 1633 - 8 2011年09月

ISSN 0047-1852

Recent clinical studies have shown that RAS inhibitors are effective not only for the prevention of end-organ damage in hypertensive patients, but also for prevention of new-onset hypertension, diabetes mellitus, and atrial fibrillation. Vaccines against the RAS have been developed since the 1950s, and a recent phase IIa placebo-controlled study has confirmed that an angiotensin vaccine causes a significant decrease in blood pressure in hypertensive patients. The results of animal experiments from our and other laboratories have suggested that vaccination against the angiotensin type 1 (AT1) receptor causes a significant decrease in blood pressure in animal models of hypertension, and also ameliorates hypertensive end-organ damage. The angiotensin receptor may therefore be an important target for the development of vaccines for the prevention of hypertension and related complications.

Human C-reactive protein exacerbates metabolic disorders in association with adipose tissue remodelling

Kaneko, H., Anzai, T., Nagai, T., Anzai, A., Takahashi, T., Mano, Y., Morimoto, K., Maekawa, Y., Itoh, H., Yoshikawa, T., Ogawa, S. and Fukuda, K.

Cardiovasc Res 91 （ 3 ） 546 - 55 2011年08月

ISSN 0008-6363

AIMS: C-reactive protein (CRP) expression is increased with metabolic alterations. We sought to clarify the effect of CRP on the development of obesity-induced metabolic disorders using human CRP-overexpressing transgenic mice (CRPTG). METHODS AND RESULTS: CRPTG and their non-transgenic littermates (CON) were fed a standard diet (STD) or a high-fat diet (HFD) from 6 weeks of age. Oral glucose tolerance and intraperitoneal insulin tolerance tests 12 weeks after starting the diets showed deterioration of glucose tolerance and insulin sensitivity in HFD/CRPTG compared with HFD/CON. Hepatocellular ballooning, oil droplets, and peri-sinusoidal fibrosis were more prominent in HFD/CRPTG than in HFD/CON. In HFD/CRPTG, hepatic triglyceride content was higher and serum adiponectin levels lower than in HFD/CON. Epididymal adipose tissue mRNA expression of mucin-like, hormone receptor-like 1, monocyte chemotactic protein-1, and tumour necrosis factor-alpha in HFD/CRPTG was up-regulated compared with that in HFD/CON. Immunohistochemical staining of epididymal adipose tissue showed that the number of Mac-3(+) macrophages was higher in HFD/CRPTG than in HFD/CON. CONCLUSION: Human CRP overexpression facilitated the development of insulin resistance and hepatosteatosis with HFD in association with adiponectin down-regulation and enhancement of macrophage infiltration and expression of pro-inflammatory cytokines in epididymal adipose tissue, suggesting its pathogenic role in the development of obesity-induced metabolic disorders.

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Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure

Watanabe, M., Horai, Y., Houten, S. M., Morimoto, K., Sugizaki, T., Arita, E., Mataki, C., Sato, H., Tanigawara, Y., Schoonjans, K., Itoh, H. and Auwerx, J.

J Biol Chem 286 （ 30 ） 26913 - 20 2011年07月

ISSN 0021-9258

We evaluated the metabolic impact of farnesoid X receptor (FXR) activation by administering a synthetic FXR agonist (GW4064) to mice in which obesity was induced by a high fat diet. Administration of GW4064 accentuated body weight gain and glucose intolerance induced by the high fat diet and led to a pronounced worsening of the changes in liver and adipose tissue. Mechanistically, treatment with GW4064 decreased bile acid (BA) biosynthesis, BA pool size, and energy expenditure, whereas reconstitution of the BA pool in these GW4064-treated animals by BA administration dose-dependently reverted the metabolic abnormalities. Our data therefore suggest that activation of FXR with synthetic agonists is not useful for long term management of the metabolic syndrome, as it reduces the BA pool size and subsequently decreases energy expenditure, translating as weight gain and insulin resistance. In contrast, expansion of the BA pool size, which can be achieved by BA administration, could be an interesting strategy to manage the metabolic syndrome.

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Functional characterization of (pro)renin receptor in association with V-ATPase

Kinouchi, K., Ichihara, A. and Itoh, H.

Front Biosci (Landmark Ed) 16 3216 - 23 2011年06月

ISSN 1093-4715

The (pro)renin receptor ((P)RR) is a unique molecule that binds prorenin and renin in tissues, not only leading to their activation, but also inducing intracellular signaling. As a key player in the local renin-angiotensin system, (P)RR activation plays an important role in the development of cardiac fibrosis and proteinuria in hypertension and diabetes. Intriguingly, the fragment (P)RR is also called ATP6AP2 because it has been shown to be associated with vacuolar-type H(+)-ATPase (V-ATPase). The V-ATPase is a multi-subunit proton pump involved in diverse and fundamental cellular processes, including receptor-mediated endocytosis, processing of proteins and signaling molecules, membrane sorting and trafficking, and activation of lysosomal enzymes. The role of (P)RR in the function of the V-ATPase is implicated in the previous findings and vigorously investigated in the recent studies. Furthermore, the novel function of the (P)RR as an adaptor protein between the Wnt receptor complex and the V-ATPase was discovered. Thus, the (P)RR is a multi-functional molecule that shows the complex structure and behaviour. This review highlights the current insights and the future perspectives in research regarding the (P)RR and mammalian V-ATPase.

Coactivation of SF-1-mediated transcription of steroidogenic enzymes by Ubc9 and PIAS1

Suda, N., Shibata, H., Kurihara, I., Ikeda, Y., Kobayashi, S., Yokota, K., Murai-Takeda, A., Nakagawa, K., Oya, M., Murai, M., Rainey, W. E., Saruta, T. and Itoh, H.

Endocrinology 152 （ 6 ） 2266 - 77 2011年06月

ISSN 0013-7227

Steroidogenic factor-1 (SF-1) is a nuclear orphan receptor, which is essential for adrenal development and regulation of steroidogenic enzyme expression. SF-1 is posttranslationally modified by small ubiquitin-related modifier-1 (SUMO-1), thus mostly resulting in attenuation of transcription. We investigated the role of sumoylation enzymes, Ubc9 and protein inhibitors of activated STAT1 (PIAS1), in SF-1-mediated transcription of steroidogenic enzyme genes in the adrenal cortex. Coimmunoprecipitation assays showed that both Ubc9 and PIAS1 interacted with SF-1. Transient transfection assays in adrenocortical H295R cells showed Ubc9 and PIAS1 potentiated SF-1-mediated transactivation of reporter constructs containing human CYP17, CYP11A1, and CYP11B1 but not CYP11B2 promoters. Reduction of endogenous Ubc9 and PIAS1 by introducing corresponding small interfering RNA significantly reduced endogenous CYP17, CYP11A1, and CYP11B1 mRNA levels, indicating that they normally function as coactivators of SF-1. Wild type and sumoylation-inactive mutants of Ubc9 and PIAS1 can similarly enhance the SF-1-mediated transactivation of the CYP17 gene, indicating that the coactivation potency of Ubc9 and PIAS1 is independent of sumoylation activity. Chromatin immunoprecipitation assays demonstrated that SF-1, Ubc9, and PIAS1 were recruited to an endogenous CYP17 gene promoter in the context of chromatin in vivo. Immunohistochemistry and Western blotting showed that SF-1, Ubc9, and PIAS1 were expressed in the nuclei of the human adrenal cortex. In cortisol-producing adenomas, the expression pattern of SF-1 and Ubc9 were markedly increased, whereas that of PIAS1 was decreased compared with adjacent normal adrenals. These results showed the physiological roles of Ubc9 and PIAS1 as SF-1 coactivators beyond sumoylation enzymes in adrenocortical steroidogenesis and suggested their possible pathophysiological roles in human cortisol-producing adenomas.

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Angiogenic and vasoprotective effects of adrenomedullin on prevention of cognitive decline after chronic cerebral hypoperfusion in mice

Maki, T., Ihara, M., Fujita, Y., Nambu, T., Miyashita, K., Yamada, M., Washida, K., Nishio, K., Ito, H., Harada, H., Yokoi, H., Arai, H., Itoh, H., Nakao, K., Takahashi, R. and Tomimoto, H.

Stroke 42 （ 4 ） 1122 - 8 2011年04月

ISSN 0039-2499

BACKGROUND AND PURPOSE: Although subcortical vascular dementia, the major subtype of vascular dementia, is caused by a disruption in white matter integrity after cerebrovascular insufficiency, no therapy has been discovered that will restore cerebral perfusion or functional cerebral vessels. Because adrenomedullin (AM) has been shown to be angiogenic and vasoprotective, the purpose of the study was to investigate whether AM may be used as a putative treatment for subcortical vascular dementia. METHODS: A model of subcortical vascular dementia was reproduced in mice by placing microcoils bilaterally on the common carotid arteries. Using mice overexpressing circulating AM, we assessed the effect of AM on cerebral perfusion, cerebral angioarchitecture, oxidative stress, white matter change, cognitive function, and brain levels of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor. RESULTS: After bilateral common carotid artery stenosis, mice overexpressing circulating AM showed significantly faster cerebral perfusion recovery due to substantial growth of the capillaries, the circle of Willis, and the leptomeningeal anastomoses and reduced oxidative damage in vascular endothelial cells compared with wild-type mice. Vascular changes were preceded by upregulation of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor. White matter damage and working memory deficits induced by bilateral common carotid artery stenosis were subsequently restored in mice overexpressing circulating AM. CONCLUSIONS: These data indicate that AM promotes arteriogenesis and angiogenesis, inhibits oxidative stress, preserves white matter integrity, and prevents cognitive decline after chronic cerebral hypoperfusion. Thus, AM may serve as a strategy to tackle subcortical vascular dementia.

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Involvement of activated prorenin in the pathogenesis of slowly progressive nephropathy in the non-clipped kidney of two kidney, one-clip hypertension

Ryuzaki, M., Ichihara, A., Ohshima, Y., Sakoda, M., Kurauchi-Mito, A., Narita, T., Kinouchi, K., Murohashi-Bokuda, K., Nishiyama, A. and Itoh, H.

Hypertens Res 34 （ 3 ） 301 - 7 2011年03月

ISSN 0916-9636

The handle region peptide (HRP), a (pro)renin receptor (P)RR blocker, did not prevent the acute nephropathy occurring 2 weeks after clipping in renovascular hypertensive rats. This study was performed to examine the effects of HRP, its scramble peptide, or a saline vehicle on slowly progressive nephropathy occurring in the kidneys of two-kidney, one-clip Goldblatt hypertensive rats. At 2 weeks after clipping, the renal morphology in the clipped and non-clipped kidneys was similar in the three groups of rats. At 12 weeks after clipping, however, the glomerulosclerosis index (GI) and the tubulointerstitial damage (TD) of the non-clipped kidneys of the HRP-treated rats were significantly lower than those of vehicle-treated rats, although the GI and the TD were similar in the rats treated with scramble peptide and vehicle. The GI and the TD of the clipped kidneys were similar in the three groups of rats at 12 weeks after clipping. In the non-clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and transforming growth factor (TGF)-beta mRNA levels of HRP-treated rats were significantly lower than those of vehicle-treated rats, although they were similar in the non-clipped kidneys from the rats treated with scramble peptide and vehicle. In the clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and TGF-beta mRNA levels were similar in the three groups of rats. These results suggest that the ((P)RR)-dependent activation of prorenin contributes to the pathogenesis of slowly progressive nephropathy in the intact kidney in a rat model of renovascular hypertension.

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[Antihypertensive therapy in the patient with diabetes mellitus or metabolic syndrome]

Miyashita, K. and Itoh, H.

Nihon Naika Gakkai Zasshi 100 （ 2 ） 376 - 84 2011年02月

ISSN 0021-5384

Rho and Rho-kinase activity in adipocytes contributes to a vicious cycle in obesity that may involve mechanical stretch

Hara, Y., Wakino, S., Tanabe, Y., Saito, M., Tokuyama, H., Washida, N., Tatematsu, S., Yoshioka, K., Homma, K., Hasegawa, K., Minakuchi, H., Fujimura, K., Hosoya, K., Hayashi, K., Nakayama, K. and Itoh, H.

Sci Signal 4 （ 157 ） ra3 2011年01月

ISSN 1945-0877

The development of obesity involves multiple mechanisms. Here, we identify adipocyte signaling through the guanosine triphosphatase Rho and its effector Rho-kinase as one such mechanism. Mice fed a high-fat diet (HFD) showed increased Rho-kinase activity in adipose tissue compared to mice fed a low-fat diet. Treatment with the Rho-kinase inhibitor fasudil attenuated weight gain and insulin resistance in mice on a HFD. Transgenic mice overexpressing an adipocyte-specific, dominant-negative form of RhoA (DN-RhoA TG mice) showed decreased Rho-kinase activity in adipocytes, decreased HFD-induced weight gain, and improved glucose metabolism compared to wild-type littermates. Furthermore, compared to HFD-fed wild-type littermates, DN-RhoA TG mice on a HFD showed decreased adipocyte hypertrophy, reduced macrophage recruitment to adipose tissue, and lower expression of mRNAs encoding various adipocytokines. Lipid accumulation in cultured adipocytes was associated with increased Rho-kinase activity and increased abundance of adipocytokine transcripts, which was reversed by a Rho-kinase inhibitor. Direct application of mechanical stretch to mature adipocytes increased Rho-kinase activity and stress fiber formation. Stress fiber formation, which was also observed in adipocytes from HFD-fed mice, was prevented by Rho-kinase inhibition and in DN-RhoA TG mice. Our findings indicate that lipid accumulation in adipocytes activates Rho to Rho-kinase (Rho-Rho-kinase) signaling at least in part through mechanical stretch and implicate Rho-Rho-kinase signaling in inflammatory changes in adipose tissue in obesity. Thus, inhibition of Rho-Rho-kinase signaling may provide a therapeutic strategy for disrupting a vicious cycle of adipocyte stretch, Rho-Rho-kinase signaling, and inflammation of adipose tissue that contributes to and aggravates obesity.

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[The cutting-edge of medicine; metabolic domino and CKD]

Itoh, H.

Nihon Naika Gakkai Zasshi 100 （ 1 ） 191 - 8 2011年01月

ISSN 0021-5384

Podocytes as a target of prorenin in diabetes

Sakoda, M., Itoh, H. and Ichihara, A.

Curr Diabetes Rev 7 （ 1 ） 17 - 21 2011年01月

ISSN 1573-3998

High plasma prorenin levels predict the onset of microvascular complications, such as albuminuria/proteinuria,in diabetic patients. In diabetic rats with elevated plasma prorenin levels, treatment with HRP, which competitively inhibits the binding of prorenin to the (pro)renin receptor [(P)RR] as a decoy peptide, significantly prevented the development of albuminuria/proteinuria and glomerulosclerosis, suggesting that (P)RR-bound prorenin plays a significant role in the pathogenesis of diabetic nephropathy. Recently, the presence of (P)RR in podocytes, which represent one of the glomerular filtration barriers, has been reported. Although podocytes are subjected to both high glucose levels and mechanical stretching caused by glomerular hyperfiltration under diabetic conditions, the expression of (P)RR is reportedly regulated by high glucose levels in in vitro mesangial cells and the in vivo kidneys of diabetic rats, whereas mechanical stretching is up-regulated by (P)RR expression in human podocytes. In addition, prorenin treatment not only leads to the generation of intracellular angiotensin (Ang)II, but also activates the phosphorylation of ERK via (P)RR in a manner that acts independently of AngII in human podocytes. Thus, the upregulation of prorenin and (P)RR in podocytes as a result of glomerular hyperfiltration might play an important role in the development of albuminuria/proteinuria via the generation of intracellular AngII and the stimulation of (P)RR-dependent intracellular signals. Further inquiry regarding podocyte (P)RR intracellular signal transduction will be needed to develop a new therapeutic approach targeting podocyte (P)RR in patients with diabetic nephropathy.

[Mitochondrial dysfunction in metabolic syndrome]

Wakino, S. and Itoh, H.

Nihon Rinsho 69 Suppl 1 26 - 31 2011年01月

ISSN 0047-1852

[Hypertension and arteriosclerosis]

Sasamura, H. and Itoh, H.

Nihon Rinsho 69 （ 1 ） 125 - 30 2011年01月

ISSN 0047-1852

Hypertension is a known risk factor for arteriosclerosis, and causes both atherosclero= sis of medium-large arteries and arteriolosclerosis of the arterioles. Elevated blood pressure causes damage to the endothelium and vascular wall through both mechanical and humoral factors. We and others have shown that inhibition of the renin-angiotensin system at a 'critical period' during the development of hypertension results in a permanent suppression of hypertension in animal models. We have also reported that high-dose renin-angiotensin inhibition results in regression of hypertension, possibly by regression of renal arteriolar hypertrophy. These results suggest that understanding the process of arterial remodeling may play a key role in the development of new strategies for prevention and regression of hypertension and arteriosclerosis.

Proatherogenic effect of interleukin-18 is exerted with high-fat diet, but not with normal diet in spontaneously hyperlipidemic mice

Imai, T., Oikawa, Y., Shimada, A., Oguchi, S., Takamiya, Y., Katsuki, T., Okubo, Y., Osaki, T., Tahara, H., Matsushima, Y., Miyazaki, J. and Itoh, H.

J Atheroscler Thromb 18 （ 12 ） 1090 - 101 2011年

ISSN 1340-3478

AIM: It has been considered that interleukin (IL)-18, a T helper 1(Th1) type cytokine, has a promoting effect on atherosclerosis development. A previous mouse study demonstrated that short-term exogenous IL-18 promoted atherosclerosis through a Th1 type immune response; however, the serum IL-18 may have increased greatly beyond its physiological range, and the effect of increased serum IL-18 on atherosclerosis development has not been investigated under different conditions of dietary fat content. The purpose of this study was to reveal the effect of increased serum IL-18 within its physiological fluctuations on atherosclerosis development under different conditions of dietary fat content. METHODS: Spontaneously hyperlipidemic (SHL) mice were systemically supplied with IL-18 for 10 weeks by means of an in vivo gene transfer system with a high-fat diet containing 0.15% cholesterol or a normal diet. RESULTS: Serum IL-18 steadily elevated within its physiological fluctuations. An atherosclerotic lesion area in the aortic root significantly increased with a high-fat diet. Systemic cytokine balance shifted to a Th1-dominant state, and IL-12 mRNA in the arterial wall significantly increased with a high-fat diet; however, these findings were not observed with a normal diet. CONCLUSIONS: It was suggested that the proatherogenic effect of IL-18 is physiologically exerted exclusively with a high-fat diet through Th1 type immune responses, but not with a normal diet.

A case of membranous nephropathy with primary biliary cirrhosis and cyclosporine-induced remission

Sakamaki, Y., Hayashi, M., Wakino, S., Fukuda, S., Konishi, K., Hashiguchi, A., Hayashi, K. and Itoh, H.

Intern Med 50 （ 3 ） 233 - 8 2011年

ISSN 0918-2918

We report a case of membranous nephropathy with primary biliary cirrhosis (PBC). A 76-year-old Japanese man had been treated for PBC and was referred to our department because of acute severe proteinuria (10 g/day). Renal biopsy was performed and was compatible with a diagnosis of membranous nephropathy. The patient was treated with cyclosporine A (CsA; Neoral(R)), which was followed by normalization of liver function and partial remission of proteinuria (0.68 g/day) within six months without any significant side effects. This case suggests that CsA monotherapy is effective for the treatment of both liver dysfunction and membranous nephropathy associated with PBC.

Postprandial serum C-peptide to plasma glucose ratio as a predictor of subsequent insulin treatment in patients with type 2 diabetes

Saisho, Y., Kou, K., Tanaka, K., Abe, T., Kurosawa, H., Shimada, A., Meguro, S., Kawai, T. and Itoh, H.

Endocr J 58 （ 4 ） 315 - 22 2011年

ISSN 0918-8959

Type 2 diabetes is a progressive disease and most patients with type 2 diabetes eventually need insulin therapy. The objective of this study was to clarify C-peptide immunoreactivity (CPR), a marker of beta cell function, as a predictor of requirement for insulin therapy. We conducted a retrospective study of 579 consecutive subjects with type 2 diabetes who were admitted to our hospital from 2000 to 2007 and were able to be followed up for at least 6 months after discharge. Fasting and postprandial serum CPR and urinary CPR levels had been measured during admission. Information about insulin therapy at the last visit was obtained from medical records. At the last visit, 364 subjects (62.9%) were treated with insulin. Mean interval between discharge and the last visit was 4.5 +/- 2.3 years. Serum and urine CPR levels at baseline were significantly associated with insulin treatment at the last visit (P<0.001 for all). Among CPR values, postprandial serum CPR to plasma glucose ratio (CPR index) showed the greatest area under the receiver operating characteristic (ROC) curve for insulin therapy. Multivariate logistic regression analysis evaluating the effect of postprandial CPR index adjusted for other confounders showed consistent results with unadjusted results. In conclusion, beta cell dysfunction is significantly correlated with future insulin therapy in patients with type 2 diabetes. Our study indicates that among CPR measurements, postprandial CPR index is the best predictive marker for future insulin therapy.

Prediction of recovery time from hypoglycemia in patients with insulin overdose

Ohyama, T., Saisho, Y., Muraki, A., Kawai, T. and Itoh, H.

Endocr J 58 （ 7 ） 607 - 11 2011年

ISSN 0918-8959

Insulin overdose results in prolonged hypoglycemia. We hypothesized that if a huge amount of insulin is subcutaneously injected, the duration of hypoglycemia depends on the dose of insulin rather than the type of insulin. We conducted a literature review of insulin overdose and 33 cases were included in this study. We assessed the correlation between recovery time from hypoglycemia and insulin dose. As a result, there was a significant correlation between recovery time from hypoglycemia and insulin dose (r=0.88, p<0.0001) and this correlation was expressed as y=0.045x; where y is time (h) and x is insulin dose (U), corresponding to that if 1000 U insulin is injected, hypoglycemia will persist for ~45 h. This equation may be useful to predict the duration of glucose supplementation for treatment of insulin overdose.

Plasma 25-hydroxyvitamin d is independently associated with hemoglobin concentration in male subjects with type 2 diabetes mellitus

Meguro, S., Tomita, M., Katsuki, T., Kato, K., Oh, H., Ainai, A., Ito, R., Takeda, S., Kawai, T., Atsumi, Y., Itoh, H. and Hasegawa, H.

Int J Endocrinol 2011 362981 2011年

ISSN 1687-8337

Introduction. It was reported that 25-hydroxyvitamin D level was independently associated with anemia in chronic kidney diseases, but the relation between vitamin D and anemia in diabetes mellitus is not still certain. We analyzed the relation between plasma 25-hydroxyvitamin D level and hemoglobin concentration. Materials and Methods. A cross-sectional study in male patients with type 2 diabetes was performed. Correlation coefficients and standardized partial regression coefficient for the hemoglobin concentration were evaluated. Results. Hemoglobin concentration was positively correlated with body mass index, HbA1c, estimated glomerular filtration rate, cholinesterase, and 25-hydroxyvitamin D level and negatively correlated with age, duration of diabetes mellitus, serum creatinine, and urinary albumin creatinine ratio. Multiple regression analysis revealed the independent relation of 25-hydroxyvitamin D to hemoglobin concentration. Conclusions. Plasma circulating form of vitamin D is significantly associated with hemoglobin concentration in diabetes mellitus independent of the clinical markers for kidney function or nutrition.

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Free cortisol/cortisone ratio in pooled urine was increased after rapid-ACTH stimulation test under dexamethasone suppression

Koyama, Y., Homma, K., Murata, M., Shibata, H., Itoh, H. and Hasegawa, T.

Endocr J 58 （ 12 ） 1099 - 103 2011年

ISSN 0918-8959

We employ rapid-ACTH stimulation test under dexamethasone (DEX) suppression to assess the adrenal function in daily clinic. However, we have little knowledge about the excretion of urinary free cortisol (FF) and cortisone (FE) in pooled urine in this setting. The purpose was to examine the changes of FF and FE as well as FF/FE ratio in pooled urine after rapid-ACTH stimulation test under DEX suppression using stable isotope dilution-gas chromatography/mass spectrometry (SID-GC/MS). Pooled urine samples were collected from 8 patients (age 33-71 years) who were suspected to have primary aldsteronism. They all were finally diagnosed as having normal glucocorticoid secretion. We performed rapid-ACTH stimulation test with DEX suppression for consecutive 4 days as follows. (1) 24 hour urine samples were serially collected from 2300 h on day 1 for 72 hours (Basal, DEX1mg, and DEX8mg-ACTH). (2) 1 and 8 mg DEX was given at 2300 h on day 2 and 3, respectively. (3) 250 microg of ACTH was given at 0900 h on day 4. Urine free steroids were delivered with bismethylenedioxy-heptafluorobutyric anhydride and analyzed by SID-GC/MS (microg/day). From DEX1mg to DXE8mg-ACTH, (1) FF and FE were significantly increased (3.9+/-1.3 to 21.3+/-14.6 and 12.4+/-4.8 to 26.1+/-11.0 microg/day, respectively), but (2) FF/FE ratio significantly increased (0.32+/-0.05 to 0.77+/-0.23). These data suggested that newly synthesized cortisol by ACTH stimulation was not efficiently metabolized to cortisone.

Differential Effects in Cardiovascular Markers between High-Dose Angiotensin II Receptor Blocker Monotherapy and Combination Therapy of ARB with Calcium Channel Blocker in Hypertension (DEAR Trial)

Kinouchi, K., Ichihara, A., Bokuda, K., Kurosawa, H. and Itoh, H.

Int J Hypertens 2011 284823 2011年

Background/Aims. Arterial stiffness is an independent risk factor for cardiovascular morbidity and mortality. This study was conducted to determine the effect of olmesartan (OLM) and azelnidipine (AZL) on arterial stiffness using the cardio-ankle vascular index (CAVI), which is a novel blood pressure (BP)-independent marker for arterial stiffness in hypertensive patients. Methods. Fifty-two consecutive hypertensive patients were randomly assigned either to a group treated with OLM monotherapy or to a group treated with OLM and AZL combination therapy. Clinical and biological parameters were measured before and 12 months after the start of this study. Results. Both therapies significantly and similarly reduced BP, augmentation index, and plasma aldosterone levels. The combination therapy significantly decreased CAVI and serum low-density lipoprotein (LDL-C) levels and these reductions were significantly greater than those produced with monotherapy. No significant differences in metabolic parameters were observed between the two therapies. Conclusion. The combination therapy with OLM and AZL had beneficial effects on arterial stiffness assessed by CAVI, LDL-C, and metabolism, despite the similar BP reduction, compared with OLM monotherapy. Since these markers are known to influence the future risk of cardiovascular events, combination therapy with OLM and AZL could be a useful choice for treating hypertensive patients.

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Effects of olmesartan medoxomil, an angiotensin II type 1 receptor antagonist, on plasma concentration of B-type natriuretic peptide, in hypertensive patients with type 2 diabetes mellitus: a preliminary, observational, open-label study

Kawai, T., Takei, I., Shimada, A., Hirata, T., Tanaka, K., Saisho, Y., Irie, J., Horimai, C., Matsumoto, H. and Itoh, H.

Clin Drug Investig 31 （ 4 ） 237 - 45 2011年

ISSN 1173-2563

BACKGROUND AND OBJECTIVE: Angiotensin II type 1 (AT1) receptor antagonists (angiotensin receptor blockers [ARBs]) are widely used for the treatment of not only hypertension but also cardiac dysfunction. B-type natriuretic peptide (BNP) is secreted mainly by the cardiac ventricle and plays an important role in the regulation of blood pressure (BP) and body fluid. It has been established that the plasma level of BNP is increased in patients with chronic heart failure in proportion to the severity of cardiac dysfunction. Because cardiac dysfunction is closely associated with a high risk of mortality in patients with diabetes mellitus, early identification and prevention of cardiac dysfunction are important. The objective of this study was to determine the effects of olmesartan medoxomil, a novel ARB, on the plasma level of BNP in hypertensive patients with type 2 diabetes. METHODS: This was a preliminary, prospective, observational, open-label study. Sixty-eight type 2 diabetic patients with hypertension (systolic BP [SBP]>/=140 mmHg or diastolic BP [DBP]>/=90 mmHg) received olmesartan medoxomil 10-20 mg/day for 24 weeks. Plasma levels of BNP, as well as several clinical parameters of glycaemic control and lipid metabolism, were compared before and after 24 weeks of treatment. Another group consisting of 22 age- and body mass index-matched subjects not treated with olmesartan medoxomil was observed for reference purposes. RESULTS: In the olmesartan medoxomil group, mean+/-SD SBP decreased from 152.8+/-16.4 at baseline to 146.8+/-14.4 mmHg after 24 weeks' treatment (p<0.05); similarly, mean+/-SD DBP decreased from 85.6+/-10.5 to 81.3+/-11.6 mmHg (p<0.05). In 53 subjects in whom plasma levels of BNP could be measured both before and after treatment, mean+/-SD BNP decreased from 41.3+/-49.9 to 32.5+/-36.3 pg/mL (p<0.05). Change in plasma BNP level over the 24-week treatment period in the olmesartan medoxomil group was not correlated with change in SBP or DBP. Multiple regression analysis revealed that change in plasma BNP level was not correlated with baseline value of or change in any other parameters. No other parameters in the olmesartan medoxomil group, and no parameters in the non-olmesartan medoxomil reference group, showed significant changes. CONCLUSION: The current preliminary study showed that olmesartan medoxomil treatment might decrease plasma BNP levels, independent of its BP-lowering effect, in hypertensive patients with type 2 diabetes.

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Tumor necrosis factor-alpha converting enzyme inactivation ameliorates high-fat diet-induced insulin resistance and altered energy homeostasis

Kaneko, H., Anzai, T., Horiuchi, K., Morimoto, K., Anzai, A., Nagai, T., Sugano, Y., Maekawa, Y., Itoh, H., Yoshikawa, T., Okada, Y., Ogawa, S. and Fukuda, K.

Circ J 75 （ 10 ） 2482 - 90 2011年

ISSN 1346-9843

BACKGROUND: Tumor necrosis factor (TNF)-alpha, which is released as a soluble form by ectodomain shedding of TNF-alpha converting enzyme (Tace), is known to play a pivotal role in obesity-induced insulin resistance. The role of Tace in obesity-induced metabolic disorders was to be clarified in this study. METHODS AND RESULTS: Transgenic mice with temporal systemic Tace deletion (TaceMx1) and their non-transgenic littermates (CON) were fed a standard diet or a high-fat diet (HFD) from 6 weeks of age. The increased body, liver and epididymal adipose tissue (EAT) weights, systolic blood pressure, and fasting glucose and lipid levels and decreased serum adiponectin level 12 weeks after starting a HFD were suppressed by Tace inactivation. A HFD/TaceMx1 showed ameliorated glucose tolerance and insulin sensitivity compared with HFD/CON. Indirect calorimetry showed that energy expenditure and oxidation of both fat and carbohydrate were higher in HFD/TaceMx1 than HFD/CON. Marked hepatosteatosis, increased triglyceride content and TNF-alpha expression in liver, and increased adipocyte size, macrophage infiltration and TNF-alpha and monocyte chemoattractant protein-1 expression in EAT induced by a HFD were attenuated in HFD/TaceMx1. CONCLUSIONS: Inactivation of Tace suppressed HFD-induced obesity, insulin resistance, hepatosteatosis and adipose tissue remodeling in association with increased energy expenditure, suggesting an important role of Tace in the development of obesity-induced metabolic disorders.

Effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy in patients with type 2 diabetes, in relation to suppression of N(varepsilon)-carboxymethyl lysine

Kawai, T., Takei, I., Tokui, M., Funae, O., Miyamoto, K., Tabata, M., Hirata, T., Saruta, T., Shimada, A. and Itoh, H.

J Diabetes Complications 24 （ 6 ） 424 - 32 2010年11月

ISSN 1056-8727

OBJECTIVE: We investigated the efficacy of epalrestat, an aldose reductase inhibitor, for diabetic peripheral neuropathy in Japanese patients with type 2 diabetes. METHODS: A total of 38 type 2 diabetic patients (22 men and 16 women; mean +/- S.E.M. age 63.3 +/- 1.0 years; duration of diabetes 9.6 +/- 0.8 years) with diabetic neuropathy were newly administered 150 mg/day epalrestat (EP group). Motor nerve conduction velocity (MCV), sensory nerve conduction velocity (SCV), and minimum F-wave latency were evaluated before administration of epalrestat and after 1 and 2 years. Serum N(varepsilon)-carboxymethyl lysine (CML) as a parameter of advanced glycation end products (AGEs), lipid peroxide, and soluble vascular cell adhesion molecule (sVCAM)-1 as a parameter of angiopathy were measured before administration and after 1 year. We compared the results with those of 36 duration of diabetes-matched type 2 diabetic patients (mean +/- S.E.M. duration of diabetes 8.2 +/- 0.7 years) as control (C group). RESULTS: The EP group showed significant suppression of deterioration of MCV (P<.01) and minimum F-wave latency (P<.01) in the tibial nerve and SCV (P<.05) in the sural nerve compared to those in the C group after 2 years. There was a significant difference in change in CML level between groups (-0.18 +/- 0.13 mU/ml in the EP group vs. +0.22 +/- 0.09 mU/ml in the C group, P<.05) after 1 year. CONCLUSIONS: Epalrestat suppressed the deterioration of diabetic peripheral neuropathy, especially in the lower extremity. Its effects might be mediated by improvement of the polyol pathway and suppression of production of AGEs.

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Acute interstitial nephritis associated with ulcerative colitis

Tokuyama, H., Wakino, S., Konishi, K., Hashiguchi, A., Hayashi, K. and Itoh, H.

Clin Exp Nephrol 14 （ 5 ） 483 - 6 2010年10月

ISSN 1342-1751

Although drugs used in inflammatory bowel diseases (IBD) cause renal injury, glomerulopathies may also accompany IBD. We report a case with the rare association of ulcerative colitis (UC) and acute progressive interstitial nephritis. Although the kidney is acknowledged as a target organ for injury as a result of drug nephrotoxicity, our findings lend support to the novel recognition that the deranged autoimmune system emerging in UC causes interstitial nephritis as an extraintestinal manifestation. Overt renal failure due to interstitial nephritis has rarely been reported in UC patients. The case presented here therefore provides novel information on UC-associated nephropathy.

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Usefulness of C-reactive protein to high-molecular-weight adiponectin ratio to predict insulin resistance and metabolic syndrome in Japanese men

Saisho, Y., Hirose, H., Seino, Y., Saito, I. and Itoh, H.

J Atheroscler Thromb 17 （ 9 ） 944 - 52 2010年09月

ISSN 1340-3478

AIM: We questioned whether the ratio of C-reactive protein to high-molecular-weight adiponectin (C/A ratio), compared to each value alone, is more useful to predict insulin resistance and/or metabolic syndrome. METHODS: We measured serum CRP and HMW adiponectin levels in 841 Japanese men who had participated in an annual health checkup. Correlations of the C/A ratio with metabolic parameters were assessed, and its predictive values for insulin resistance and MetS were compared with CRP or HMW adiponectin alone. RESULTS: The C/A ratio was higher in subjects with MetS (n = 114) than in those without MetS (0.46 +/- 0.67 vs. 0.23 +/- 0.39, p<0.0001). The C/A ratio was correlated with a larger number of metabolic parameters than CRP, but the correlation was comparable to HMW adiponectin. Likewise, the area under the curve of the C/A ratio in receiver operator characteristic analysis for MetS was greater than that of CRP, but comparable to that of HMW adiponectin. However, the AUC of the C/A ratio in ROC analysis for insulin resistance (HOMA-IR >2.5) was greater than that of CRP or HMW adiponectin alone. CONCLUSION: While the C/A ratio provided little advantage to predict MetS, it might be more useful to predict insulin resistance than CRP or HMW adiponectin alone.

Sirt1 plays an important role in mediating greater functionality of human ES/iPS-derived vascular endothelial cells

Homma, K., Sone, M., Taura, D., Yamahara, K., Suzuki, Y., Takahashi, K., Sonoyama, T., Inuzuka, M., Fukunaga, Y., Tamura, N., Itoh, H., Yamanaka, S. and Nakao, K.

Atherosclerosis 212 （ 1 ） 42 - 7 2010年09月

ISSN 0021-9150

OBJECTIVE: We previously succeeded in inducing and isolating vascular endothelial cells (ECs) from both human embryonic stem (ES) and induced pluripotent stem (iPS) cells. Here, we compared the functionality of human adult ECs (HAECs), human ES-derived ECs (ESECs) and human iPS-derived ECs (iPSECs). METHODS AND RESULTS: We compared the cell proliferative potential, potential for migration, and tolerance to oxidative stress. ESECs were significantly superior to HAECs in all of these cell functions. The cell functions of iPSECs were comparable to those of ESECSs and also superior to HAECs. We then analyzed the gene expressions of HAECs, ESECs and iPSECs, and observed that the expression level of Sirt1, a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase, is higher in ESECs and iPSECs than in HAECs. The inhibition of Sirt1 with a Sirt1-specific inhibitor and siRNA antagonized these differences between the three types of cells. CONCLUSIONS: Sirt1 plays a key role in the high cellular function of ESECs and iPSECs. Although further in vivo investigations are required, this study initially demonstrated the potential of ESECs and iPSECs as the cell source for regenerative medicine, and also showed the potential of ES cells as a useful tool for elucidating the molecular mechanism of cell aging.

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Blood pressure-independent effect of candesartan on cardio-ankle vascular index in hypertensive patients with metabolic syndrome

Bokuda, K., Ichihara, A., Sakoda, M., Mito, A., Kinouchi, K. and Itoh, H.

Vasc Health Risk Manag 6 571 - 8 2010年08月

ISSN 1176-6344

Angiotensin receptor blockers (ARBs) are known to reduce the cardiovascular risk in hypertensive patients. This study was designed to examine the effect of an ARB candesartan on subclinical atherosclerosis assessed by cardio-ankle vascular index (CAVI) in comparison with calcium channel blockers (CCBs) alone in hypertensive patients with metabolic syndrome (MetS). A total of 53 consecutive hypertensive patients with MetS were randomly assigned to the candesartan group, in which candesartan was added on, or the CCBs group, in which CCBs were added on. Clinical and biological parameters were obtained before and after the 12-month treatment period. The primary measure of efficacy was the %change in CAVI. When treated with candesartan, but not CCBs, CAVI significantly decreased from 8.7 to 7.7 by 11%. Blood pressure (BP) significantly decreased with both treatments, but the differences between groups were not significant. The changes in other parameters remained unchanged in both the groups. Analysis of covariance found that both the BP reduction and the therapy difference contributed to the decrease in CAVI, but the BP reduction was not involved in the decrease in CAVI caused by the difference in the therapy. Candesartan may be a better antihypertensive drug than CCBs to improve subclinical atherosclerosis of patients with MetS.

The (pro)renin receptor/ATP6AP2 is essential for vacuolar H+-ATPase assembly in murine cardiomyocytes

Kinouchi, K., Ichihara, A., Sano, M., Sun-Wada, G. H., Wada, Y., Kurauchi-Mito, A., Bokuda, K., Narita, T., Oshima, Y., Sakoda, M., Tamai, Y., Sato, H., Fukuda, K. and Itoh, H.

Circ Res 107 （ 1 ） 30 - 4 2010年07月

ISSN 0009-7330

RATIONALE: The (pro)renin receptor [(P)RR], encoded in ATP6AP2, plays a key role in the activation of local renin-angiotensin system (RAS). A truncated form of (P)RR, termed M8.9, was also found to be associated with the vacuolar H(+)-ATPase (V-ATPase), implicating a non-RAS-related function of ATP6AP2. OBJECTIVE: We investigated the role of (P)RR/ATP6AP2 in murine cardiomyocytes. METHODS AND RESULTS: Cardiomyocyte-specific ablation of Atp6ap2 resulted in lethal heart failure; the cardiomyocytes contained RAB7- and lysosomal-associated membrane protein 2 (LAMP2)-positive multivesicular vacuoles, especially in the perinuclear regions. The myofibrils and mitochondria remained at the cell periphery. Cardiomyocyte death was accompanied by numerous autophagic vacuoles that contained undigested cellular constituents, as a result of impaired autophagic degradation. Notably, ablation of Atp6ap2 selectively suppressed expression of the V(O) subunits of V-ATPase, resulting in deacidification of the intracellular vesicles. Furthermore, the inhibition of intracellular acidification by treatment with bafilomycin A1 or chloroquine reproduced the phenotype observed for the (P)RR/ATP6AP2-deficient cardiomyocytes. CONCLUSIONS: Genetic ablation of Atp6ap2 created a loss-of-function model for V-ATPase. The gene product of ATP6AP2 is considered to act as in 2 ways: (1) as (P)RR, exerting a RAS-related function; and (2) as the V-ATPase-associated protein, exerting a non-RAS-related function that is essential for cell survival.

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Regression of glomerulosclerosis in response to transient treatment with angiotensin II blockers is attenuated by blockade of matrix metalloproteinase-2

Hayashi, K., Sasamura, H., Ishiguro, K., Sakamaki, Y., Azegami, T. and Itoh, H.

Kidney Int 78 （ 1 ） 69 - 78 2010年07月

ISSN 0085-2538

Understanding mechanisms that contribute to the regression of glomerulosclerosis is important for developing new strategies to treat chronic kidney disease. We reported that transient high-dose treatment with an angiotensin receptor blocker causes regression of renal arteriolar hypertrophy and hypertension in spontaneously hypertensive rats. To extend those findings to another form of kidney disease, we examined the short- and long-term effects of transient high-dose angiotensin receptor blocker treatment in a mouse model of adriamycin-induced glomerulosclerosis. A 2-week course of candesartan caused a dose-dependent regression of established glomerulosclerotic lesions sustained for over 6 months following cessation of treatment. Highly sensitive in situ zymography and activity assays showed that glomerular matrix metalloproteinase (MMP)-2 activity was increased after high-dose angiotensin blocker therapy. Treatment of cultured podocytes with candesartan resulted in an increase in MMP-2 activity. The regression of glomerulosclerosis was partially attenuated in mice pretreated with the MMP inhibitor doxycycline, as well as in MMP-2 knockout mice. Our results suggest that transient high-dose angiotensin receptor blocker treatment effectively induced sustained regression of glomerulosclerosis by a mechanism mediated, in part, by changes in MMP-2 activity.

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Add-on blockade of (pro)renin receptor in imidapril-treated diabetic SHRsp

Seki, Y., Ichihara, A., Mizuguchi, Y., Sakoda, M., Kurauchi-Mito, A., Narita, T., Kinouchi, K., Bokuda, K. and Itoh, H.

Front Biosci (Elite Ed) 2 972 - 9 2010年06月

ISSN 1945-0494

To examine the involvement of (pro)renin receptor in the accelerated organ damage in streptozotocin-induced diabetic male SHRsp, the rats fed a high-salt diet were divided into 5 groups: a group treated with the vehicle, a group treated with 15 mg/kg/day of imidapril (ACEi), a group treated with 60 mg/kg/day of imidapril (High ACEi), a group treated with handle region peptide (HRP), and a group treated with both ACEi and HRP (ACEi+HRP). After 8 weeks, the arterial pressure was similar in the vehicle and HRP groups and decreased in the ACEi-treated groups. The renal angiotensin II content decreased similarly in the groups treated with ACEi and/or HRP. Urinary protein excretion also decreased in the ACEi, High ACEi, and HRP groups and significantly further decreased in the ACEi+HRP group. The heart weight of the ACEi+HRP group was significantly lower than that of any other groups, although the cardiac angiotensin II levels decreased similarly in the groups treated with ACEi and/or HRP. Thus, (pro)renin receptor contributes to the accelerated pathogenesis in the heart and kidneys of diabetic SHRsp.

Pancreatic beta-cell function and fetal growth in gestational impaired glucose tolerance

Miyakoshi, K., Tanaka, M., Saisho, Y., Shimada, A., Minegishi, K., Kim, S. H., Asai, S., Itoh, H. and Yoshimura, Y.

Acta Obstet Gynecol Scand 89 （ 6 ） 769 - 75 2010年06月

ISSN 0001-6349

OBJECTIVE: To investigate the metabolic phenotype and pregnancy outcomes of gestational impaired glucose tolerance (IGT) defined by isolated hyperglycemia during an oral glucose tolerance test (OGTT). DESIGN: Retrospective cohort study. SETTING: University referral hospital. POPULATION: A total of 4,789 women were screened for gestational diabetes mellitus (GDM) between 1996 and 2008 with a glucose challenge test (GCT), followed by a 2-hour 75-g OGTT if the GCT result was abnormal; in addition, measurement of plasma insulin concentration during the OGTT was implemented from 2004. METHODS: The insulin sensitivity (IS(OGTT)) and beta-cell function (insulinogenic index/homeostasis model assessment for insulin resistance) were calculated for 283 women who underwent a diagnostic OGTT between 2004 and 2008. Perinatal complications were examined in 4,789 women who were screened for GDM between 1996 and 2008. MAIN OUTCOME MEASURES: Comparison of outcomes among women stratified by glucose tolerance status using the GCT and OGTT profiles. RESULTS: Insulin sensitivity and beta-cell function significantly decreased from normal OGTT to 2-hour IGT (single hyperglycemia at 2 hours) to 1-hour IGT (single hyperglycemia at 1 hour) to GDM, with significant differences between normal OGTT and 1-hour IGT or GDM. The occurrence of large-for-gestational age (LGA) neonates was significantly increased in women with GDM or 1-hour IGT (adjusted odds ratio: 2.15, 2.22; 95% confidence interval 1.23-3.75 and 1.04-4.35, respectively) compared to those with normal GCT or normal diagnostic OGTT results. CONCLUSIONS: Like GDM, isolated 1-hour hyperglycemia on the OGTT is associated with beta-cell dysfunction and an increased risk for LGA neonates.

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Renoprotective effects of mineralocorticoid receptor blockade in heminephrectomized (pro)renin receptor transgenic rats

Mizuguchi, Y., Ichihara, A., Seki, Y., Sakoda, M., Kurauchi-Mito, A., Narita, T., Kinouchi, K., Bokuda, K. and Itoh, H.

Clin Exp Pharmacol Physiol 37 （ 5-6 ） 569 - 73 2010年05月

ISSN 0305-1870

1. Nephropathy and elevated plasma aldosterone concentrations (PAC) have been observed in (pro)renin receptor transgenic (TG) rats. In the present study, we hypothesized that PAC and/or mineralocorticoid receptor contribute to the nephropathy of TG rats. To test this hypothesis, the effects of a high-sodium (8% NaCl) diet and heminephrectomy on PAC were examined. 2. Feeding of the high-sodium diet for 12 weeks similarly decreased PAC in TG and wild-type (WT) rats. Heminephrectomy further reduced PAC in TG rats fed a high-sodium diet, but had no effect on PAC in WT rats fed a high-sodium diet. 3. Next, the effects of eplerenone (125 mg/kg per day) and dietary salt restriction (0.36% NaCl diet) on proteinuria and renal morphology were examined in rats fed a high-sodium diet or subjected to heminephrectomy. Both eplerenone and dietary sodium restriction significantly reduced the arterial pressure of TG rats, but had no effect in WT rats. In TG rats, treatment with eplerenone significantly decreased urinary protein excretion, but dietary sodium restriction did not. 4. Nephrin and podocin mRNA levels, as determined by real-time quantitative reverse transcription-polymerase chain reaction, were significantly lower in TG rats than in WT rats. In TG rats, eplerenone treatment significantly increased nephrin mRNA levels, but not podocin mRNA levels. Dietary salt restriction significantly increased mRNA levels of both nephrin and podocin. Although zonula occludens (ZO)-1 mRNA levels were similar in both WT and TG rats, eplerenone treatment significantly decreased ZO-1 mRNA levels in TG rats. 5. The results of the present study suggest that the improvement in proteinuria following eplerenone treatment is independent of its effects on sodium balance and may be mediated by effects on the expression of slit diaphragm proteins.

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Aliskiren inhibits intracellular angiotensin II levels without affecting (pro)renin receptor signals in human podocytes

Sakoda, M., Ichihara, A., Kurauchi-Mito, A., Narita, T., Kinouchi, K., Murohashi-Bokuda, K., Saleem, M. A., Nishiyama, A., Suzuki, F. and Itoh, H.

Am J Hypertens 23 （ 5 ） 575 - 80 2010年05月

ISSN 0895-7061

BACKGROUND: A direct renin inhibitor (DRI) had a benefit in decreasing albuminuria in type 2 diabetic patients having already been treated with angiotensin (Ang) II type 1 receptor blocker (ARB), suggesting that aliskiren may have another effect other than blockade of the traditional renin-angiotensin system (RAS). Recently, prorenin bound to (pro)renin receptor ((P)RR) was found and shown to evoke two pathways; the generation of Ang peptides and the receptor-dependent activation of extracellular signal-related protein kinase (ERK). Because (P)RR is present in the podocytes, a central component of the glomerular filtration barrier, we hypothesized that aliskiren influences the (P)RR-induced two pathways in human podocytes. METHODS: Human podocytes were treated with 2 nmol/l prorenin in the presence and absence of an angiotensin-converting enzyme inhibitor (ACEi) imidaprilat, an ARB candesartan, a DRI aliskiren, or the siRNA knocking down the (P)RR mRNA and the intracellular AngII levels and the phosphorylation of ERK were determined. RESULTS: The expression of (P)RR mRNA of human podocytes was unaffected by the treatment with RAS inhibitors, but decreased by 69% with the siRNA treatment. The basal levels of intracellular AngII and the prorenin-induced increase in intracellular AngII were significantly reduced by aliskiren and siRNA treatment, compared with imidaprilat and candesartan. The prorenin-induced ERK activation was reduced to control level by the siRNA treatment, but it was unaffected by imidaprilat, candesartan, or aliskiren. CONCLUSIONS: Aliskiren is the most potent inhibitor of intracellular AngII levels of human podocytes among RAS inhibitors, although it is incapable of inhibiting the (P)RR-dependent ERK phosphorylation.

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Adrenocortical zonation in humans under normal and pathological conditions

Nishimoto, K., Nakagawa, K., Li, D., Kosaka, T., Oya, M., Mikami, S., Shibata, H., Itoh, H., Mitani, F., Yamazaki, T., Ogishima, T., Suematsu, M. and Mukai, K.

J Clin Endocrinol Metab 95 （ 5 ） 2296 - 305 2010年05月

ISSN 0021-972

CONTEXT: Aldosterone synthase (CYP11B2) and steroid 11 beta-hydroxylase (CYP11B1) catalyze the terminal steps for aldosterone and cortisol syntheses, respectively, thereby determining the functional differentiation of human adrenocortical cells. Little is known, however, about how the cells expressing the enzymes are actually distributed in the adrenals under normal and pathological conditions. OBJECTIVE: The objective of the study was to determine the localization of CYP11B2 and -B1 in human adrenal specimens by using developed antibodies capable of distinguishing the two enzymes from each other. RESULTS: Under normal conditions, CYP11B2 was sporadically detected in the zona glomerulosa, whereas CYP11B1 was entirely detected in the zonae fasciculata-reticularis. Adrenocortical cells lacking both enzymes were observed in the outer cortical regions. In addition to conventional zonation, we found a variegated zonation consisting of a subcapsular cell cluster expressing CYP11B2, which we termed aldosterone-producing cell cluster, and a CYP11B1-expressing area. Aldosterone-producing adenomas differed in cell populations expressing CYP11B2 from one another, whereas CYP11B1-expressing and double-negative cells were also intermingled. Adenomas from patients with Cushing's syndrome expressed CYP11B1 entirely but not CYP11B2, resulting in atrophic nontumor glands. The nontumor portions of both types of adenomas bore frequently one or more aldosterone-producing cell clusters, which sustained CYP11B2 expression markedly under the conditions of the suppressed renin-angiotensin system. CONCLUSION: Immunohistochemistry of the human normal adrenal cortex for CYP11B2 and CYP11B1 revealed a variegated zonation with cell clusters constitutively expressing CYP11B2. This technique may provide a pathological confirmatory diagnosis of adrenocortical adenomas.

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Kidney-specific overexpression of Sirt1 protects against acute kidney injury by retaining peroxisome function

Hasegawa, K., Wakino, S., Yoshioka, K., Tatematsu, S., Hara, Y., Minakuchi, H., Sueyasu, K., Washida, N., Tokuyama, H., Tzukerman, M., Skorecki, K., Hayashi, K. and Itoh, H.

J Biol Chem 285 （ 17 ） 13045 - 56 2010年04月

ISSN 0021-9258

Sirt1, a NAD-dependent protein deacetylase, is reported to regulate intracellular metabolism and attenuate reactive oxidative species (ROS)-induced apoptosis leading to longevity and acute stress resistance. We created transgenic (TG) mice with kidney-specific overexpression of Sirt1 using the promoter sodium-phosphate cotransporter IIa (Npt2) driven specifically in proximal tubules and investigated the kidney-specific role of Sirt1 in the protection against acute kidney injury (AKI). We also elucidated the role of number or function of peroxisome and mitochondria in mediating the mechanisms for renal protective effects of Sirt1 in AKI. Cisplatin-induced AKI decreased the number and function of peroxisomes as well as mitochondria and led to increased local levels of ROS production and renal tubular apoptotic cells. TG mice treated with cisplatin mitigated AKI, local ROS, and renal tubular apoptotic tubular cells. Consistent with these results, TG mice treated with cisplatin also exhibited recovery of peroxisome number and function, as well as rescued mitochondrial function; however, mitochondrial number was not recovered. Immunoelectron microscopic findings consistently demonstrated that the decrease in peroxisome number by cisplatin in wild type mice was restored in transgenic mice. In HK-2 cells, a cultured proximal tubule cell line, overexpression of Sirt1 rescued the cisplatin-induced cell apoptosis through the restoration of peroxisome number, although the mitochondria number was not restored. These results indicate that Sirt1 overexpression in proximal tubules rescues cisplatin-induced AKI by maintaining peroxisomes number and function, concomitant up-regulation of catalase, and elimination of renal ROS levels. Renal Sirt1 can be a potential therapeutic target for the treatment of AKI.

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NF-YC functions as a corepressor of agonist-bound mineralocorticoid receptor

Murai-Takeda, A., Shibata, H., Kurihara, I., Kobayashi, S., Yokota, K., Suda, N., Mitsuishi, Y., Jo, R., Kitagawa, H., Kato, S., Saruta, T. and Itoh, H.

J Biol Chem 285 （ 11 ） 8084 - 93 2010年03月

ISSN 0021-9258

The role of aldosterone has been implicated in the metabolic syndrome and cardiovascular diseases. The biological actions of aldosterone are mediated through mineralocorticoid receptor (MR). Nuclear receptor-mediated gene expression is regulated by dynamic and coordinated recruitment of coactivators and corepressors. To identify new coregulators of the MR, full-length MR was used as bait in yeast two-hybrid screening. We isolated NF-YC, one of the subunits of heterotrimeric transcription factor NF-Y. Specific interaction between MR and NF-YC was confirmed by yeast two-hybrid, mammalian two-hybrid, coimmunoprecipitation assays, and fluorescence subcellular imaging. Transient transfection experiments in COS-7 cells demonstrated that NF-YC repressed MR transactivation in a hormone-sensitive manner. Moreover, reduction of NF-YC protein levels by small interfering RNA potentiated hormonal activation of endogenous target genes in stably MR-expressing cells, indicating that NF-YC functions as an agonist-dependent MR corepressor. The corepressor function of NF-YC is selective for MR, because overexpression of NF-YC did not affect transcriptional activity mediated by androgen, progesterone, or glucocorticoid receptors. Chromatin immunoprecipitation experiments showed that endogenous MR and steroid receptor coactivator-1 were recruited to an endogenous ENaC gene promoter in a largely aldosterone-dependent manner, and endogenous NF-YC was sequentially recruited to the same element. Immunohistochemistry showed that endogenous MR and NF-YC were colocalized within the mouse kidney. Although aldosterone induces interaction of the N and C termini of MR, NF-YC inhibited the N/C interaction. These findings indicate that NF-YC functions as a new corepressor of agonist-bound MR via alteration of aldosterone-induced MR conformation.

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Possible roles of human (pro)renin receptor suggested by recent clinical and experimental findings

Ichihara, A., Sakoda, M., Kurauchi-Mito, A., Narita, T., Kinouchi, K., Murohashi-Bokuda, K. and Itoh, H.

Hypertens Res 33 （ 3 ） 177 - 80 2010年03月

ISSN 0916-9636

Numerous in vitro and in vivo animal studies using the (pro)renin receptor (P)RR blocker handle region peptide have suggested an important role of (P)RR in the pathogenesis of end-stage organ damage in patients with diabetes and hypertension. In addition, a limited number of clinical studies have suggested an association between (P)RR gene polymorphisms and blood pressure levels and between (P)RR mRNA levels and angiotensin-converting enzyme mRNA levels in human arteries. However, recent studies have shown that the (P)RR is divided into its soluble form and a residual hydrophobic part, which includes ATPase 6 associated protein 2, within cells. Therefore, the (P)RR may have a more complex function than previously thought. In addition, the physiological roles of the (P)RR remain undetermined, because the construction of (P)RR null mice has not been successful. As a next step for research in this area, a method for determining the soluble (P)RR levels in plasma and urine and the construction of tissue-specific (P)RR-knockout mice are needed to elucidate the roles of the (P)RR in physiology and pathophysiology.

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Brachial-ankle pulse wave velocity predicts silent cerebrovascular diseases in patients with end-stage renal diseases

Washida, N., Wakino, S., Hayashi, K., Kuwahara, T. and Itoh, H.

J Atheroscler Thromb 17 （ 2 ） 165 - 72 2010年02月

ISSN 1340-3478

AIM: Cerebrovascular disease (CVD) is a major determinant of the prognosis in end-stage renal diseases (ESRD). The purpose of this study was to examine whether factors associated with arterial stiffness contributed to the development of CVD in patients with ESRD. METHODS: CVD (lacunes and carotid/intracranial artery stenosis) was evaluated with brain magnetic resonance imaging (MRI), and carotid/intracranial artery magnetic resonance angiography (MRA) in 44 pre-dialytic patients. The severity of CVD was evaluated by the number of lacunes and the degree of stenosis, respectively. The association between CVD and atherosclerotic parameters was evaluated. RESULTS: Patients with severe lacunes (n=18) manifested older age, lower diastolic blood pressure, serum creatinine and albumin, and higher CRP and serum calcium than those with absent-moderate lacunes (n=26). When assessed by multivariate analysis, only baPWV was adopted as an independent risk factor for severe lacunes. Furthermore, baPWV and i-PTH were associated with the severity of carotid/intracranial artery stenosis, both of which were independent of other risk factors, including age and diabetes. CONCLUSIONS: Arterial stiffness may constitute a novel determinant predicting the severity of CVD in pre-dialytic patients besides classical risk factors.

[Anti-atherosclerotic effects by PPARgamma and its ligands through the activation of reverse cholesterol transport system]

Wakino, S. and Itoh, H.

Nihon Rinsho 68 （ 2 ） 217 - 23 2010年02月

ISSN 0047-1852

Peroxisome proliferator-activated receptor gamma (PPARgamma) belongs to a nuclear receptor superfamily which agonists were in clinical use for anti-diabetic therapy. Recent studies both in vivo and in vitro revealed that PPARgamma agonists have anti-atherosclerotic effects which is also demonstrated by a large clinical trial including PROactive study. One of the mechanisms for this effect is the activation of reverse cholesterol transport through the induction of ABCA1 transporter by PPARgamma agonists. The transporter exports cholesterol from macrophages migrating in the vasculature and inhibits the formation of foam cell which contains lipid droplet in the cytosol as cholesterol ester. Clinical application of PPARgamma agonists have beneficial effects by preventing the cardiovascular events in diabetic patients.

T-type Ca channel blockade as a determinant of kidney protection

Hayashi, K., Homma, K., Wakino, S., Tokuyama, H., Sugano, N., Saruta, T. and Itoh, H.

Keio J Med 59 （ 3 ） 84 - 95 2010年

ISSN 0022-9717

Voltage-dependent Ca channels are classified into several subtypes based on the isoform of their alpha1 subunits. Traditional Ca channels blockers (CCBs), including nifedipine and amlodipine, act predominantly on L-type Ca channels, whereas novel CCBs such as efonidipine, benidipine and azelnidipine inhibit both L-type and T-type Ca channels. Furthermore, cilnidipine blocks L-type and N-type Ca channels. These CCBs exert divergent actions on renal microvessels. L-type CCBs preferentially dilate afferent arterioles, whereas both L-/T-type and L-/N-type CCBs potently dilate afferent and efferent arterioles. The distinct actions of CCBs on the renal microcirculation are reflected by changes in glomerular capillary pressure and subsequent renal injury: L-type CCBs favor an increase in glomerular capillary pressure, whereas L-/T-type and L-/N-type CCBs alleviate glomerular hypertension. The renal protective action of L-/T-type CCBs is also mediated by non-hemodynamic mechanisms, i.e., inhibition of the inflammatory process and inhibition of Rho kinase and aldosterone secretion. Finally, a growing body of evidence indicates that T-type CCBs offer more beneficial action on proteinuria and renal survival rate than L-type CCBs in patients with chronic kidney disease (CKD). Similarly, in CKD patients treated with renin-angiotensin blockers, add-on therapy with N-type CCBs is more potent in reducing proteinuria than that with L-type CCBs, although no difference is found in the subgroup with diabetic nephropathy. Thus, the strategy for hypertension treatment with CCBs has entered a new era: treatment selection depends not only on blood pressure control but also on the subtypes of CCBs.

Absence of gelatinase (MMP-9) or collagenase (MMP-13) attenuates adriamycin-induced albuminuria and glomerulosclerosis

Sakamaki, Y., Sasamura, H., Hayashi, K., Ishiguro, K., Takaishi, H., Okada, Y., D'Armiento, J. M., Saruta, T. and Itoh, H.

Nephron Exp Nephrol 115 （ 2 ） e22 - 32 2010年

ISSN 1660-2129

BACKGROUND/AIMS: The role of matrix metalloproteinases (MMPs) in the pathogenesis of glomerular injury appears to be complex. To investigate the role of individual MMPs, we examined the course of Adriamycin-induced albuminuria and glomerulosclerosis in mice lacking either a gelatinase (MMP-9) or a collagenase (MMP-13). METHODS: Adriamycin was administered to MMP-9 or MMP-13 knockout (KO) mice. Glomerular injury was assessed by the quantification of albuminuria, the glomerular injury score and type IV collagen immunostaining. RESULTS: Treatment of mice with Adriamycin (18 mg/kg i.v.) resulted in marked albuminuria and glomerulosclerosis reaching a peak at 4-8 weeks. The albuminuria and glomerulosclerosis were significantly (p < 0.05) attenuated in both the MMP-9 KO and MMP-13 KO mice compared to controls. In contrast, treatment of wild-type mice with the broad-spectrum MMP inhibitor doxycycline did not have a beneficial effect on the albuminuria and glomerulosclerosis. CONCLUSION: These results support a role for both gelatinase (MMP-9) and collagenase (MMP-13) in the pathogenesis of glomerular injury in the Adriamycin-induced glomerulosclerosis model. MMP inhibitors with high specificity towards MMP-9 and/or MMP-13 may be potential future candidates to provide more effective therapies to inhibit the development of glomerulosclerosis.

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Beta cell dysfunction and its clinical significance in gestational diabetes

Saisho, Y., Miyakoshi, K., Tanaka, M., Shimada, A., Ikenoue, S., Kadohira, I., Yoshimura, Y. and Itoh, H.

Endocr J 57 （ 11 ） 973 - 80 2010年

ISSN 0918-8959

The aim of this study is to explore beta cell dysfunction and its clinical significance in gestational diabetes mellitus (GDM). We assessed insulin sensitivity and insulin secretion in a total of 277 Japanese women between 24 and 27 weeks of pregnancy who underwent a 2 h, 75 g oral glucose tolerance test (OGTT) because of an abnormal result on a 1 h 50 g oral glucose challenge conducted as part of a standard screening for GDM. Insulin sensitivity was evaluated by an insulin sensitivity index derived from OGTT (IS(OGTT)), whereas insulin secretion was calculated as a ratio of the total area under the insulin curve to the total area under the glucose curve (AUC(ins/glu)). Beta cell function in relation to insulin sensitivity (i.e. disposition index) was derived from the product of insulin sensitivity and insulin secretion (i.e. AUC(ins/glu) x IS(OGTT)). In women diagnosed with GDM (n=57), the disposition index was significantly lower than that in those without GDM, irrespective of obesity. The disposition index in women with GDM was significantly correlated with levels of fasting and mean preprandial capillary glucose and HbA1c before initiating insulin therapy (r = -0.45, -0.38, -0.49, respectively). Furthermore, there was a significant correlation between the disposition index and total insulin dosage to achieve glycemic goal (r = -0.41). In conclusion, we demonstrated beta cell dysfunction in Japanese women with GDM irrespective of obesity. The level of beta cell dysfunction in GDM was associated with the severity of glucose intolerance and total insulin dosage required. These findings underpin clinical significance of beta cell dysfunction in GDM.

CXC chemokine ligand 10 DNA vaccination plus Complete Freund's Adjuvant reverses hyperglycemia in non-obese diabetic mice

Oikawa, Y., Shimada, A., Yamada, Y., Okubo, Y., Katsuki, T., Shigihara, T., Miyazaki, J., Narumi, S. and Itoh, H.

Rev Diabet Stud 7 （ 3 ） 209 - 24 2010年

ISSN 1613-6071

OBJECTIVE: Complete Freund's Adjuvant (CFA) is known to arrest autoimmune diabetes development in non-obese diabetic (NOD) mice. However, CFA alone cannot induce effective remission in diabetic NOD mice. Previously, we reported that anti-CXC chemokine ligand 10 (CXCL10) antibody can promote beta-cell proliferation in NOD mice. In the present study, we aimed to examine whether anti-CXCL10 plus CFA treatment can effectively reverse autoimmune diabetes development. METHODS: Systemic supply of anti-CXCL10 antibody by CXCL10 DNA vaccination in combination with CFA injection was performed in new-onset diabetic NOD mice. Remission rate of diabetes, histological characteristics of residual insulitis lesions, residual beta-cell mass, and regulatory T cell population in local pancreas were examined. RESULTS: A high frequency of diabetes reversal was observed after combination treatment with anti-CXCL10 plus CFA. In mice showing diabetes reversal, residual beta-cell mass was significantly increased, and some beta-cells were in a proliferative state. Although systemic cytokine profiles were unaffected, the frequency of "hybrid regulatory T cells", i.e. regulatory T cells expressing CXCR3, was significantly increased in local pancreatic lesions. This was possibly associated with the regulation of anti-islet autoimmunity. CONCLUSIONS: Anti-CXCL10 plus appropriate immune adjuvant therapy arrested, and reversed, type 1 diabetes development.

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Effects of telmisartan on arterial stiffness assessed by the cardio-ankle vascular index in hypertensive patients

Kinouchi, K., Ichihara, A., Sakoda, M., Kurauchi-Mito, A., Murohashi-Bokuda, K. and Itoh, H.

Kidney Blood Press Res 33 （ 4 ） 304 - 12 2010年

ISSN 1420-4096

BACKGROUND/AIMS: This study was conducted to determine the effect of telmisartan on the cardio-ankle vascular index (CAVI), a novel blood pressure (BP)-independent marker for arterial stiffness in hypertensive patients. METHODS: One hundred consecutive hypertensive patients were randomly assigned either to a group treated with calcium channel blocker (CCB)-based therapy or a group treated with telmisartan-based therapy. Clinical and biological parameters were then measured before and 12 months after the start of this study. RESULTS: CAVI, the logarithm of urinary albumin excretion, and BP were reduced significantly after telmisartan-based therapy. The decreases in 24-hour diastolic BP and daytime systolic BP associated with telmisartan-based therapy were significantly greater than those associated with CCB-based therapy. Both therapies significantly and similarly decreased the clinical BP, 24-hour systolic BP, daytime diastolic BP and serum levels of low-density lipoprotein cholesterol. No significant differences in the metabolic parameters were observed between the two therapies. CONCLUSION: Telmisartan-based therapy had beneficial effects on arterial stiffness assessed by CAVI, albuminuria, 24-hour BP and metabolism compared with CCB-based therapy. Since these markers are known to influence the future risk of cardiovascular events, telmisartan could be a useful drug for hypertensive patients.

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New approaches to blockade of the renin-angiotensin-aldosterone system: characteristics and usefulness of the direct renin inhibitor aliskiren

Ichihara, A., Sakoda, M., Kurauchi-Mito, A., Narita, T., Kinouchi, K., Bokuda, K. and Itoh, H.

J Pharmacol Sci 113 （ 4 ） 296 - 300 2010年

ISSN 1347-8613

Since renin inhibition interferes with the first and rate-limiting steps in the renin-angiotensin system, the renin step is a very attractive target for lowering blood pressure and minimizing target-organ damage. The newly developed direct renin inhibitor aliskiren has several attractive characteristics: it definitively reduces plasma renin activity among inhibitors of the renin-angiotensin system, is remarkably specific for human renin, exhibits a long half-life in plasma comparable to that of amlodipine, and has a high affinity for renal glomeruli and vasculature. Although these characteristics suggest the clinical usefulness and safety of aliskiren, several problems remain unsolved. Why does aliskiren have beneficial effects on the heart and kidneys of patients treated with angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II type 1-receptor blockers (ARBs)? Is the blood-pressure-lowering effect of aliskiren dependent on the plasma renin activity? Does aliskiren exert a possible adverse effect via (pro)renin receptor-dependent intracellular signals? Here, we review the characteristics and usefulness of aliskiren and discuss the current issues associated with this direct renin inhibitor.

Differentiation of murine embryonic stem and induced pluripotent stem cells to renal lineage in vitro

Morizane, R., Monkawa, T. and Itoh, H.

Biochem Biophys Res Commun 390 （ 4 ） 1334 - 9 2009年12月

ISSN 0006-291

Embryonic stem (ES) cells which have the unlimited proliferative capacity and extensive differentiation potency can be an attractive source for kidney regeneration therapies. Recent breakthroughs in the generation of induced pluripotent stem (iPS) cells have provided with another potential source for the artificially-generated kidney. The purpose of this study is to know how to differentiate mouse ES and iPS cells into renal lineage. We used iPS cells from mouse fibroblasts by transfection of four transcription factors, namely Oct4, Sox2, c-Myc and Klf4. Real-time PCR showed that renal lineage markers were expressed in both ES and iPS cells after the induction of differentiation. It also showed that a tubular specific marker, KSP progressively increased to day 18, although the differentiation of iPS cells was slower than ES cells. The results indicated that renal lineage cells can be differentiated from both murine ES and iPS cells. Several inducing factors were tested whether they influenced on cell differentiation. In ES cells, both of GDNF and BMP7 enhanced the differentiation to metanephric mesenchyme, and Activin enhanced the differentiation of ES cells to tubular cells. Activin also enhanced the differentiation of iPS cells to tubular cells, although the enhancement was lower than in ES cells. ES and iPS cells have a potential to differentiate to renal lineage cells, and they will be an attractive resource of kidney regeneration therapy. This differentiation is enhanced by Activin in both ES and iPS cells.

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Safety and benefits of a tablet combining losartan and hydrochlorothiazide in Japanese diabetic patients with hypertension

Kinouchi, K., Ichihara, A., Sakoda, M., Kurauchi-Mito, A. and Itoh, H.

Hypertens Res 32 （ 12 ） 1143 - 7 2009年12月

ISSN 0916-9636

This study was conducted to determine the effects of a tablet combining losartan/hydrochlorothiazide (L/HCTZ) in comparison with losartan alone in Japanese diabetic patients with hypertension. Thirty consecutive Japanese diabetic patients with hypertension were randomly assigned to group A, receiving losartan alone for the first 3 months, then L/HCTZ for the next 3 months, or group B, receiving L/HCTZ for the first 3 months, then losartan alone for the next 3 months. Clinical and biological parameters were obtained before, and 3 and 6 months after the start of this study. The decreases in systolic and diastolic blood pressure (BP) during treatment with L/HCTZ were significantly greater than in treatment with losartan alone. Both treatments significantly and similarly decreased urinary albumin excretion, the cardio-ankle vascular index (CAVI) and augmentation index (AI). There was no significant difference in metabolic change during both the mono- and combination pharmacotherapies. The tablet combining L/HCTZ significantly reduced systolic and diastolic BP compared with the losartan monotherapy, and offered benefits similar to losartan monotherapy for albuminuria, arterial stiffness assessed by the CAVI and AI, and metabolic effects. Thus, the L/HCTZ tablet could be a useful drug for Japanese diabetic patients with hypertension.

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MCP-1 gene A-2518G polymorphism and carotid artery atherosclerosis in patients with type 2 diabetes

Yuasa, S., Maruyama, T., Yamamoto, Y., Hirose, H., Kawai, T., Matsunaga-Irie, S. and Itoh, H.

Diabetes Res Clin Pract 86 （ 3 ） 193 - 8 2009年12月

ISSN 0168-8227

AIMS: Cardiovascular diseases are the major cause of mortality in patients with diabetes mellitus. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine and plays an important role in cardiovascular diseases. The objective of this study was to evaluate the relation between the genotypes of the MCP-1 A-2518G polymorphism and the development of carotid atherosclerosis in patients with type 2 diabetes. METHODS: The subjects were 303 unrelated patients who were diagnosed with type 2 diabetes mellitus. To evaluate macroangiopathy, we measured carotid artery intima-media thickness (IMT) by ultrasonography. The MCP-1 A-2518G polymorphism was determined by TaqMan PCR method. RESULTS: IMT in patients with the MCP-1 -2518 AG or GG genotype was significantly greater than the AA-genotype (P=0.007). Simple regression analysis showed that age, systolic blood pressure, LDL-cholesterol, the MCP-1 -2518 AG+GG polymorphism, and HbA1c level were correlated with IMT (P<0.0001, <0.0001, 0.006, 0.007, 0.025, respectively). In multiple regression analysis, the MCP-1 -2518 AG+GG polymorphism was the third strongest independent determinant of IMT in patients with type 2 diabetes (P=0.021), subsequent to age and systolic blood pressure. CONCLUSION: Assessment of the MCP-1 A-2518G polymorphism would be useful in identifying the risk of developing carotid atherosclerosis in patients with type 2 diabetes.

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Natriuretic peptides/cGMP/cGMP-dependent protein kinase cascades promote muscle mitochondrial biogenesis and prevent obesity

Miyashita, K., Itoh, H., Tsujimoto, H., Tamura, N., Fukunaga, Y., Sone, M., Yamahara, K., Taura, D., Inuzuka, M., Sonoyama, T. and Nakao, K.

Diabetes 58 （ 12 ） 2880 - 92 2009年12月

ISSN 0012-1797

OBJECTIVE: Natriuretic peptides (NPs) have been characterized as vascular hormones that regulate vascular tone via guanylyl cyclase (GC), cyclic GMP (cGMP), and cGMP-dependent protein kinase (cGK). Recent clinical studies have shown that plasma NP levels were lower in subjects with the metabolic syndrome. The present study was conducted to elucidate the roles for NP/cGK cascades in energy metabolism. RESEARCH DESIGN AND METHODS: We used three types of genetically engineered mice: brain NP (BNP) transgenic (BNP-Tg), cGK-Tg, and guanylyl cyclase-A (GCA) heterozygous knockout (GCA(+/-)) mice and analyzed the metabolic consequences of chronic activation of NP/cGK cascades in vivo. We also examined the effect of NPs in cultured myocytes. RESULTS: BNP-Tg mice fed on high-fat diet were protected against diet-induced obesity and insulin resistance, and cGK-Tg mice had reduced body weight even on standard diet; surprisingly, giant mitochondria were densely packed in the skeletal muscle. Both mice showed an increase in muscle mitochondrial content and fat oxidation through upregulation of peroxisome proliferator-activated receptor (PPAR)-gamma coactivator (PGC)-1alpha and PPARdelta. The functional NP receptors, GCA and guanylyl cyclase-B, were downregulated by feeding a high-fat diet, while GCA(+/-) mice showed increases in body weight and glucose intolerance when fed a high-fat diet. NPs directly increased the expression of PGC-1alpha and PPARdelta and mitochondrial content in cultured myocytes. CONCLUSIONS: The findings together suggest that NP/cGK cascades can promote muscle mitochondrial biogenesis and fat oxidation, as to prevent obesity and glucose intolerance. The vascular hormone, NP, would contribute to coordinated regulation of oxygen supply and consumption.

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Cyclic GMP kinase and RhoA Ser188 phosphorylation integrate pro- and antifibrotic signals in blood vessels

Sawada, N., Itoh, H., Miyashita, K., Tsujimoto, H., Sone, M., Yamahara, K., Arany, Z. P., Hofmann, F. and Nakao, K.

Mol Cell Biol 29 （ 22 ） 6018 - 32 2009年11月

ISSN 0270-7306

Vascular fibrosis is a major complication of hypertension and atherosclerosis, yet it is largely untreatable. Natriuretic peptides (NPs) repress fibrogenic activation of vascular smooth muscle cells (VSMCs), but the intracellular mechanism mediating this effect remains undetermined. Here we show that inhibition of RhoA through phosphorylation at Ser188, the site targeted by the NP effector cyclic GMP (cGMP)-dependent protein kinase I (cGK I), is critical to fully exert antifibrotic potential. cGK I(+/-) mouse blood vessels exhibited an attenuated P-RhoA level and concurrently increased RhoA/ROCK signaling. Importantly, cGK I insufficiency caused dynamic recruitment of ROCK into the fibrogenic programs, thereby eliciting exaggerated vascular hypertrophy and fibrosis. Transgenic expression of cGK I-unphosphorylatable RhoA(A188) in VSMCs augmented ROCK activity, vascular hypertrophy, and fibrosis more prominently than did that of wild-type RhoA, consistent with the notion that RhoA(A188) escapes the intrinsic inhibition by cGK I. Additionally, VSMCs expressing RhoA(A188) became refractory to the antifibrotic effects of NPs. Our results identify cGK I-mediated Ser188 phosphorylation of RhoA as a converging node for pro- and antifibrotic signals and may explain how diminished cGMP signaling, commonly associated with vascular malfunction, predisposes individuals to vascular fibrosis.

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Serum bile acid along with plasma incretins and serum high-molecular weight adiponectin levels are increased after bariatric surgery

Nakatani, H., Kasama, K., Oshiro, T., Watanabe, M., Hirose, H. and Itoh, H.

Metabolism 58 （ 10 ） 1400 - 7 2009年10月

ISSN 0026-0495

Bariatric surgery has been shown to improve glucose tolerance, although the mechanism has not been fully elucidated. Animal studies have suggested important roles of bile acid (BA) as a regulator of energy homeostasis and glucose metabolism. However, little is known about its role in humans. We investigated the longitudinal changes of BA, incretins, and adipokines after significant weight reduction in 34 Japanese adults with morbid obesity who underwent laparoscopic bariatric surgery. In subjects who underwent malabsorptive or restrictive surgery, body mass index had markedly decreased from 43.0 +/- 6.5 (SD) to 37.8 +/- 5.7 kg/m(2) and from 45.3 +/- 11.2 to 41.5 +/- 10.5 kg/m(2), respectively, at 1 month after surgery. Glycated hemoglobin decreased from 6.1% +/- 1.5% to 5.2% +/- 0.4% and from 6.2% +/- 1.3% to 5.4% +/- 0.7%, and total BA level increased from 3.1 +/- 3.5 to 7.2 +/- 5.3 mumol/L and from 3.2 +/- 2.6 to 9.4 +/- 10.0 mumol/L, respectively. At baseline, serum concentration of primary BA was positively correlated with plasma gastric inhibitory polypeptide level (r = 0.548, P = .001); and change in primary BA level was positively correlated with changes in plasma gastric inhibitory polypeptide (r = 0.626, P = .001) and serum immunoreactive insulin level (r = 0.592, P = .002) at 1 month after surgery. Furthermore, plasma glucagon-like peptide-1 and serum high-molecular weight adiponectin levels increased in both surgeries. These hormonal changes might explain the mechanism(s) of improved glucose tolerance after bariatric surgery in morbidly obese subjects.

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Prevention and regression of hypertension: role of renal microvascular protection

Sasamura, H., Hayashi, K., Ishiguro, K., Nakaya, H., Saruta, T. and Itoh, H.

Hypertens Res 32 （ 8 ） 658 - 64 2009年08月

ISSN 0916-9636

Hypertension is a disease which affects over 26.4% of the world adult population, therefore novel approaches to the prevention and treatment of this disease need to be examined. Previous studies from our and other laboratories have shown that treatment of spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats with a renin-angiotensin system (RAS) inhibitor during the 'critical period' in hypertension development results in prevention of the later development of hypertension. In humans, Julius et al. reported similar findings in the landmark TROPHY study. Recently, we reported that 'pulse' treatment of SHR with high-dose angiotensin receptor blocker (ARB) is effective in causing sustained reduction of already established hypertension, even when the treatment was started after the 'critical period'. These results suggest the possibility that 'regression' of established hypertension may become feasible, and we have started a prospective, multicenter clinical study (STAR CAST study) to examine this possibility. In our animal studies, we found that treatment of rats during the 'critical period' with an ARB inhibits the development of renal arteriolar hypertrophy. Moreover, a high-dose angiotensin blocker caused a remarkable reversal of renal arteriolar hypertrophy in SHR, which was associated with changes in microvascular MMP expression. These results suggest that changes in the renal microvasculature may have an important role in the mechanisms of hypertension prevention and regression by ARB.

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Clinical importance of Stenotrophomonas maltophilia nosocomial pneumonia due to its high mortality in hemodialysis patients

Wakino, S., Imai, E., Yoshioka, K., Kamayachi, T., Minakuchi, H., Hayashi, K., Inamoto, H. and Itoh, H.

Ther Apher Dial 13 （ 3 ） 193 - 8 2009年06月

ISSN 1744-9979

Patients undergoing hemodialysis are immunocompromised and can suffer from pneumonia with various pathogens in nosocomial conditions. We investigated the fundamental information on the characteristics of hemodialysis inpatients and nosocomial pneumonia. We surveyed 1803 hemodialysis patients admitted to our university hospital between 2001 and 2007. The mean patient age was 64.8 years and the average period of hospitalization was 28.1 days, which was considerably longer than the average stay in our hospital (14.2 days). Patients were admitted to many different departments and for various reasons. We isolated 391 microorganisms from the sputum of 120 pneumonia patients undergoing hemodialysis, including Candida albicans, methicillin-resistant Staphylococcus aureus, and Staphylococcus epidermidis, which were the leading three isolates. From these 120 patients, a total of 199 pathogens were identified as being responsible for the pneumonia. Multi-drug resistant Stenotrophomonas maltophilia was found to be susceptible to a new fluoroquinolone, but is resistant to older generation quinolones. Out of the 120 patients with pneumonia, 12 out of 18 patients infected with S. maltophilia died, indicating the highest fatality rate for this pathogen. In this survey, we found that hemodialysis patients were hospitalized for long periods, and for various reasons in many departments. They suffered from nosocomial pneumonia caused by multi-drug resistant pathogens, including S. maltophilia. For pneumonia due to S. maltophilia, new generation fluoroquinolones can be the treatment of choice, although S. maltophilia-related pneumonia should be treated very carefully because of its high fatality rate.

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Renin, prorenin and the kidney: a new chapter in an old saga

Ichihara, A., Sakoda, M., Kurauchi-Mito, A., Kaneshiro, Y. and Itoh, H.

J Nephrol 22 （ 3 ） 306 - 11 2009年05月

ISSN 1121-8428

The binding of prorenin to the (pro)renin receptor triggers 2 major pathways: a nonproteolytic conformational change in prorenin to its active form (angiotensin II-dependent pathway) and an intracellular pathway via the (pro)renin receptor itself (angiotensin II-independent pathway). In diabetic animals, an increased plasma prorenin level not only causes the generation of angiotensin II via the angiotensin II-dependent pathway, it also stimulates the transliteration receptors own intracellular signaling pathway in a manner that is independent of the generated angiotensin II. Thus, the administration of a "handle" region peptide (HRP), which acts as a decoy peptide and competitively inhibits the binding of prorenin to the (pro)renin receptor, has a beneficial effect in the kidneys of diabetic animals with low plasma renin levels. However, the benefits of HRP are slightly reduced in animal models of essential hypertension with relatively high plasma renin levels, and these benefits disappear altogether in animal models of hypertension with extremely high plasma renin levels. Thus, in the kidneys of animal models of diabetes and/or hypertension, both renin and prorenin competitively bind to the (pro)renin receptor and contribute to the pathophysiology of nephropathy. Consequently, renin, prorenin and the (pro) renin receptor may be important therapeutic targets for the prevention and regression of nephropathy in patients with diabetes and/or hypertension.

Effects of telmisartan therapy on metabolic profiles and serum high molecular weight (HMW)-adiponectin level in Japanese male hypertensive subjects with abdominal obesity

Komiya, N., Hirose, H., Kawabe, H., Itoh, H. and Saito, I.

J Atheroscler Thromb 16 （ 2 ） 137 - 42 2009年04月

ISSN 1340-3478

AIM: Telmisartan, an angiotensin II receptor blocker (ARB), was reported to have partial peroxisome proliferator-activated receptor gamma (PPAR gamma) activity in vitro. Also, adipocyte-derived protein adiponectin, especially its high molecular weight (HMW) form, has been reported to have beneficial effects on insulin resistance and atherosclerosis. We investigated the effects of 3-month telmisartan therapy on various metabolic parameters, including serum HMW adiponectin and high-sensitivity C-reactive protein (hs-CRP) levels in male hypertensive subjects with abdominal obesity. METHODS: This study included 19 Japanese male hypertensive subjects, aged 51.2+/-7.6 (mean+/-SD) years, and body mass index 27.7+/-4.1 kg/m(2). In these subjects, 14 were naive to telmisartan treatment (40.0+/-15.7 mg daily), and 5 were changed from other ARBs to telmisartan. Serum HMW adiponectin concentration was assayed using HMW-selective ELISA kit. RESULTS: In all 19 subjects, systolic/diastolic blood pressure (BP) decreased from 153/98 to 134/85 mmHg (p<0.001 for both). Serum HMW-adiponectin level increased from 2.06+/-0.81 to 2.40+/-0.96 microg/mL (+16.4%, p=0.017). Body weight, glucose, insulin, lipids and hs-CRP did not change during the study period, and there were no adverse effects in any subject. In the newly administered group (n=14), the results were almost the same: BP decreased from 155/98 to 134/84 mmHg (p=0.0015 for both), and serum HMW-adiponectin level increased from 2.07+/-0.68 to 2.39+/-0.99 microg/mL (+15.5%, p=0.089). CONCLUSION: These data suggest that telmisartan therapy is efficient for controlling BP, and may exert beneficial effects on HMW adiponectin in male hypertensive subjects with abdominal obesity.

Adipogenic differentiation of human induced pluripotent stem cells: comparison with that of human embryonic stem cells

Taura, D., Noguchi, M., Sone, M., Hosoda, K., Mori, E., Okada, Y., Takahashi, K., Homma, K., Oyamada, N., Inuzuka, M., Sonoyama, T., Ebihara, K., Tamura, N., Itoh, H., Suemori, H., Nakatsuji, N., Okano, H., Yamanaka, S. and Nakao, K.

FEBS Lett 583 （ 6 ） 1029 - 33 2009年03月

ISSN 0014-5793

Induced pluripotent stem (iPS) cells were recently established from human fibroblasts. In the present study we investigated the adipogenic differentiation properties of four human iPS cell lines and compared them with those of two human embryonic stem (ES) cell lines. After 12 days of embryoid body formation and an additional 10 days of differentiation on Poly-l-ornithine and fibronectin- coated dishes with adipogenic differentiation medium, human iPS cells exhibited lipid accumulation and transcription of adipogenesis-related molecules such as C/EBPalpha, PPARgamma2, leptin and aP2. These results demonstrate that human iPS cells have an adipogenic potential comparable to human ES cells.

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Induction of anti-whole GAD65 reactivity in vivo results in disease suppression in type 1 diabetes

Kanazawa, Y., Shimada, A., Oikawa, Y., Okubo, Y., Tada, A., Imai, T., Miyazaki, J. and Itoh, H.

J Autoimmun 32 （ 2 ） 104 - 9 2009年03月

ISSN 0896-8411

Most type 1 diabetes mellitus is caused by autoimmune pancreatic beta-cell destruction. Several antigens such as insulin, glutamic acid decarboxylase (GAD) and islet-specific glucose-6-phosphatase catalytic subunit related protein (IGRP) are considered to take part in the autoimmune destructive process. Because the role of GAD in the disease process of type 1 diabetes is still controversial, we investigated the disease phenotype upon in vivo induction of whole GAD65 reactivity using a GAD65 homo knockout NOD splenocytes to NOD-scid transfer system. Splenocytes from 8 to 10-week-old female GAD65 homo knockout (=KOT splenocytes) or age-matched wild type (=WTT splenocytes) NOD mice were transferred into female NOD-scid recipients. As compared to recipients of WTT splenocytes, the onset of diabetes in recipients of KOT splenocytes was significantly delayed (p<0.001). Moreover, TGF-beta expression was enhanced in the pancreas from recipients of KOT splenocytes. Splenocytes from recipients of KOT splenocytes produced IL-10 (/IFN-gamma) upon GAD65 stimulation, whereas those from recipients of WTT splenocytes did not. Based upon these results, we propose that anti-whole GAD65-reactive T cells have the ability to regulate the development of type 1 diabetes.

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High-molecular-weight adiponectin is a predictor of progression to metabolic syndrome: a population-based 6-year follow-up study in Japanese men

Seino, Y., Hirose, H., Saito, I. and Itoh, H.

Metabolism 58 （ 3 ） 355 - 60 2009年03月

ISSN 0026-0495

Adiponectin is an adipocyte-specific secretory protein, which possesses antidiabetic and antiatherosclerotic properties. Adiponectin exists as multimers in serum, and high-molecular-weight (HMW) adiponectin is particularly considered to be the active form of the protein. The objective of the present study was to examine whether decreased HMW adiponectin is a predictor of progression to metabolic syndrome during a 6-year follow-up period in Japanese men. The study subjects were 416 Japanese men without metabolic syndrome, aged 30 to 59 years at baseline, who had participated in annual health checkups in both 2000 and 2006. Low concentration of HMW adiponectin (< or =2.65 microg/mL) was associated with substantially higher hazard ratio of the progression to metabolic syndrome after adjustment for age and body mass index (hazard ratio, 1.561; 95% confidence interval, 1.051-2.292; P = .028). The number of subjects with the progression to metabolic syndrome in each tertile based on baseline HMW adiponectin concentration was significantly different among the 3 groups (HMW adiponectin: chi(2) = 7.473, P = .0238; total adiponectin: chi(2) = 4.477, P = .1066; HMW-total adiponectin ratio: chi(2) = 1.676, P = .4325). It was suggested that decreased HMW adiponectin is a predictor of the progression to metabolic syndrome in a 6-year follow-up study of Japanese men. Furthermore, it was suggested longitudinally that measuring HMW adiponectin is efficient to predict the progression to metabolic syndrome compared with measuring total adiponectin or HMW-total adiponectin ratio.

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Angiotensin II reduces mitochondrial content in skeletal muscle and affects glycemic control

Mitsuishi, M., Miyashita, K., Muraki, A. and Itoh, H.

Diabetes 58 （ 3 ） 710 - 7 2009年03月

ISSN 0012-1797

OBJECTIVE: Blockade of angiotensin (Ang) II has been shown to prevent new-onset type 2 diabetes. We focused on the effects of AngII on muscle mitochondria, especially on their biogenesis, as an underlining mechanism of type 2 diabetes. RESEARCH DESIGN AND METHODS: C2C12 cells and C57bl/6 mice were used to examine roles for AngII in the regulation of muscle mitochondria and to explore whether the effect was mediated by type 1 AngII receptor (AT1R) or type 2 receptor (AT2R). RESULTS: C2C12 cells treated with 10(-8)-10(-6) mol/l AngII reduced the mitochondrial content associated with downregulation of the genes involved in mitochondrial biogenesis. The action of AngII was diminished by blockade of AT2R but not AT1R, whereas overexpression of AT2R augmented the effect. AngII increased mitochondrial ROS and decreased mitochondrial membrane potential, and these effects of AngII were significantly suppressed by blockade of either AT1R or AT2R. Chronic AngII infusion in mice also reduced muscle mitochondrial content in association with increased intramuscular triglyceride and deteriorated glycemic control. The AngII-induced reduction in muscle mitochondria in mice was partially, but significantly, reversed by blockade of either AT1R or AT2R, associated with increased fat oxidation, decreased muscle triglyceride, and improved glucose tolerance. Genes involved in mitochondrial biogenesis were decreased via AT2R but not AT1R under these in vivo conditions. CONCLUSIONS: Taken together, these findings imply the novel roles for AngII in the regulation of muscle mitochondria and lipid metabolism. AngII reduces mitochondrial content possibly through AT1R-dependent augmentation of their degradation and AT2R-dependent direct suppression of their biogenesis.

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FOXP3/Scurfin gene polymorphism is associated with adult onset type 1 diabetes in Japanese, especially in women and slowly progressive-type patients

Iwase, K., Shimada, A., Kawai, T., Okubo, Y., Kanazawa, Y., Irie, J., Oikawa, Y., Hirose, H., Maruyama, T. and Itoh, H.

Autoimmunity 42 （ 2 ） 159 - 67 2009年02月

ISSN 0891-6934

PURPOSE: Some reports have shown that the cause of type 1 diabetes is associated with dysfunction of regulatory T cells (Tregs). The FOXP3/Scurfin gene is known to be a master gene of Tregs. Therefore, we tried to analyze the relation between the gene polymorphism and adult onset type 1 diabetes and its subtype in the Japanese population. METHODS: In this study, we recruited 316 Japanese patients with type 1 diabetes (155 male and 161 female, mean onset age 35.4 years) and 432 healthy Japanese controls (263 male and 169 female, mean age 44.4 years). Then we subdivided the patients by onset type, sex, and islet-associated autoantibody positivity. RESULTS: The genotype frequency of (GT)(16)/(GT)(16) in female patients with overall type 1 diabetes was especially lower than that in controls (19.9% vs. 38.5%, p = 0.0002). Moreover, the genotype frequency of (GT)(16)/(GT)(16) in female patients with slowly progressive type 1 diabetes was significantly lower than that in controls (15.4% vs. 38.5%, p = 0.002). CONCLUSION: Our data showed that the (GT)n microsatelloite polymorphism in the FOXP3/Scrufin gene was associated with Japanese adult onset type 1 diabetes, especially in females, and slowly progressive type 1 diabetes.

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Close examination of steroidogenesis disorders in a DOC- and progesterone-producing adrenocortical carcinoma

Sone, M., Shibata, H., Homma, K., Tamura, N., Akahira, J., Hamada, S., Yahata, M., Fukui, N., Itoh, H., Sasano, H. and Nakao, K.

Endocrine 35 （ 1 ） 25 - 33 2009年02月

ISSN 1355-008X

We report a case of hypertension, hypokalemia, and amenorrhea accompanying an adrenocortical carcinoma. A 27-year-old woman was admitted to our hospital because of a left adrenal incidentaloma. She presented with hypertension, hypokalemia, and amenorrhea; her plasma renin activity was low, but her plasma aldosterone concentration was normal, as were cortisol and androgens. By contrast, her serum concentrations of deoxycorticosterone (DOC), 18-hydroxydeoxycorticosterone, and progesterone were high, and her urinary steroid profile showed elevated secretion of 17-deoxysteroids and 11-deoxysteroids (progesterone, DOC, 11-dehydrocorticosterone, and 11-deoxycortisol), and 3beta-hydroxy 5-en steroids (pregnenolone, 17-hydroxypregnenolone, and DHEA). Decreased ratios of metabolites of (1) 17-OHpregnenolone to pregnenolone and 17-OHprogesterone to progesterone, (2) corticosterone to DOC and cortisol to 11-deoxycortisol, and (3) progesterone to pregnenolone, 17-OHprogesterone to 17-OHpregnenolone and androstenedione to DHEA suggested the impairment of 17alpha-hydroxylase, 11beta-hydroxylase, and 3beta-HSD activities, respectively. After the tumor was removed, levels of all adrenal steroids were normalized. Based on the Weiss criteria, the tumor was diagnosed as an adrenocortical carcinoma, and immunohistochemical analysis of steroidogenic enzymes revealed disorganized steroidogenesis in the tumor tissue. With adrenocortical carcinomas, heterogeneity of individual steroid producing enzymes within tumor cells can lead to hypersecretion of various steroid intermediates, even when steroid end products are within the normal range.

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[Metabolic syndrome]

Mitsuishi, M., Miyashita, K. and Itoh, H.

Nihon Rinsho 67 （ 2 ） 321 - 6 2009年02月

ISSN 0047-1852

Metabolic syndrome, which is consisted of hypertension, dyslipidemia and impaired glucose tolerance, is one of the most significant lifestyle-related disorders that lead to cardiovascular diseases. Among many upstream factors that are related to metabolic syndrome, obesity, especially visceral obesity, plays an essential role in its pathogenesis. In recent studies, possible mechanisms which connect obesity to metabolic syndrome have been elucidated, such as inflammation, abnormal secretion of adipokines and mitochondrial dysfunction. In this review, we focus on the relationship between obesity and metabolic syndrome; and illustrate how visceral obesity contributes to, and how the treatments for obesity act on metabolic syndrome.

Drug discovery for overcoming chronic kidney disease (CKD): new therapy for CKD by a (pro)renin-receptor-blocking decoy peptide

Ichihara, A., Sakoda, M., Kurauchi-Mito, A., Narita, T., Kinouchi, K. and Itoh, H.

J Pharmacol Sci 109 （ 1 ） 20 - 3 2009年01月

ISSN 1347-8613

Discovery of the (pro)renin receptor uncovered a novel function of renin/prorenin as the receptor ligands in addition to the enzyme and its precursor. The bindings of renin and prorenin to the (pro)renin receptor trigger two major pathways: the angiotensin II-dependent pathway as a result of the enzymatic activation of renin/prorenin and the angiotensin II-independent intracellular pathway involving hypertrophic, hyperplastic, and profibrotic signals. A specific blocker of the receptor was discovered through identification of the amino acid sequence of prorenin prosegment that binds to the receptor and leads to non-proteolytic conversion of prorenin to its active form. A peptide containing this sequence was found to block the binding of prorenin to its receptor. Its infusion in animal models of diabetes and low-renin hypertension significantly inhibited the development and progression of nephropathy, but (pro)renin receptor blockade had no benefit in the clipped kidney of 2K1C rats or rat models of high-renin hypertension. Since renin is still active without a (pro)renin receptor, (pro)renin-receptor blockade elicits a maximum benefit under low-renin conditions. Thus, (pro)renin-receptor blockade can be a useful therapy for chronic kidney disease with low renin levels in the plasma.

"Pulse" treatment with high-dose angiotensin blocker reverses renal arteriolar hypertrophy and regresses hypertension

Ishiguro, K., Hayashi, K., Sasamura, H., Sakamaki, Y. and Itoh, H.

Hypertension 53 （ 1 ） 83 - 9 2009年01月

ISSN 0194-911

One ultimate goal of hypertension therapy is to cause permanent reversal ("regression") of already established hypertension. Our aim was to examine whether high-dose "pulse" treatment with a renin-angiotensin system inhibitor could cause regression of established hypertension and to link this action to reversal of arteriolar hypertrophy and changes in vascular matrix metalloproteinase activities. First, 16-week-old male spontaneously hypertensive rats (n=60) were pulse treated for 2 weeks with high-dose angiotensin-converting enzyme inhibitor (enalapril), angiotensin receptor blocker (candesartan), calcium channel blocker (nifedipine), or vasodilator (hydralazine) with or without salt restriction, and the long-term effects on blood pressure were examined. Second, spontaneously hypertensive rats were treated with angiotensin receptor blocker or calcium channel blocker, and the effects on renal gene expressions, arteriolar structure, and vascular matrix metalloproteinase were compared. Treatment of spontaneously hypertensive rats with different antihypertensive agents caused apparently similar reductions in blood pressure during the course of the pulse treatment, within the limitations of the tail-cuff method. After cessation of medications, blood pressure in the rats treated with renin-angiotensin system inhibitor remained reduced by >30 to 40 mm Hg for 4 months. No such effect was seen with calcium channel blocker or vasodilator. The 2-week angiotensin receptor blocker treatment induced a marked reversal of the arteriolar hypertrophy specifically in the small (30 to 100 microm) renal arterioles, together with increased expression and activity of matrix metalloproteinase-13. In conclusion, transient high-dose pulse treatment with angiotensin receptor blocker caused changes in vascular matrix metalloproteinase activity, specific reversal of renal arteriolar hypertrophy, and regression of hypertension in spontaneously hypertensive rats.

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Relation of blood pressure quantitative trait locus on rat chromosome 1 to hyperactivity of rostral ventrolateral medulla

Iigaya, K., Kumagai, H., Nabika, T., Harada, Y., Onimaru, H., Oshima, N., Takimoto, C., Kamayachi, T., Saruta, T. and Itoh, H.

Hypertension 53 （ 1 ） 42 - 8 2009年01月

ISSN 0194-911

Genetic factors that induce essential hypertension have been examined using genome-wide linkage analyses. A quantitative trait locus (QTL) region that is closely linked to hypertension has been found on chromosome 1 in stroke-prone spontaneously hypertensive rats (SHRSPs). We used 2 congenic rats in which the blood pressure QTL on rat chromosome 1 was introgressed from SHRSP/Izm to Wistar-Kyoto (WKY)/Izm (WKYpch1.0) and from WKY/Izm to SHRSP/Izm (SHRSPwch1.0) rats by repeated backcrossing. Previous studies reported that the intermediate phenotype of this QTL for hypertension is characterized by the hyperactivity of the sympathetic nervous system in response to physiological and psychological stress. We performed intracellular patch-clamp recordings of rostral ventrolateral medulla (RVLM) neurons from WKY, WKYpch1.0, SHRSPwch1.0, and SHRSPs and compared the basal electrophysiological activities of RVLM neurons and the responses of these neurons to angiotensin II. The basal membrane potential of RVLM neurons from WKYpch1.0 was significantly "shallower" than that of the neurons from WKY. The depolarization of RVLM neurons from WKYpch1.0 in response to angiotensin II was significantly larger than that in neurons from WKY rats, whereas the depolarization of RVLM neurons from SHRSPwch1.0 was significantly smaller than that in neurons from SHRSPs. The response to angiotensin II of RVLM neurons from WKYpch1.0 and SHRSPs was sustained even after the blockade of all of the synaptic transmissions using tetrodotoxin. The QTL on rat chromosome 1 was primarily related to the postsynaptic response of RVLM bulbospinal neurons to brain angiotensin II, whereas both the QTL and other genomic regions influenced the basal activity of RVLM neurons.

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Add-on benefits of amlodipine and thiazide in nondiabetic chronic kidney disease stage 1/2 patients treated with valsartan

Kaneshiro, Y., Ichihara, A., Sakoda, M., Kurauchi-Mito, A., Kinouchi, K. and Itoh, H.

Kidney Blood Press Res 32 （ 1 ） 51 - 8 2009年

ISSN 1420-4096

Hypertension frequently requires combination therapy to attain efficient control to prevent cardiovascular diseases effectively. This study was conducted to determine which add-on treatment is better, namely calcium channel blockers or diuretics, in improving vascular damage. In 70 nondiabetic chronic kidney disease stage 1/2 patients who had been already treated with angiotensin II type 1 receptor blocker valsartan for at least 12 months, amlodipine or hydrochlorothiazide was added to their existing medication. Pulse wave velocity (PWV), intima-media thickness (IMT) of the carotid arteries, urinary albumin excretion (UAE), and 24-hour ambulatory blood pressure (BP) were determined before and 12 months after the start of add-on treatments. Add-on amlodipine and add-on hydrochlorothiazide significantly and similarly decreased 24-hour ambulatory BP by 18 and 19 mm Hg, respectively, PWV by 206 and 184 cm/s, respectively, and UAE, but did not change the IMT. The decreases in BP significantly contributed to the decreases in PWV and UAE and suggested that the decrease in serum cholesterol level brought about by add-on amlodipine also contributed to the decrease in UAE. These results suggest that 12 months of add-on treatment with either amlodipine or hydrochlorothiazide could have beneficial effects in nondiabetic chronic kidney disease stage 1/2 patients already being treated with valsartan.

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Association of (pro)renin receptor mRNA expression with angiotensin-converting enzyme mRNA expression in human artery

Takemitsu, T., Ichihara, A., Kaneshiro, Y., Sakoda, M., Kurauchi-Mito, A., Narita, T., Kinouchi, K., Yamashita, N. and Itoh, H.

Am J Nephrol 30 （ 4 ） 361 - 70 2009年

ISSN 0250-8095

BACKGROUND/AIMS: A significant role of (pro)renin receptor in the pathogenesis of end-organ damage has been suggested only in animal studies. This study was conducted to examine the mRNA expression of (pro)renin receptor in human artery. METHODS: In 141 kidney failure patients, the mRNA was harvested from arterial fragments obtained during surgery constructing an arteriovenous access for hemodialysis therapy, and expression levels of (pro)renin receptor and other components of the renin-angiotensin system were determined. RESULTS: Arterial (pro)renin receptor expression was similar in diabetic and non-diabetic patients, although plasma prorenin levels were significantly higher in the diabetic patients than in the non-diabetic patients. The arterial (pro)renin receptor mRNA levels of the hypertensive patients, who had not been treated with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers, were significantly lower than those of the patients who had been treated with either drug. Multiple regression analyses showed a significant association with a large coefficient between the arterial mRNA level of the (pro)renin receptor and the arterial mRNA level of ACE; this significant association disappeared in patients who had been treated with either drug. CONCLUSION: (Pro)renin receptor may contribute to the generation of arterial angiotensin II in kidney failure patients.

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(Pro)renin receptor promotes choroidal neovascularization by activating its signal transduction and tissue renin-angiotensin system

Satofuka, S., Ichihara, A., Nagai, N., Noda, K., Ozawa, Y., Fukamizu, A., Tsubota, K., Itoh, H., Oike, Y. and Ishida, S.

Am J Pathol 173 （ 6 ） 1911 - 8 2008年12月

ISSN 0002-9440

The receptor-associated prorenin system (RAPS) refers to pathogenic mechanisms whereby prorenin binding to its receptor activates both the tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling pathways. Although we found significant involvement of angiotensin II type 1 receptor (AT1-R)-mediated inflammation in choroidal neovascularization (CNV), a central abnormality of vision-threatening age-related macular degeneration, the association of receptor-associated prorenin system with CNV has not been defined. Here, (pro)renin receptor blockade in a murine model of laser-induced CNV led to the significant suppression of CNV together with macrophage infiltration and the up-regulation of intercellular adhesion molecule-1, (ICAM-1) monocyte chemotactic protein-1, (MCP-1) vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-1, and VEGFR-2. To clarify the role of signal transduction via the (pro)renin receptor in CNV, we used mice in which renin-angiotensin system was deactivated by either the pharmacological blockade of AT1-R with losartan or the genetic ablation of AT1-R or angiotensinogen. Compared with wild-type controls, these mice exhibited significant reduction of CNV and macrophage infiltration, both of which were further suppressed by (pro)renin receptor blockade. The (pro)renin receptor and phosphorylated extracellular signal-regulated kinases (ERK) were co-localized in vascular endothelial cells and macrophages in CNV. (Pro)renin receptor blockade suppressed ERK activation and the production of MCP-1 and VEGF, but not ICAM-1, VEGFR-1, or VEGFR-2, in AT1-R-deficient mice with CNV and in losartan-treated microvascular endothelial cells and macrophages. These results indicate the significant contribution of RAPS to CNV pathogenesis.

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Eradication of Helicobactor pylori may trigger onset of type 1 diabetes: a case report

Tada, A., Komiya, N., Shimada, A., Katsuki, T., Oikawa, Y. and Itoh, H.

Ann N Y Acad Sci 1150 208 - 9 2008年12月

ISSN 0077-8923

In patients with idiopathic thrombocytopenic purpura (ITP), which is considered an autoimmune disease, eradication of Helicobacter pylori cures a significant number of patients. However, here we report an adult patient who developed type 1 diabetes (T1D), which is also considered an autoimmune disease, after eradication of Helicobacter pylori. Although further investigation is needed to understand the pathophysiology of T1D, we would like to emphasize that clinicians should consider the risk of its development after eradication of Helicobactor pylori.

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Activated prorenin as a therapeutic target for diabetic nephropathy

Ichihara, A., Sakoda, M., Mito-Kurauchi, A. and Itoh, H.

Diabetes Res Clin Pract 82 Suppl 1 S63 - 6 2008年11月

ISSN 0168-8227

High plasma prorenin levels in diabetic patients predict microvascular complications, but the mechanism of the connection between these factors has remained unclear. (Pro)renin receptors were recently found in the human kidney, and their distribution in the kidneys include the mesangium and podocytes. The binding of prorenin to the (pro)renin receptor triggers two major pathways: the angiotensin II-dependent pathway as a result of the conversion of prorenin to the active form of prorenin through a conformational change, and the angiotensin II-independent, (pro)renin-receptor-dependent intracellular mitogen-activated protein kinase pathway. To investigate whether the (pro)renin-receptor-dependent pathways contribute to the pathophysiology of the end-organ damage that occurs in diabetes, the handle region peptide, which binds to the receptor and competitively inhibits prorenin from binding to the receptor, was administered to rats with streptozotocin-induced type I diabetes and to a model of type II diabetes, db/db mice. The handle region peptide significantly inhibited the development of end-organ damage in these diabetic animals, and had a greater benefit than angiotensin-converting enzyme inhibitors in diabetic angiotensin II-type 1a-receptor-deficient mice. In addition, the infusion of the handle region peptide in animals with streptozotocin-induced type I diabetes significantly regressed the nephropathy that had already occurred. These results suggest that prorenin and the (pro)renin receptor play a pivotal role in the pathophysiology of diabetic nephropathy. Receptor-bound prorenin may prove useful as an important therapeutic target for the prevention and regression of end-organ damage in patients with diabetes.

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Cardio-ankle vascular index and ankle pulse wave velocity as a marker of arterial fibrosis in kidney failure treated by hemodialysis

Ichihara, A., Yamashita, N., Takemitsu, T., Kaneshiro, Y., Sakoda, M., Kurauchi-Mito, A. and Itoh, H.

Am J Kidney Dis 52 （ 5 ） 947 - 55 2008年11月

ISSN 0272-6386

BACKGROUND: Patients with kidney failure treated with hemodialysis have a high incidence of cardiovascular diseases caused by accelerated arteriosclerosis. However, accurate evaluation of the extent of arteriosclerosis is difficult. This study sought to compare the strength of predictions of arterial fibrosis by using a new parameter, the cardio-ankle vascular index (CAVI), versus pulse wave velocity (PWV) in patients with kidney failure treated with hemodialysis. STUDY DESIGN: Diagnostic test study. SETTING & PARTICIPANTS: 103 patients with kidney failure undergoing surgical construction of an arteriovenous access for hemodialysis therapy. INDEX TEST: CAVI and PWV. REFERENCE TEST: Arterial fibrosis, evaluated by using Masson trichrome stain on part of the brachial artery obtained during surgery, expressed as percentage of fibrosis of the layer of vascular smooth muscle cells. RESULTS: Median percentage of arterial stiffness was 52.85%. Mean PWV and CAVI were 18.3 +/- 5.6 (SD) m/s and 9.9 +/- 2.6, respectively. Multivariate regression analysis showed that arterial fibrosis was significantly associated with older age (0.247%/y; 95% confidence interval, 0.013 to 0.482) and CAVI (6.117%/unit; 95% confidence interval, 4.764 to 4.740), but not with systolic blood pressure (0.039%/mm Hg; 95% confidence interval, -0.076 to 0.153) or PWV (-0.044%/m/s; 95% confidence interval, -0.646 to 0.558). The area under the receiver operating characteristic curve to predict greater than median percentage of arterial stiffness was 0.892 for CAVI and 0.779 for PWV (P = 0.006). LIMITATION: It is unclear whether arterial fibrosis of the brachial artery evaluated by using CAVI is applicable for arteriosclerosis of other arterial districts, and clinical outcomes were not evaluated in this study. CONCLUSION: CAVI reflects the histological arterial fibrosis of hemodialysis patients and is a useful clinical marker for evaluating arterial stiffness in these patients.

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Effects of 12-month valsartan therapy on glycation and oxidative stress markers in type 2 diabetic subjects with hypertension

Komiya, N., Hirose, H., Saisho, Y., Saito, I. and Itoh, H.

Int Heart J 49 （ 6 ） 681 - 9 2008年11月

ISSN 1349-2365

Although it has been reported that angiotensin II receptor blockers inhibited the formation and accumulation of advanced glycation endproducts (AGEs) in vitro and in vivo, whether they can do so clinically is not clear. We investigated the effects of 12-month valsartan therapy on various markers of inflammation, glycation, and oxidation in type 2 diabetic subjects with hypertension. We started 40 mg/day valsartan treatment in 15 type 2 diabetic patients with hypertension. In 6 patients, the dose of valsartan was increased to 80 mg/day after 6 months and maintained until 12 months. Metabolic parameters including BMI and serum high molecular weight (HMW)-adiponectin, high-sensitivity C-reactive protein (hs-CRP) as an inflammation marker, AGEs, paraoxonase activity, platelet-activating factor (PAF)- acetylhydrolase activity, and urine 8-isoprostane levels were measured at baseline and after 6 and 12 months of treatment. Urine microalbumin level and carotid artery intima-media thickness (IMT) were also measured. Even after valsartan therapy, the blood pressure levels of the patients were not decreased significantly. Serum AGEs and urine 8-isoprostane levels decreased at both 6 and 12 months (P < 0.05 for both), although other metabolic and oxidative markers were unchanged. Though urine microalbumin levels tended to be decreased after 6 and 12 months of valsartan treatment, the changes were not significant. Mean IMT at 12 months was not changed from the baseline value. In conclusion, the findings suggest that treatment with valsartan, even at a low dose, may ameliorate some glycation and oxidative stress markers independently of an effect on blood pressure in hypertensive type 2 diabetic subjects.

The short treatment with the angiotensin receptor blocker candesartan surveyed by telemedicine (STAR CAST) study: rationale and study design

Sasamura, H., Nakaya, H., Julius, S., Takebayashi, T., Sato, Y., Uno, H., Takeuchi, M., Ishiguro, K., Murakami, M., Ryuzaki, M. and Itoh, H.

Hypertens Res 31 （ 10 ） 1843 - 9 2008年10月

ISSN 0916-9636

Previous studies have shown that transient treatment of animal models of hypertension with an angiotensin receptor blocker (ARB) causes a sustained decrease in blood pressure values that persists even after the drug treatment is discontinued (J Am Soc Nephrol 12: 659-666, 2001; Nephron 91: 710-718, 2002; Hypertens Res 30: 63-75, 2007). These results have been shown to be clinically relevant by the recent TROPHY study (N Engl J Med 354: 1685-1697, 2006). We have recently found that transient treatment with an ARB may also cause regression of established hypertension in hypertensive rats (J Am Soc Nephrol 18: 157A, 2007). The Short Treatment with the Angiotensin Receptor Blocker Candesartan Surveyed by Telemedicine (STAR CAST) study is a prospective, randomized, open, blinded end-point study in patients aged 30-59 with a positive family history of hypertension that will be conducted in several centers in Japan. The aim of the study is to evaluate the antihypertensive drug withdrawal success rate, the median duration of drug withdrawal, and the changes in home and office blood pressure values in patients with mild hypertension after tapering and withdrawal of antihypertensive treatment following treatment for 1 year with the ARB candesartan or the calcium channel blocker (CCB) nifedipine slow-release. A unique feature of this study is the use of a home blood pressure monitoring telemedicine system (i-TECHO) to allow frequent evaluation of the changes in blood pressure in the trial patients. This study will be the first clinical study to examine if regression from stage 1 (mild) hypertension to prehypertension (high-normal blood pressure) is possible using an ARB or CCB.

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Candesartan and insulin reduce renal sympathetic nerve activity in hypertensive type 1 diabetic rats

Takimoto, C., Kumagai, H., Osaka, M., Sakata, K., Onami, T., Kamayachi, T., Iigaya, K., Hayashi, K., Saruta, T. and Itoh, H.

Hypertens Res 31 （ 10 ） 1941 - 51 2008年10月

ISSN 0916-9636

The nonlinearity of cardiovascular regulation is higher in normal physiology, whereas several diseases are characterized by a reduction in this nonlinearity. Reduced nonlinearity of heart rate regulation is a robust risk factor for high mortality in patients with myocardial infarction. We investigated the changes in linear and nonlinear correlations of cardiovascular regulation after administering drugs in hypertensive diabetic rats. Type 1 diabetes was induced in rats by intraperitoneally injecting spontaneously hypertensive rats with streptozotocin. The animals were then divided into 4 groups and each group was given vehicle, candesartan, amlodipine, or insulin for 2 weeks. Blood pressure, heart rate, renal sympathetic nerve activity, and renal blood flow were simultaneously recorded in the conscious state, and the linear and nonlinear correlations were compared by using coherence and the mutual information method. Candesartan and amlodipine decreased blood pressure to a similar extent, but renal sympathetic nerve activity was significantly lower in the candesartan group than in the vehicle group. The renal sympathetic nerve activity in the insulin group was also lower than in the vehicle group. There were no significant differences in linear correlation among the 4 groups. In contrast, the nonlinear correlations between renal sympathetic nerve activity and blood pressure in the candesartan group and the insulin group were significantly higher than in the vehicle group. Candesartan and insulin decreased renal sympathetic nerve activity and increased the nonlinearity. These results suggest that reducing the activity of renin-angiotensin system and insulin that lowers blood glucose level may improve autonomic nervous system dysfunction and neurohumoral regulation of the cardiovascular system in diabetic hypertensive rats.

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Transplantation of vascular cells derived from human embryonic stem cells contributes to vascular regeneration after stroke in mice

Oyamada, N., Itoh, H., Sone, M., Yamahara, K., Miyashita, K., Park, K., Taura, D., Inuzuka, M., Sonoyama, T., Tsujimoto, H., Fukunaga, Y., Tamura, N. and Nakao, K.

J Transl Med 6 54 2008年09月

ISSN 1479-5876

BACKGROUND: We previously demonstrated that vascular endothelial growth factor receptor type 2 (VEGF-R2)-positive cells induced from mouse embryonic stem (ES) cells can differentiate into both endothelial cells (ECs) and mural cells (MCs) and these vascular cells construct blood vessel structures in vitro. Recently, we have also established a method for the large-scale expansion of ECs and MCs derived from human ES cells. We examined the potential of vascular cells derived from human ES cells to contribute to vascular regeneration and to provide therapeutic benefit for the ischemic brain. METHODS: Phosphate buffered saline, human peripheral blood mononuclear cells (hMNCs), ECs-, MCs-, or the mixture of ECs and MCs derived from human ES cells were intra-arterially transplanted into mice after transient middle cerebral artery occlusion (MCAo). RESULTS: Transplanted ECs were successfully incorporated into host capillaries and MCs were distributed in the areas surrounding endothelial tubes. The cerebral blood flow and the vascular density in the ischemic striatum on day 28 after MCAo had significantly improved in ECs-, MCs- and ECs+MCs-transplanted mice compared to that of mice injected with saline or transplanted with hMNCs. Moreover, compared to saline-injected or hMNC-transplanted mice, significant reduction of the infarct volume and of apoptosis as well as acceleration of neurological recovery were observed on day 28 after MCAo in the cell mixture-transplanted mice. CONCLUSION: Transplantation of ECs and MCs derived from undifferentiated human ES cells have a potential to contribute to therapeutic vascular regeneration and consequently reduction of infarct area after stroke.

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Involvement of receptor-bound prorenin in development of nephropathy in diabetic db/db mice

Ichihara, A., Sakoda, M., Kurauchi-Mito, A., Nishiyama, A. and Itoh, H.

J Am Soc Hypertens 2 （ 5 ） 332 - 40 2008年09月

ISSN 1933-1711

Previous studies have demonstrated that prorenin plays a significant role in the development and progression of nephropathy in streptozotocin-induced diabetic animals, a model for type 1 diabetes, through a (pro)renin receptor-dependent mechanism. However, whether this novel mechanism also contributes to the mechanism of diabetic nephropathy in type 2 diabetes has remained undetermined. In 16-week-old db/db mice, a model for type 2 diabetes, we found a significant degree of glomerulosclerosis, enhanced immunostaining for the active site of renin (representing non-proteolytically activated prorenin), and an increased immunoreactivity to activated extracellular-signal-related protein kinase 1/2 in the kidneys. These changes were blocked by the chronic subcutaneous administration (1 mg/kg/day) of a decoy peptide with the "handle region" structure, which competitively inhibits prorenin binding to a "handle region"-specific binding protein, such as the (pro)renin receptor. The kidneys of db/db mice also contained increased angiotensin (Ang) I and II levels, eliciting significant microalbuminuria. Treatment with the "handle region" peptide significantly decreased the renal content of Ang I and II and inhibited the development of microalbuminuria. Thus prorenin also contributes to the development of nephropathy in type II diabetes, probably through a (pro)renin receptor-dependent mechanism.

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The role of mineralocorticoid receptor expression in brain remodeling after cerebral ischemia

Oyamada, N., Sone, M., Miyashita, K., Park, K., Taura, D., Inuzuka, M., Sonoyama, T., Tsujimoto, H., Fukunaga, Y., Tamura, N., Itoh, H. and Nakao, K.

Endocrinology 149 （ 8 ） 3764 - 77 2008年08月

ISSN 0013-7227

Mineralocorticoid receptors (MRs) are classically known to be expressed in the distal collecting duct of the kidney. Recently it was reported that MR is identified in the heart and vasculature. Although MR expression is also found in the brain, it is restricted to the hippocampus and cerebral cortex under normal condition, and the role played by MRs in brain remodeling after cerebral ischemia remains unclear. In the present study, we used the mouse 20-min middle cerebral artery occlusion model to examine the time course of MR expression and activity in the ischemic brain. We found that MR-positive cells remarkably increased in the ischemic striatum, in which MR expression is not observed under normal conditions, during the acute and, especially, subacute phases after stroke and that the majority of MR-expressing cells were astrocytes that migrated to the ischemic core. Treatment with the MR antagonist spironolactone markedly suppressed superoxide production within the infarct area during this period. Quantitative real-time RT-PCR revealed that spironolactone stimulated the expression of neuroprotective or angiogenic factors, such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), whereas immunohistochemical analysis showed astrocytes to be cells expressing bFGF and VEGF. Thereby the incidence of apoptosis was reduced. The up-regulated bFGF and VEGF expression also appeared to promote endogenous angiogenesis and blood flow within the infarct area and to increase the number of neuroblasts migrating toward the ischemic striatum. By these beneficial effects, the infarct volume was significantly reduced in spironolactone-treated mice. Spironolactone may thus provide therapeutic neuroprotective effects in the ischemic brain after stroke.

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Monosynaptic excitatory connection from the rostral ventrolateral medulla to sympathetic preganglionic neurons revealed by simultaneous recordings

Oshima, N., Kumagai, H., Onimaru, H., Kawai, A., Pilowsky, P. M., Iigaya, K., Takimoto, C., Hayashi, K., Saruta, T. and Itoh, H.

Hypertens Res 31 （ 7 ） 1445 - 54 2008年07月

ISSN 0916-9636

To directly investigate whether a monosynaptic connection exists between neurons in the rostral ventrolateral medulla (RVLM) and sympathetic preganglionic neurons (SPNs), we used simultaneous extracellular recordings of RVLM neurons and whole-cell patch-clamp recordings of SPNs at the Th2 level and analyzed them by spike-triggered averaging. We averaged 200 sweeps of membrane potentials in SPN triggered by the spikes in the RVLM neuron. No clear postsynaptic potentials were detected in the averaged wave of SPNs before angiotensin II (Ang II) superfusion, whereas during superfusion with Ang II (6 micromol/L) on the medulla oblongata side alone excitatory postsynaptic potentials (EPSPs) were clearly found in the SPN of 3 out of 10 pairs at 40 +/- 1 ms after the averaged triggering spike in the RVLM neuron. We consider them to be monosynaptic EPSPs, because 1) the averaged EPSPs exhibited a sharp rise time, 2) the onset latency of the averaged EPSPs in the SPNs after the trigger spike in the RVLM was the same as the latency of the antidromic action potentials in the RVLM neurons in response to electrical stimulation of the SPNs, and 3) the amplitude of the averaged EPSPs was over 2 mV. In summary, combining simultaneous recording and spike-triggered averaging allowed us to demonstrate a monosynaptic excitatory connection between a single RVLM neuron and a single SPN in the thoracic spinal cord. Such connections provide the basis for the maintenance of sympathetic tone and the integrative reflex that relays through the RVLM. The results explain the mechanism by which Ang II in the RVLM area increases peripheral sympathetic activity and blood pressure.

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Pathologic roles of prorenin and (pro)renin receptor in the eye

Satofuka, S., Ichihara, A., Nagai, N., Tsubota, K., Itoh, H. and Ishida, S.

Front Biosci 13 3884 - 95 2008年05月

ISSN 1093-9946

Recent reports indicated that tissue renin-angiotensin system (RAS) was upregulated and angiotensin II type 1 receptor signaling plays crucial roles in ocular inflammation and neovascularization; however, the precise mechanism for activating tissue RAS had not been defined until recently. (Pro)renin receptor, a recently identified molecule existing in the major organs but not in the circulation, has attracted growing attention as an activator of tissue RAS. When the handle region of the prorenin prosegment binds to (pro)renin receptor, prorenin undergoes a conformational change to its enzymatically active state without the conventional proteolysis of the prorenin prosegment. Systemic treatment with a peptide with the structure of the handle region (handle region peptide; HRP), which competitively binds to (pro)renin receptor as a decoy peptide and inhibit the nonproteolytic activation of prorenin, resulted in the suppression of retinal inflammation and neovascularizaion in the rodent models. Retinal expression of RAS-related inflammatory and angiogenic molecules, such as intercellular adhesion molecule-1, monocyte chemotactic protein-1, and vascular endothelial growth factor, was also suppressed with application of HRP. These findings demonstrate that nonproteolytically activated prorenin plays a significant role in the ocular inflammation and neovascularization.

Augmentation of neovascularization [corrected] in hindlimb ischemia by combined transplantation of human embryonic stem cells-derived endothelial and mural cells

Yamahara, K., Sone, M., Itoh, H., Yamashita, J. K., Yurugi-Kobayashi, T., Homma, K., Chao, T. H., Miyashita, K., Park, K., Oyamada, N., Sawada, N., Taura, D., Fukunaga, Y., Tamura, N. and Nakao, K.

PLoS One 3 （ 2 ） e1666 2008年02月

ISSN 1932-6203

BACKGROUND: We demonstrated that mouse embryonic stem (ES) cells-derived vascular endothelial growth factor receptor-2 (VEGF-R2) positive cells could differentiate into both endothelial cells (EC) and mural cells (MC), and termed them as vascular progenitor cells (VPC). Recently, we have established a method to expand monkey and human ES cells-derived VPC with the proper differentiation stage in a large quantity. Here we investigated the therapeutic potential of human VPC-derived EC and MC for vascular regeneration. METHODS AND RESULTS: After the expansion of human VPC-derived vascular cells, we transplanted these cells to nude mice with hindlimb ischemia. The blood flow recovery and capillary density in ischemic hindlimbs were significantly improved in human VPC-derived EC-transplanted mice, compared to human peripheral and umbilical cord blood-derived endothelial progenitor cells (pEPC and uEPC) transplanted mice. The combined transplantation of human VPC-derived EC and MC synergistically improved blood flow of ischemic hindlimbs remarkably, compared to the single cell transplantations. Transplanted VPC-derived vascular cells were effectively incorporated into host circulating vessels as EC and MC to maintain long-term vascular integrity. CONCLUSIONS: Our findings suggest that the combined transplantation of human ES cells-derived EC and MC can be used as a new promising strategy for therapeutic vascular regeneration in patients with tissue ischemia.

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Therapeutic potential of atrial natriuretic peptide administration on peripheral arterial diseases

Park, K., Itoh, H., Yamahara, K., Sone, M., Miyashita, K., Oyamada, N., Sawada, N., Taura, D., Inuzuka, M., Sonoyama, T., Tsujimoto, H., Fukunaga, Y., Tamura, N. and Nakao, K.

Endocrinology 149 （ 2 ） 483 - 91 2008年02月

ISSN 0013-7227

Peripheral arterial diseases are caused by arterial sclerosis and impaired collateral vessel formation, which are exacerbated by diabetes, often leading to leg amputation. We have reported that an activation of the natriuretic peptides/cGMP/cGMP-dependent protein kinase pathway accelerated vascular regeneration and blood flow recovery in murine legs, for which ischemia had been induced by a femoral arterial ligation as a model for peripheral arterial diseases. In this study, ip injection of carperitide, a human recombinant atrial natriuretic peptide, accelerated blood flow recovery with increasing capillary density in ischemic legs not only in nondiabetic mice but also in mice kept upon streptozotocin-induced hyperglycemia for 16 wk, which significantly impaired the blood flow recovery compared with nondiabetic mice. Based on these findings, we tried to apply the administration of carperitide to the treatment of peripheral arterial diseases. The study group comprised a continuous series of 13 patients with peripheral arterial diseases (Fontaine's classification I, one; II, five; III, two; and IV, five), for whom conventional therapies had not accomplished appreciable results. Carperitide was administrated continuously and intravenously for 2 wk to Fontaine's class I-III patients and for 4 weeks to class IV patients. The dose was gradually increased to the maximum, with the patient's systolic blood pressure being kept above 100 mm Hg. Carperitide administration improved the ankle-brachial pressure index, intermittent claudication, rest pain, and ulcers. In conclusion, this study showed a therapeutic potential of carperitide to treat peripheral arterial diseases refractory to conventional therapies.

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Effects of pretreatment with low-dose metformin on metabolic parameters and weight gain by pioglitazone in Japanese patients with type 2 diabetes

Kawai, T., Funae, O., Shimada, A., Tabata, M., Hirata, T., Atsumi, Y. and Itoh, H.

Intern Med 47 （ 13 ） 1181 - 8 2008年

ISSN 0918-2918

OBJECTIVE: We investigated whether or not "low dose" metformin could prevent weight gain induced by pioglitazone. RESEARCH DESIGN AND METHODS: Sixty-nine patients with type 2 diabetes received 500-750 mg metformin a day for 12 weeks as an observation period before the start of the intervention. After an observation period, inadequately controlled patients (hemoglobin A1c >or=7.5%, n=34) received additional treatment with 15 mg pioglitazone (+P, M+P group). The other patients (n= 35) continued metformin monotherapy (Met group). In addition, another group consisting of 28 patients treated with 15 mg pioglitazone alone (Pio group) was observed. Body mass index (BMI), as well as several clinical parameters of glycemic control and lipid metabolism, was compared before and after 24 weeks of intervention. RESULTS: BMI increased significantly in the Pio group [24.0+/-3.8 vs. 24.8+/-4.3 kg/m(2), (mean +/- SD), p<0.001], but not in the M+P group (25.1+/-3.5 vs. 25.3+/-3.4 kg/m(2), NS) and Met group (24.0+/-3.3 vs. 24.0+/-3.5 kg/m(2), NS). In addition to improvement in glycemic control, a significant reduction in the atherogenic index of plasma (AIP), defined as log [TG x0.0112/HDL-C x0.02586], was observed in the Pio group (0.06+/-0.23 vs. -0.04+/-0.27, p<0.05) and M+P group (0.08+/-0.24 vs. -0.001+/-0.252, p<0.01), but not in the Met group. CONCLUSION: This study indicates potential benefits of the addition of pioglitazone to "low dose" metformin in terms of improvement of glucose and lipid metabolism without weight gain.

Pathway for differentiation of human embryonic stem cells to vascular cell components and their potential for vascular regeneration

Sone, M., Itoh, H., Yamahara, K., Yamashita, J. K., Yurugi-Kobayashi, T., Nonoguchi, A., Suzuki, Y., Chao, T. H., Sawada, N., Fukunaga, Y., Miyashita, K., Park, K., Oyamada, N., Sawada, N., Taura, D., Tamura, N., Kondo, Y., Nito, S., Suemori, H., Nakatsuji, N., Nishikawa, S. and Nakao, K.

Arterioscler Thromb Vasc Biol 27 （ 10 ） 2127 - 34 2007年10月

ISSN 1079-5642

OBJECTIVE: We demonstrated previously that mouse embryonic stem (ES) cell-derived vascular endothelial growth factor receptor-2 (VEGF-R2)-positive cells can differentiate into both vascular endothelial cells and mural cells. This time, we investigated kinetics of differentiation of human ES cells to vascular cells and examined their potential as a source for vascular regeneration. METHODS AND RESULTS: Unlike mouse ES cells, undifferentiated human ES cells already expressed VEGF-R2, but after differentiation, a VEGF-R2-positive but tumor rejection antigen 1-60 (TRA1-60)-negative population emerged. These VEGF-R2-positive but tumor rejection antigen 1-60-negative cells were also positive for platelet-derived growth factor receptor alpha and beta chains and could be effectively differentiated into both VE-cadherin+ endothelial cell and alpha-smooth muscle actin+ mural cell. VE-cadherin+ cells, which were also CD34+ and VEGF-R2+ and thought to be endothelial cells in the early differentiation stage, could be expanded while maintaining their maturity. Their transplantation to the hindlimb ischemia model of immunodeficient mice contributed to the construction of new blood vessels and improved blood flow. CONCLUSIONS: We could identify the differentiation process from human ES cells to vascular cell components and demonstrate that expansion and transplantation of vascular cells at the appropriate differentiation stage may constitute a novel strategy for vascular regenerative medicine.

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心血管事故の元、動脈硬化は食い止められるか

伊藤裕

まいんど 19 （ 8月） 39702 2007年08月

研究論文（学術雑誌）, 単著

Role of Asymmetric Dimethylarginine in Vascular Injury in Transgenic Mice Overexpressing Dimethylarginie, Dimethylaminohydrolase 2

長谷川一宏、　脇野修、　立松覚、　吉岡恭子、　本間康一郎、　菅野直紀、　木本ますみ、　林晃一、　伊藤裕

Circulation Research e2-e10 2007年07月

研究論文（学術雑誌）, 共著

Meet The Expert 慢性腎臓病（CKD）を知る。生活習慣病のイベントを防ぐ

栗山哲、　小田原雅人、　伊藤裕

週刊日本医事新報（ 4342 ）Ｃ1-Ｃ4 2007年07月

研究論文（学術雑誌）, 共著

概念（特集メタボリックシンドローム）

河合俊英、　島田朗、　伊藤裕

総合リハビリテーション 35 （ 7 ） 643-647 2007年07月

研究論文（学術雑誌）, 共著

高血圧—動脈硬化の危険因子としての高血圧とその発症抑制・退行

篠村裕之、　伊藤裕

医学のあゆみ 221 （ 13 ） 1086-1092 2007年06月

研究論文（学術雑誌）, 共著

メタボリックシンドロームとレニン・アンジオテンシン系—メタボリックドミノからのアプローチ—

篠村裕之、　伊藤裕

日本医師会雑誌特別号（1）『メタボリックシンドローム up to date』 136 （特別号(1) ） S84-S87 2007年06月

研究論文（学術雑誌）, 共著

糖尿病合併高血圧治療について考える—高血圧治療薬の位置づけ—

伊藤裕、　門脇孝

PROGRESS IN MEDICINE 27 （ 6 ） 93(1367)-99(1373) 2007年06月

研究論文（学術雑誌）, 共著

メタボリックシンドロームとアルドステロン

柴田洋孝、　伊藤裕

医学のあゆみ 221 （ 9 ） 747-751 2007年06月

研究論文（学術雑誌）, 共著

TZD

脇野修、　伊藤裕

糖尿病カレントライブラリー７「脂肪細胞と脂肪組織」（株式会社文光堂） 231-235 2007年05月

研究論文（学術雑誌）, 共著

肥満

河合俊英、　島田朗、　及川洋一、　伊藤裕

日本内科学会雑誌 96 （ 5 ） 916（56）-921（61） 2007年05月

研究論文（学術雑誌）, 共著

メタボリックドミノから考える治療戦略とPPAR-γの役割

伊藤裕、　Theodore W. Kurz

Pharma Medica 25 （ 5 ） 199-203 2007年05月

研究論文（学術雑誌）, 共著

メタボリックドミノ

脇野修、　伊藤裕

アンチ・エイジング医学 3 （ 2 ） 40(180)-46(186) 2007年05月

研究論文（学術雑誌）, 単著

E. Addison病

横田健一、　柴田洋孝、　伊藤裕

内分泌代謝専門医ガイドブック（株式会社診断と治療社） 177-181 2007年04月

研究論文（学術雑誌）, 共著

「循環器病学の論点—controversy in cardiology—」メタボリックは存在するか？

浦信行、　伊藤裕、　曽根博仁、　下澤達雄

Therapeutic Research 28 （ 4 ） 547-556 2007年04月

研究論文（学術雑誌）, 共著

偽アルドステロン症の重症副作用への疾患別対応

柴田洋孝、　伊藤裕

日本内科学会雑誌 96 （ 4 ） 805（153）-810（158） 2007年04月

研究論文（学術雑誌）, 共著

メタボリックシンドロームと高血圧管理—生活習慣病発症予防の観点から—

篠村裕之、　伊藤裕

動脈硬化予防 6 （ 1 ） 63-71 2007年04月

研究論文（学術雑誌）, 共著

RA系阻害による高血圧発症抑制の可能性

篠村裕之、　伊藤裕

血圧 14 （ 4 ） 70（426）-75（431） 2007年04月

研究論文（学術雑誌）, 共著

アンジオテンシンとアディポカイン（メタボリックシンドロームを含む）

脇野修、　伊藤裕

血圧 14 （ 4 ） 56(412)-60(416) 2007年04月

研究論文（学術雑誌）, 共著

メタボリックシンドロームをめぐって—実地医家としての対処法

伊藤裕、　船橋徹、　塚本和久、　門脇孝

Vita 24 （ 2 ） 39526 2007年04月

研究論文（学術雑誌）, 共著

メタボリックドミノの概念と治療

河合俊英、　伊藤裕

PHYSICIAN'S THERAPY MANUAL 4 （ 2 ） 2007年04月

研究論文（学術雑誌）, 単著, ISSN 1343-3598

メタボリックシンドロームでなぜ組織レニン−アンジオテンシン系が活性されるのか

市原淳宏、　伊藤裕

医学のあゆみ 220 （ 13 ） 1118-1122 2007年03月

研究論文（学術雑誌）, 共著

Novel axonal projection from the caudal end of the ventrolateral medulla to the intermediolateral cell column

Iigaya, K., Kumagai, H., Onimaru, H., Kawai, A., Oshima, N., Onami, T., Takimoto, C., Kamayachi, T., Hayashi, K., Saruta, T. and Itoh, H.

Am J Physiol Regul Integr Comp Physiol 292 （ 2 ） R927 - 36 2007年02月

ISSN 0363-6119

We used an optical imaging technique to investigate whether axons of neurons in the caudal end of the ventrolateral medulla (CeVLM), as well as axons of neurons in the rostral ventrolateral medulla (RVLM), project to neurons in the intermediolateral cell column (IML) of the spinal cord. Brain stem-spinal cord preparations from neonatal normotensive Wistar-Kyoto and spontaneously hypertensive rats were stained with a voltage-sensitive dye, and responses to electrical stimulation of the IML at the Th2 level were detected as changes in fluorescence intensity with an optical imaging apparatus (MiCAM-01). The results were as follows: 1) depolarizing responses to IML stimulation during low-Ca high-Mg superfusion were detected on the ventral surface of the medulla at the level of the CeVLM, as well as at the level of the RVLM, 2) depolarizing responses were also detected on cross sections at the level of the CeVLM, and they had a latency of 24.0 +/- 5.5 (SD) ms, 3) antidromic action potentials in response to IML stimulation were demonstrated in the CeVLM neurons where optical images were detected, and 4) glutamate application to the CeVLM increased the frequency of excitatory postsynaptic potentials (EPSPs) and induced depolarization of the IML neurons. The optical imaging findings suggested a novel axonal and functional projection from neurons in the CeVLM to the IML. The increase in EPSPs of the IML neurons in response to glutamate application suggests that the CeVLM participates in the regulation of sympathetic nerve activity and blood pressure and may correspond to the caudal pressor area.

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Developmental activity of the renin-angiotensin system during the "critical period" modulates later L-NAME-induced hypertension and renal injury

Ishiguro, K., Sasamura, H., Sakamaki, Y., Itoh, H. and Saruta, T.

Hypertens Res 30 （ 1 ） 63 - 75 2007年01月

ISSN 0916-9636

The incidence of hypertension and hypertensive renal disease is increasing worldwide, and new strategies to prevent these diseases need to be investigated. The aims of this study were 1) to examine if transient exposure to an angiotensin receptor blocker (ARB) during an early period in hypertension development confers protection against subsequent worsening of hypertension and renal injury induced by the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), and 2) conversely, to examine the effects of transient exposure to angiotensin II (Ang II) during the same period. First, spontaneously hypertensive rats (SHR) were treated transiently from age 3 to 10 weeks with an ARB (candesartan cilexetil), a calcium channel antagonist or a vasodilator, then taken off treatment for 2 months. Administration of L-NAME at age 18 weeks caused severe hypertension and renal injury. However, the rats that had been exposed to the ARB not only had a lower blood pressure, but also failed to show signs of renal injury or increase of oxidative stress. Furthermore, the elevation of components of the renin-angiotensin-aldosterone system was also suppressed in these rats. In the second study, Wistar-Kyoto rats (WKY) and SHR were exposed to Ang II from age 4 to 8 weeks. The follow-up showed that the blood pressures in the WKY remained elevated compared to controls, while the SHR had heightened increases in blood pressure, renal renin mRNA, and urinary 8-hyroxydeoxyguanosine after L-NAME administration. Together, these experiments demonstrate that transient treatment of rats during an early phase in the development of hypertension with an ARB suppresses the renin-angiotensin-aldosterone system and confers long-term protection against subsequent L-NAME-induced renal injury and increases in renal oxidative stress. Conversely, developmental exposure to Ang II during this "critical" period had the opposite effect, predisposing rats to higher blood pressure, renal injury, and oxidative stress after L-NAME administration.

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Regression of Nephropathy Developed in Diabetes by (Pro)rennin Receptor Blockade

高橋秀奈、　市原淳宏、　金城雪、　猪俣けんた、　迫田万理代、　武光智子、　西山あきら、　伊藤裕

J Am Soc Nephrol 18 2054-2061 2007年

研究論文（学術雑誌）, 共著

Coactivation of the N-terminal transactivation of mineralocorticoid receptor by Ubc9

横田健一、　柴田洋孝、　栗原勲、　小林佐紀子、　須田徳子、　武田彩乃、　齋藤郁夫、　北川H、　加藤S、　猿田享男、伊藤裕

J Biol Chem 282 1998-2010 2007年

研究論文（学術雑誌）, 共著

Novel axonal projection from the caudal end of the ventrolateral medulla to the intermediolateral cell column

飯ケ谷嘉門、　熊谷裕生、　鬼丸H、　河合A、　大島直紀、　大波敏子、　滝本千恵、　釜萢正、　林晃一、　猿田享男、　伊藤裕

Am. J. Physiol. Regul Integr Comp Physiol （ 292 ） 927-936 2007年

研究論文（学術雑誌）, 共著

Role of nonproteolytically activated prorenin in pathologic, but not physiologic, retinal neovascularization

里深信吾、　市原淳宏、　ながいN、　厚東T、　篠田H、　野田K、　小沢Y、　井上M、　坪田一男、　伊藤裕、　尾池Y、　石田S

Investigative Ophthalmology & Visual Science （ 48 ） 422-429 2007年

研究論文（学術雑誌）, 共著

Add-on amlodipine improves arterial function and structure in hypertensive patients treated with an angiotensin receptor blocker

市原淳宏、　金城雪、　迫田万理代、　武光智子、　伊藤裕

J. Cardiovasc. Pharmacol （ 49 ） 161-166 2007年

研究論文（学術雑誌）, 共著

Developmental Activity of the Renin-Angiotensin System during the “Critical Period” Modulates Later L-NAME-Induced Hypertension and Renal Injury

石黒喜美子、　篠村裕之、　坂巻裕介、　伊藤裕、　猿田享男

Hypertens Res 30 （ 1 ） 63-75 2007年

研究論文（学術雑誌）, 共著

Adrenomedullin/cyclic AMP pathway induces Notch activation and differentiation of arterial endothelial cells from vascular progenitors

Yurugi-Kobayashi, T., Itoh, H., Schroeder, T., Nakano, A., Narazaki, G., Kita, F., Yanagi, K., Hiraoka-Kanie, M., Inoue, E., Ara, T., Nagasawa, T., Just, U., Nakao, K., Nishikawa, S. and Yamashita, J. K.

Arterioscler Thromb Vasc Biol 26 （ 9 ） 1977 - 84 2006年09月

ISSN 1079-5642

OBJECTIVE: The acquisition of arterial or venous identity is highlighted in vascular development. Previously, we have reported an embryonic stem (ES) cell differentiation system that exhibits early vascular development using vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2)-positive cells as common vascular progenitors. In this study, we constructively induced differentiation of arterial and venous endothelial cells (ECs) in vitro to elucidate molecular mechanisms of arterial-venous specification. METHODS AND RESULTS: ECs were induced from VEGFR2+ progenitor cells with various conditions. VEGF was essential to induce ECs. Addition of 8bromo-cAMP or adrenomedullin (AM), an endogenous ligand-elevating cAMP, enhanced VEGF-induced EC differentiation. Whereas VEGF alone mainly induced venous ECs, 8bromo-cAMP (or AM) with VEGF supported substantial induction of arterial ECs. Stimulation of cAMP pathway induced Notch signal activation in ECs. The arterializing effect of VEGF and cAMP was abolished in recombination recognition sequence binding protein at the Jkappa site deficient ES cells lacking Notch signal activation or in ES cells treated with gamma-secretase inhibitor. Nevertheless, forced Notch activation by the constitutively active Notch1 alone did not induce arterial ECs. CONCLUSIONS: Adrenomedullin/cAMP is a novel signaling pathway to activate Notch signaling in differentiating ECs. Coordinated signaling of VEGF, Notch, and cAMP is required to induce arterial ECs from vascular progenitors.

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[PPARgamma]

Itoh, H.

Nihon Rinsho 64 Suppl 5 182 - 91 2006年07月

ISSN 0047-1852

[Idiopathic hyperaldosteronism (IHA)]

Miyashita, K., Itoh, H. and Nakao, K.

Nihon Rinsho Suppl 1 624 - 7 2006年05月

ISSN 0047-1852

[ACTH-independent macronodular adrenal hyperplasia]

Miyashita, K., Itoh, H. and Nakao, K.

Nihon Rinsho Suppl 1 614 - 7 2006年05月

ISSN 0047-1852

The neuroprotective and vasculo-neuro-regenerative roles of adrenomedullin in ischemic brain and its therapeutic potential

Miyashita, K., Itoh, H., Arai, H., Suganami, T., Sawada, N., Fukunaga, Y., Sone, M., Yamahara, K., Yurugi-Kobayashi, T., Park, K., Oyamada, N., Sawada, N., Taura, D., Tsujimoto, H., Chao, T. H., Tamura, N., Mukoyama, M. and Nakao, K.

Endocrinology 147 （ 4 ） 1642 - 53 2006年04月

ISSN 0013-7227

Adrenomedullin (AM) is a vasodilating hormone secreted mainly from vascular wall, and its expression is markedly enhanced after stroke. We have revealed that AM promotes not only vasodilation but also vascular regeneration. In this study, we focused on the roles of AM in the ischemic brain and examined its therapeutic potential. We developed novel AM-transgenic (AM-Tg) mice that overproduce AM in the liver and performed middle cerebral artery occlusion for 20 min (20m-MCAO) to examine the effects of AM on degenerative or regenerative processes in ischemic brain. The infarct area and gliosis after 20m-MCAO was reduced in AM-Tg mice in association with suppression of leukocyte infiltration, oxidative stress, and apoptosis in the ischemic core. In addition, vascular regeneration and subsequent neurogenesis were enhanced in AM-Tg mice, preceded by increase in mobilization of CD34(+) mononuclear cells, which can differentiate into endothelial cells. The vasculo-neuro-regenerative actions observed in AM-Tg mice in combination with neuroprotection resulted in improved recovery of motor function. Brain edema was also significantly reduced in AM-Tg mice via suppression of vascular permeability. In vitro, AM exerted direct antiapoptotic and neurogenic actions on neuronal cells. Exogenous administration of AM in mice after 20m-MCAO also reduced the infarct area, and promoted vascular regeneration and functional recovery. In summary, this study suggests the neuroprotective and vasculo-neuro-regenerative roles of AM and provides basis for a new strategy to rescue ischemic brain through its multiple hormonal actions.

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Expression of the adrenomedullin gene in adipose tissue

Nambu, T., Arai, H., Komatsu, Y., Yasoda, A., Moriyama, K., Kanamoto, N., Itoh, H. and Nakao, K.

Regul Pept 132 （ 1-3 ） 17 - 22 2005年12月

ISSN 0167-0115

Adrenomedullin (AM) is a potent vasodilating peptide originally isolated from human pheochromocytoma cells. This report concerns the expression and secretion of AM from adipose tissue. Northern blot analysis demonstrated marked expression of AM mRNA in mouse adipose tissue. Expression levels in adipose tissues were 2.5-3.2 times higher than in the kidney. AM mRNA level in mature adipocytes was 7.3 times higher than in the stroma-vascular fraction of adipose tissue. In mature adipocyte culture, time-dependent increase of AM peptide concentration in the culture medium was detected. AM expression was also detected in human subcutaneous adipose tissue. Adipose AM expression significantly increased in obesity mouse model, high-fat diet fed mice and ob/ob mice. These results suggest that adipose tissue, especially mature adipocytes, is major source of AM in the body, and that adipocyte-derived AM plays a pathophysiological role in obesity.

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Papillary thyroid carcinoma without metastases manifesting as an autonomously functioning thyroid nodule

Majima, T., Doi, K., Komatsu, Y., Itoh, H., Fukao, A., Shigemoto, M., Takagi, C., Corners, J., Mizuta, N., Kato, R. and Nakao, K.

Endocr J 52 （ 3 ） 309 - 16 2005年06月

ISSN 0918-8959

A 59-year-old woman with papillary thyroid carcinoma inside of an autonomously functioning thyroid nodule is described in this report. The patient was referred to our clinic because of rapid weight loss and swelling on the left side of the neck. Ultrasonography of the thyroid demonstrated a nonhomogeneous nodule in the lower part of an enlarged left lobe. Both 99mTc and 123I thyroid scintigraphic imaging showed a hot area corresponding to the nodule with lower uptake in the remaining thyroid tissue. Histopathological examination of the nodule revealed papillary adenocarcinoma, and the immunohistochemistry proved weak but positive staining for triiodothyronine and thyroxine. Based on these findings, the nodule was diagnosed as a functioning papillary adenocarcinoma. Although thyroid carcinoma manifesting as a hot nodule on the radionuclide isotope scan is an extremely rare occurrence, the current case is clinically important because it suggests that the diagnosis of a hot nodule cannot always rule out thyroid carcinoma in the nodule, and that even a hot nodule requires careful management so that the malignancy is not overlooked.

Analysis of rat insulin II promoter-ghrelin transgenic mice and rat glucagon promoter-ghrelin transgenic mice

Iwakura, H., Hosoda, K., Son, C., Fujikura, J., Tomita, T., Noguchi, M., Ariyasu, H., Takaya, K., Masuzaki, H., Ogawa, Y., Hayashi, T., Inoue, G., Akamizu, T., Hosoda, H., Kojima, M., Itoh, H., Toyokuni, S., Kangawa, K. and Nakao, K.

J Biol Chem 280 （ 15 ） 15247 - 56 2005年04月

ISSN 0021-9258

We developed and analyzed two types of transgenic mice: rat insulin II promoter-ghrelin transgenic (RIP-G Tg) and rat glucagon promoter-ghrelin transgenic mice (RGP-G Tg). The pancreatic tissue ghrelin concentration measured by C-terminal radioimmunoassay (RIA) and plasma desacyl ghrelin concentration of RIP-G Tg were about 1000 and 3.4 times higher than those of nontransgenic littermates, respectively. The pancreatic tissue n-octanoylated ghrelin concentration measured by N-terminal RIA and plasma n-octanoylated ghrelin concentration of RIP-G Tg were not distinguishable from those of nontransgenic littermates. RIP-G Tg showed suppression of glucose-stimulated insulin secretion. Arginine-stimulated insulin secretion, pancreatic insulin mRNA and peptide levels, beta cell mass, islet architecture, and GLUT2 and PDX-1 immunoreactivity in RIP-G Tg pancreas were not significantly different from those of nontransgenic littermates. Islet batch incubation study did not show suppression of insulin secretion of RIP-G Tg in vitro. The insulin tolerance test showed lower tendency of blood glucose levels in RIP-G Tg. Taking lower tendency of triglyceride level of RIP-G Tg into consideration, these results may indicate that the suppression of insulin secretion is likely due to the effect of desacyl ghrelin on insulin sensitivity. RGP-G Tg, in which the pancreatic tissue ghrelin concentration measured by C-RIA was about 50 times higher than that of nontransgenic littermates, showed no significant changes in insulin secretion, glucose metabolism, islet mass, and islet architecture. The present study raises the possibility that desacyl ghrelin may have influence on glucose metabolism.

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Angiotensin II suppresses growth arrest specific homeobox (Gax) expression via redox-sensitive mitogen-activated protein kinase (MAPK)

Saito, T., Itoh, H., Yamashita, J., Doi, K., Chun, T. H., Tanaka, T., Inoue, M., Masatsugu, K., Fukunaga, Y., Sawada, N., Sakaguchi, S., Arai, H., Tojo, K., Tajima, N., Hosoya, T. and Nakao, K.

Regul Pept 127 （ 1-3 ） 159 - 67 2005年04月

ISSN 0167-0115

Oxidative stress is known to be involved in growth control of vascular smooth muscle cells (VSMCs). We and others have demonstrated that angiotensin II (Ang II) has an important role in vascular remodeling. Several reports suggested that VSMC growth induced by Ang II was elicited by oxidative stress. Gax, growth arrest-specific homeobox is a homeobox gene expressed in the cardiovascular system. Over expression of Gax is demonstrated to inhibit VSMC growth. We previously reported that Ang II down-regulated Gax expression. To address the regulatory mechanism of Gax, we investigated the significance of oxidative stress in Ang II-induced suppression of Gax expression. We further examined the involvement of mitogen-activated protein kinases (MAPKs), which is crucial for cell growth and has shown to be activated by oxidative stress, on the regulation of Gax expression by Ang II. Ang II markedly augmented intracellular H2O2 production which was decreased by pretreatment with N-acetylcystein (NAC), an anti-oxidant. Ang II and H2O2 decreased Gax expression dose-dependently and these effects were blocked by administration of both NAC and pyrrolidine dithiocarbamate (PDTC), another anti-oxidant. Ang II and H2O2 induced marked activation of extracellular signal-responsive kinase1/2 (ERK1/2), which was blocked by NAC. Ang II and H2O2 also activated p38MAPK, and they were blocked by pre-treatment with NAC. However, the level of activated p38MAPK was quite low in comparison with ERK1/2. Ang II- or H2O2 -induced Gax down-regulation was significantly inhibited by PD98059, an ERK1/2 inhibitor but not SB203580, a p38MAPK inhibitor. The present results demonstrated the significance of regulation of Gax expression by redox-sensitive ERK1/2 activation.

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[PPARs and hypertension]

Itoh, H.

Nihon Rinsho 63 （ 4 ） 631 - 42 2005年04月

ISSN 0047-1852

PPARs (peroxisome proliferator-activated receptors) alpha, delta and gamma are expressed in adipocytes, skeletal myocytes and hepatocytes and also in endothelial cells, vascular smooth muscle cells and monocytes/macrophages, in distinct distributions. They are critically involved in the pathophysiology of obesity, diabetes, hyperlipidemia and hypertension, the complex of which is recognized as "metabolic syndrome", as well as, of their vascular complications. In addition to modulation of insulin sensitivity, PPARs can regulate oxidative stress and local production of various vasoactive substances in blood vessels, and thus control vascular tone and remodeling as one of the determinants of hypertension.

[Renin-angiotensin system and metabolic domino]

Itoh, H.

Nihon Rinsho 63 Suppl 3 180 - 7 2005年03月

ISSN 0047-1852

Therapeutic potential of thiazolidinediones in activation of peroxisome proliferator-activated receptor gamma for monocyte recruitment and endothelial regeneration

Tanaka, T., Fukunaga, Y., Itoh, H., Doi, K., Yamashita, J., Chun, T. H., Inoue, M., Masatsugu, K., Saito, T., Sawada, N., Sakaguchi, S., Arai, H. and Nakao, K.

Eur J Pharmacol 508 （ 1-3 ） 255 - 65 2005年01月

ISSN 0014-2999

Thiazolidinediones, a new class of antidiabetic drugs that increase insulin sensitivity, have been shown to be ligands for peroxisome proliferator-activated receptor gamma (PPARgamma). Recent studies demonstrating that PPARgamma occurs in macrophages have focused attention on its role in macrophage functions. In this study, we investigated the effect of thiazolidinediones on monocyte proliferation and migration in vitro and the mechanisms involved. In addition, we examined the therapeutic potentials of thiazolidinediones for injured atherosclerotic lesions. Troglitazone and pioglitazone, the two thiazolidinediones, as well as 15-deoxy-delta12,14-prostaglandin J2 inhibited in a dose-dependent manner the serum-induced proliferation of THP-1 (human monocytic leukemia cells) and of U937 (human monoblastic leukemia cells), which permanently express PPARgamma. These ligands for PPARgamma also significantly inhibited migration of THP-1 induced by monocyte chemoattractant protein-1 (MCP-1). Troglitazone and 15-deoxy-delta12,14-prostaglandin J2 significantly suppressed the mRNA expression of the MCP family-specific receptor CCR2 (chemokine CCR2 receptor) in THP-1 at the transcriptional level. Furthermore, troglitazone significantly inhibited MCP-1 binding to THP-1. Oral administration of troglitazone to Watanabe heritable hyperlipidemic (WHHL) rabbits after balloon injury suppressed acute recruitment of monocytes/macrophages and accelerated re-endothelialization. These results suggest that thiazolidinediones have therapeutic potential for the treatment of diabetic vascular complications.

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[Clinical application of adrenomedullin to therapeutic angiogenesis]

Miyashita, K., Itoh, H. and Nakao, K.

Nihon Rinsho 62 Suppl 9 307 - 13 2004年09月

ISSN 0047-1852

[Natriuretic peptides and atherosclerosis]

Yamahara, K., Itoh, H. and Nakao, K.

Nihon Rinsho 62 Suppl 9 117 - 20 2004年09月

ISSN 0047-1852

[Current status and future prospects of C-type natriuretic peptide]

Park, K., Itoh, H. and Nakao, K.

Nihon Rinsho 62 Suppl 9 151 - 6 2004年09月

ISSN 0047-1852

[Significant roles of natriuretic peptides in vascular physiology]

Miyashita, K., Itoh, H. and Nakao, K.

Nihon Rinsho 62 Suppl 9 51 - 5 2004年09月

ISSN 0047-1852

[Involvement of PPARgamma in the pathogenesis of hypertension and hypertensive target-organ damage]

Itoh, H.

Nihon Rinsho 62 Suppl 3 179 - 90 2004年03月

ISSN 0047-1852

[What is 'metabolic domino effect'?--new concept in lifestyle-related diseases]

Itoh, H.

Nihon Rinsho 61 （ 10 ） 1837 - 43 2003年10月

ISSN 0047-1852

Lifestyle-related diseases such as hypertension, hyperlipidemia, and impaired glucose tolerance are independent risk factors for cardiovascular diseases. When these risk factors accumulate, the risk of cardiovascular diseases remarkably increases. This condition, marked by an accumulation of these risk factors in one person, is considered a disease entity by itself called the 'metabolic syndrome'. The effects of this syndrome over time are now being referred to as 'metabolic domino effect'. This new concept considers factors such as the flow of time and the chain reaction of the risk factors. When these risk factors accumulate in one person over time, the risk factors interact and multiply the cardiovascular risk, leading to a process similar to falling dominoes; once the process begins, it leads to cardiovascular diseases that are irreversible. Data strongly suggests that angiotensin II is a contributing factor at every step of the process in this metabolic domino effect, starting from obesity to the progression of macroangiopathy and microangiopathy. The key to effectively preventing cardiovascular diseases is to suppress production of angiotensin II at an early stage of the metabolic syndrome.

Successful treatment of primary aldosteronism due to computed tomography-negative microadenoma

Nishizawa, K., Nakamura, E., Kobayashi, T., Kamoto, T., Terai, A., Terachi, T., Ogawa, O., Itoh, H. and Nakao, K.

Int J Urol 10 （ 10 ） 544 - 6 2003年10月

ISSN 0919-8172

We report a case of aldosterone-producing microadenoma that was correctly diagnosed and thus treated less invasively by laparoscopic adrenalectomy. A 58-year-old woman presented with palpitation and muscular weakness. She exhibited hypertension, hypokalemia and increased aldosterone excretion with suppressed renin activity. Therefore, primary aldosteronism was suggested. Although adrenal scintigram and computed tomography findings in the adrenal glands were normal, adrenal venous sampling tests indicated an overproduction of aldosterone in the right adrenal gland. We diagnosed an aldosterone-producing microadenoma in the right adrenal gland and performed an adrenalectomy. The patient became normotensive postoperatively and histopathological examination demonstrated a microadenoma, 5 mm in diameter.

[Significance of renin-angiotensin system in diabetes mellitus with hypertension]

Itoh, H.

Nihon Rinsho 61 （ 7 ） 1145 - 53 2003年07月

ISSN 0047-1852

Diabetes mellitus and hypertension frequently occur in the same individual, based upon 'insulin resistance', which is caused by obesity and impairment of secretion of several adipocyte-derived hormones(adipocytokines), including leptin and adiponectin. Insulin resistance and activation of tissue renin-angiotensin system mutually affect each other to promote diabetes mellitus/hypertension and their complications. Especially, renin-angiotensin system in the adipose tissue modulate adipocyte differentiation and adipose tissue mass. Vascular renin-angiotensin system causes endothelial dysfunction and promotes inflammatory process to accelerate atherosclerosis. Blockade of renin-angiotensin system is reasonable for prevention and suppression of diabetes mellitus/hypertension and their complications.

Modification of GATA-2 transcriptional activity in endothelial cells by the SUMO E3 ligase PIASy

Chun, T. H., Itoh, H., Subramanian, L., Iniguez-Lluhi, J. A. and Nakao, K.

Circ Res 92 （ 11 ） 1201 - 8 2003年06月

ISSN 0009-7330

GATA sequences are required for the optimal expression of endothelial cell-specific genes, including endothelin-1 (ET-1). We have identified PIASy in a search for new GATA-2 interacting proteins that can regulate GATA-2-mediated endothelial gene expression. Notably, among the cell populations comprising vascular walls, PIASy mRNA is selectively expressed in endothelial cells, and its expression can be regulated by angiogenic growth factors. We show that GATA-2 is covalently modified by small ubiquitin-like modifier (SUMO)-1 and -2 and that PIASy, through its E3 SUMO ligase activity, preferentially enhances the conjugation of SUMO-2 to GATA-2. Through a functional analysis, we demonstrate that PIASy potently suppresses the activity of the GATA-2-dependent human ET-1 promoter in endothelial cells. The suppressive effect of PIASy requires the GATA-binding site in the ET-1 promoter and depends on its interaction with GATA-2, which requires both N-terminal (amino acids 1-183) and C-terminal (amino acids 414-510) sequences in PIASy. We conclude that PIASy enhances the conjugation of SUMO-2 to GATA-2 and that the interaction of PIASy with GATA-2 can modulate GATA-mediated ET-1 transcription activity in endothelial cells through a RING-like domain-independent mechanism.

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Adrenomedullin provokes endothelial Akt activation and promotes vascular regeneration both in vitro and in vivo

Miyashita, K., Itoh, H., Sawada, N., Fukunaga, Y., Sone, M., Yamahara, K., Yurugi-Kobayashi, T., Park, K. and Nakao, K.

FEBS Lett 544 （ 1-3 ） 86 - 92 2003年06月

ISSN 0014-5793

We previously reported that adrenomedullin (AM), a vasodilating hormone secreted from blood vessels, promotes proliferation and migration of human umbilical vein endothelial cells (HUVECs). In this study, we examined the ability of AM to promote vascular regeneration. AM increased the phosphorylation of Akt in HUVECs and the effect was inhibited by the AM antagonists and the inhibitors for protein kinase A (PKA) or phosphatidylinositol 3-kinase (PI3K). AM promoted re-endothelialization in vitro of wounded monolayer of HUVECs and neo-vascularization in vivo in murine gel plugs. These effects were also inhibited by the AM antagonists and the inhibitors for PKA or PI3K. The findings suggest that AM plays significant roles in vascular regeneration, associated with PKA- and PI3K-dependent activation of Akt in endothelial cells, and possesses therapeutic potential for vascular injury and tissue ischemia.

Different differentiation kinetics of vascular progenitor cells in primate and mouse embryonic stem cells

Sone, M., Itoh, H., Yamashita, J., Yurugi-Kobayashi, T., Suzuki, Y., Kondo, Y., Nonoguchi, A., Sawada, N., Yamahara, K., Miyashita, K., Park, K., Shibuya, M., Nito, S., Nishikawa, S. and Nakao, K.

Circulation 107 （ 16 ） 2085 - 8 2003年04月

ISSN 0009-7322

BACKGROUND: We demonstrated that vascular endothelial growth factor receptor 2 (VEGF-R2)-positive cells derived from mouse embryonic stem (ES) cells can differentiate into both endothelial cells and mural cells to suffice as vascular progenitor cells (VPCs). Here we examined whether VPCs occur in primate ES cells and investigated the differences in VPC differentiation kinetics between primate and mouse ES cells. METHODS AND RESULTS: In contrast to mouse ES cells, undifferentiated monkey ES cells expressed VEGF-R2. By culturing these undifferentiated ES cells for 4 days on OP9 feeder layer, VEGF-R2 expression disappeared, and then reappeared after 8 days of differentiation. We then isolated these VEGF-R2-positive and vascular endothelial cadherin (VEcadherin)-negative cells by flow cytometry sorting. Additional 5-day reculture of these VEGF-R2+ VEcadherin- cells on OP9 feeder layer resulted in the appearance of platelet endothelial cell adhesion molecule-1 (PECAM1)-positive, VEcadherin-positive, endothelial nitric oxide synthase (eNOS)-positive endothelial cells. On a collagen IV-coated dish in the presence of serum, these cells differentiated into smooth muscle actin (SMA)-positive and calponin-positive mural cells (pericytes or vascular smooth muscle cells). Addition of 50 ng/mL VEGF to the culture on a collagen IV-coated dish resulted in the appearance of PECAM1+ cells surrounded by SMA+ cells. In addition, these differentiated VEGF-R2+ cells can form tube-like structures in a 3-dimensional culture. CONCLUSIONS: Our findings indicate that differentiation kinetics of VPCs derived from primate and mouse ES cells were different. Differentiated VEGF-R2+ VEcadherin- cells can act as VPCs in primates. To seek the clinical potential of VPCs for vascular regeneration, investigations of primate ES cells are indispensable.

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Effective contribution of transplanted vascular progenitor cells derived from embryonic stem cells to adult neovascularization in proper differentiation stage

Yurugi-Kobayashi, T., Itoh, H., Yamashita, J., Yamahara, K., Hirai, H., Kobayashi, T., Ogawa, M., Nishikawa, S., Nishikawa, S. and Nakao, K.

Blood 101 （ 7 ） 2675 - 8 2003年04月

ISSN 0006-4971

We demonstrated that Flk-1(+) cells derived from mouse embryonic stem (ES) cells can differentiate into both endothelial cells (ECs) and mural cells (MCs) to suffice as vascular progenitor cells (VPCs). In the present study, we investigated the importance of the stage of ES cell differentiation on effective participation in adult neovascularization. We obtained Flk-1(+) LacZ-expressing undifferentiated VPCs. Additional culture of these VPCs with vascular endothelial growth factor (VEGF) resulted in a mixture of ECs and MCs (differentiated VPCs). We injected VPCs subcutaneously into tumor-bearing mice. Five days after the injection, whereas undifferentiated VPCs were often detected as nonvascular cells, differentiated VPCs were more specifically incorporated into developing vasculature mainly as ECs. VPC-derived MCs were also detected in vascular walls. Furthermore, transplantation of differentiated VPCs augmented tumor blood flow in nude mice. These results indicate that a specific vascular contribution in adult neovascularization can be achieved by selective transplantation of ES cell-derived VPCs in appropriate differentiation stages, which should be the basis for vascular regeneration schemes.

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Shear stress attenuates endothelin and endothelin-converting enzyme expression through oxidative stress

Masatsugu, K., Itoh, H., Chun, T. H., Saito, T., Yamashita, J., Doi, K., Inoue, M., Sawada, N., Fukunaga, Y., Sakaguchi, S., Sone, M., Yamahara, K., Yurugi, T. and Nakao, K.

Regul Pept 111 （ 1-3 ） 13 - 9 2003年03月

ISSN 0167-0115

Shear stress is known to dilate blood vessels and exert an antiproliferative effect on vascular walls. These effects have partly been ascribed to shear stress-induced regulation of the secretion of endothelium-derived vasoactive substances. In this study, to elucidate the role of shear stress in endothelin production by endothelial cells, we examined the effect of physiological shear stress on the mRNA expression of endothelin-converting enzyme-1 (ECE-1) as well as endothelin-1 (ET-1) in cultured bovine carotid artery endothelial cells (BAECs) and human umbilical vein endothelial cells (HUVECs), using a parallel plate-type flow chamber. ECE-1 mRNA expression was significantly down-regulated by shear stress in an intensity- and time-dependent manner within the physiological range (1.5 to 15 dyn/cm(2)). ET-1 mRNA expression decreased together with ECE-1 mRNA expression. Shear stress at 15 dyn/cm(2) for 30 min induced a significant increase in the intracellular peroxide concentration, and the down-regulation of ECE-1 and ET-1 mRNA expression by shear stress was attenuated almost completely on treatment with N-acetyl cysteine (NAC), an antioxidant (20 mM). Furthermore, when H(2)O(2) (0.5 to 2 mM) was added to BAECs in static culture, the ECE-1 as well as ET-1 mRNA expression was attenuated in proportion to the concentration of H(2)O(2). It is suggested that endothelial cells sense shear stress as oxidative stress and transduce signal for the regulation of the gene expression of ECE as well as ET to attenuate vascular tone and inhibit the proliferation of vascular smooth muscle cells.

Significance and therapeutic potential of the natriuretic peptides/cGMP/cGMP-dependent protein kinase pathway in vascular regeneration

Yamahara, K., Itoh, H., Chun, T. H., Ogawa, Y., Yamashita, J., Sawada, N., Fukunaga, Y., Sone, M., Yurugi-Kobayashi, T., Miyashita, K., Tsujimoto, H., Kook, H., Feil, R., Garbers, D. L., Hofmann, F. and Nakao, K.

Proc Natl Acad Sci U S A 100 （ 6 ） 3404 - 9 2003年03月

ISSN 0027-8424

Natriuretic peptides (NPs), which consist of atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP, respectively), are characterized as cardiac or vascular hormones that elicit their biological effects by activation of the cGMPcGMP-dependent protein kinase (cGK) pathway. We recently reported that adenoviral gene transfer of CNP into rabbit blood vessels not only suppressed neointimal formation but also accelerated reendothelialization, a required step for endothelium-dependent vasorelaxation and antithrombogenicity. Accordingly, we investigated the therapeutic potential of the NPscGMPcGK pathway for vascular regeneration. In transgenic (Tg) mice that overexpress BNP in response to hindlimb ischemia, neovascularization with appropriate mural cell coating was accelerated without edema or bleeding, and impaired angiogenesis by the suppression of nitric oxide production was effectively rescued. Furthermore, in BNP-Tg mice, inflammatory cell infiltration in ischemic tissue and vascular superoxide production were suppressed compared with control mice. Ischemia-induced angiogenesis was also significantly potentiated in cGK type I Tg mice, but attenuated in cGK type I knockout mice. NPs significantly stimulated capillary network formation of cultured endothelial cells by cGK stimulation and subsequent Erk12 activation. Furthermore, gene transfer of CNP into ischemic muscles effectively accelerated angiogenesis. These findings reveal an action of the NPscGMPcGK pathway to exert multiple vasculoprotective and regenerative actions in the absence of apparent adverse effects, and therefore suggest that NPs as the endogenous cardiovascular hormone can be used as a strategy of therapeutic angiogenesis in patients with tissue ischemia.

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Adrenomedullin promotes proliferation and migration of cultured endothelial cells

Miyashita, K., Itoh, H., Sawada, N., Fukunaga, Y., Sone, M., Yamahara, K., Yurugi, T. and Nakao, K.

Hypertens Res 26 Suppl S93 - 8 2003年02月

ISSN 0916-9636

Adrenomedullin (AM) is a vasoactive hormone which exerts its action through cyclic adenosine monophosphate(cAMP) /cAMP-dependent protein kinase (PKA) cascade and intracellular Ca2+ mobilization. Recently, evidence has accumulated that AM plays a critical role in the regulation of vascular tone, remodeling and morphogenesis. And although numerous reports have examined the action of AM on cultured vascular cells, the results have not been consistent and have depended on the experimental conditions used. Accordingly, the purpose of this study was to clarify the effect of AM on the proliferation and migration of cultured endothelial cells. Our results revealed that AM promoted the growth and migration of endothelial cells (ECs). AM significantly promoted the proliferation of human umbilical vein endothelial cells (HUVECs) (56.0 +/- 8.7% over the controls at 10(-9) mol/l) and this stimulative effect was inhibited by two AM antagonists, AM(22-52) and calcitonin gene-related peptide (CGRP) (8-37). The number of HUVECs migrated to the lower surface of the transwell apparatus was also increased dose-dependently in the AM group (30.4 +/- 4.2% over the controls at 10(-7) mol/l), and this increase was suppressed by the two AM antagonists and by two PKA antagonists, adenosine 3'5'-cyclic monophosphorothioate Rp-isomer and myristoylated protein kinase A inhibitor amide 14-22. The promoting action of AM on endothelial migration was also suppressed by LY294002, an inhibitor for phosphatidylinositol 3-kinase, but not by N(G)-nitro-L-arginine-methyl ester (L-NAME), an antagonist for nitric oxide synthase (NOS). These results indicate that AM promotes proliferation and migration of ECs via a cAMP/PKA dependent pathway and lend support to the idea that AM exerts beneficial effects on vascular regeneration and might be used as a novel therapeutic strategy for patients with vascular disease.

Lowering of blood pressure improves endothelial dysfunction by increase of nitric oxide production in hypertensive rats

Hatta, T., Nakata, T., Harada, S., Kiyama, M., Moriguchi, J., Morimoto, S., Itoh, H., Sasaki, S., Takeda, K. and Nakagawa, M.

Hypertens Res 25 （ 3 ） 455 - 60 2002年05月

ISSN 0916-9636

To investigate the effects of angiotensin converting enzyme inhibitor (ACE-I) and other antihypertensive agents on the nitric oxide (NO) release during hypertension, seven- and fourteen-week-old SHR and deoxycorticosterone acetate (DOCA)-salt rats were treated with hydralazine, manidipine (Ca antagonist) or quinapril (ACE-I) for 3 weeks to lower blood pressure. Systolic blood pressure (SBP) was measured by the tail cuff method once each week. Endothelial cells (ECs) derived from the descending aorta of the treated rats were cultured and NOx levels in culture media were measured with an NO analyzer based on the Griess reaction. In both SHR and DOCA-salt rats, antihypertensive therapy lowered SBP to levels similar to those of control rats. The only exception was quinapril treatment of DOCA-salt rats. Although NOx release by ECs derived from hypertensive rats was improved by antihypertensive therapy, the effect was most pronounced in SHR treated with quinapril. In addition, restoration of NOx release was much more remarkable in younger SHR. NOx release was significantly higher in DOCA-salt rats treated with quinapril than in control rats without reduction of SBP. These results suggest that lowering blood pressure improves release of NO by ECs during hypertension and that the time at which antihypertensive therapy is started is also important to preserve endothelial function. Furthermore, ACE-I is suggested to protect endothelial function by increasing NO production in addition to lowering blood pressure.

[Stroke prevention by statins]

Sawada, N., Itoh, H. and Nakao, K.

Nihon Rinsho 60 （ 5 ） 993 - 1001 2002年05月

ISSN 0047-1852

The correlation between stroke incidence and serum lipid level has been equivocal, and conventional lipid-lowering agents such as fibrates were ineffective for stroke prevention. Recent clinical trials for HMG-CoA reductase inhibitors(statins) have demonstrated 20-30% reduction in the risk of cerebrovascular events and mortality in the population with previous coronary heart disease(CHD). The beneficial effect of statins was most evident for thromboembolic stroke, and no significant increase in hemorrhagic events was noted. Equal reduction in stroke risk was observed between hyper- and normocholesterolemic populations, indicating the non-lipid mechanisms of statins. The efficacy and safety of statin treatment make it a promising approach for the management of both CHD and non-CHD patients at high risk of stroke, especially the elderly.

New diagnostic procedure for primary aldosteronism: adrenal venous sampling under adrenocorticotropic hormone and angiotensin II receptor blocker--application to a case of bilateral multiple adrenal microadenomas

Yamahara, K., Itoh, H., Yamamoto, A., Sasano, H., Masatsugu, K., Sawada, N., Fukunaga, Y., Sakaguchi, S., Sone, M., Yurugi, T. and Nakao, K.

Hypertens Res 25 （ 2 ） 145 - 52 2002年03月

ISSN 0916-9636

Formerly, the incidence of primary aldosteronism (PA) among patients with hypertension was believed to be less than 1%. However, recent studies have suggested a much higher incidence of 6.59%-14.4% among such patients. These findings suggest that many cases of PA caused by small aldosterone-producing adenoma (APA) or idiopathic hyperaldosteronism (IHA) have not been properly diagnosed. To make a more accurate diagnosis in such cases, we developed a new diagnostic procedure for localization of PA, namely, adrenal venous sampling under continuous infusion of adrenocorticotropic hormone (ACTH) and administration of angiotensin II receptor blocker (AVS with ACTH and ARB). Here, we confirm the efficacy of this procedure in the case of a 37-year-old male suspected of having PA. The anticipated diagnosis of PA was based on the presence of hypokalemia, low plasma renin activity (PRA), elevated plasma aldosterone concentration (PAC) and left adrenal mass. However, AVS with ACTH and ARB revealed the presence of bilateral multiple adrenal microadenomas. In the new AVS method, neither ACTH nor the renin-angiotensin system (RAS) exert any influence on the plasma aldosterone level, and a more accurate aldosterone secretary state and a more accurate assessment of the aldosterone secretion of both adrenal glands can be recognized than by conventional AVS. Use of this new method should enable identification of additional cases of APA among patients diagnosed with essential hypertension.

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