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Papers - ITOH Hiroshi

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Importance of Adipose Tissue NAD+ Biology in Regulating Metabolic Flexibility.

Michael P Franczyk, Nathan Qi, Kelly L Stromsdorfer, Chengcheng Li, Shintaro Yamaguchi, Hiroshi Itoh, Mihoko Yoshino, Yo Sasaki, Rita T Brookheart, Brian N Finck, Brian J DeBosch, Samuel Klein, Jun Yoshino

Endocrinology 162 ( 3 ) 2021.03

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.

Takeru Amiya, Nobuhiro Nakamoto, Junichiro Irie, Nobuhito Taniki, Po-Sung Chu, Yuzo Koda, Kentaro Miyamoto, Akihiro Yamaguchi, Shunsuke Shiba, Rei Morikawa, Hiroshi Itoh, Takanori Kanai

Diabetologia 64 ( 3 ) 603 - 617 2021.03

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.

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4) Kidney-gut Axis in Chronic Renal Failure

Wakino Shu, Itoh Hiroshi

Nihon Naika Gakkai Zasshi (The Japanese Society of Internal Medicine) 110 ( Suppl ) 93a - 93a 2021.02

ISSN 00215384

Difficulty in managing nephrotic syndrome-associated cerebral venous thrombosis.

Takashin Nakayama, Ryunosuke Mitsuno, Takuto Torimitsu, Norifumi Yoshimoto, Takeshi Kanda, Hirobumi Tokuyama, Shu Wakino, Hiroshi Itoh

CEN case reports 10 ( 1 ) 132 - 138 2021.02

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.

Ran Nakamichi, Kaori Hayashi, Hiroshi Itoh

Nutrients 13 ( 1 ) 1 - 11 2021.01

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.

Shotaro Kosugi, Tadashi Yoshida, Norifumi Yoshimoto, Hiroshi Itoh, Mototsugu Oya

Clinical medicine insights. Case reports 14 11795476211056172 - 11795476211056172 2021

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.

Kohkichi Morimoto, Tadashi Yoshida, Naoki Washida, Kiyotaka Uchiyama, Takashin Nakayama, Hiroshi Itoh, Mototsugu Oya

Renal failure 43 ( 1 ) 651 - 657 2021

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.

Takashin Nakayama, Kiyotaka Uchiyama, Naoki Washida, Kohkichi Morimoto, Kaori Muraoka, Keika Adachi, Takahiro Kasai, Kazutoshi Miyashita, Shu Wakino, Hiroshi Itoh

Blood purification 50 ( 3 ) 380 - 389 2021

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 Kenichi, Kurihara Isao, Matsusaka Yohji, Emoto Katsura, Hishida Tomoyuki, Oshida Takuma, Kobayashi Sakiko, Murai-Takeda Ayano, Miyashita Kazutoshi, Matsuda Kohei, Nakagomi Takahiro, Matsuda Kosuke, Itoh Hiroshi

Internal Medicine (The Japanese Society of Internal Medicine) 60 ( 10 ) 1555 - 1560 2021

ISSN 09182918

<p>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 (<sup>99m</sup>Tc-MIBI) with single-photon emission computed tomography did not yield definite results. In contrast, somatostatin receptor scintigraphy successfully identified the lesion responsible for the over-secretion 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. </p>

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

Kazutoshi Sugiyama, Sakiko Kobayashi, Isao Kurihara, Kazutoshi Miyashita, Kenichi Yokota, Takashi Kohno, Jaeduk Yoshimura Noh, Hiroshi Itoh

Endocrine journal 67 ( 12 ) 1247 - 1252 2020.12

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) 2020.12

<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.

Kiyotaka Uchiyama, Naoki Washida, Kohkichi Morimoto, Kaori Muraoka, Takashin Nakayama, Keika Adachi, Takahiro Kasai, Kazutoshi Miyashita, Shu Wakino, Hiroshi Itoh

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 2020.12

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.

Takashin Nakayama, Shu Wakino, Hiroshi Itoh

Clinical and experimental nephrology 24 ( 11 ) 1084 - 1085 2020.11

ISSN 1342-1751

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

Takuya Tsuchihashi, Toshihiko Ishimitsu, Katsuyuki Ando, Miho Kusaka, Atsuhiro Ichihara, Katsuyuki Miura, Yuhei Kawano, Takafumi Ishida, Hiroo Kumagai, Atsushi Sakima, Hiroyuki Takase, Hitomi Hayabuchi, Hiroshi Itoh

Hypertension research : official journal of the Japanese Society of Hypertension 43 ( 11 ) 1133 - 1134 2020.11

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.

Hitoshi Minakuchi, Tadashi Yoshida, Noriko Kaburagi, Teppei Fujino, Sho Endo, Tomoko Yamashita Takemitsu, Norimasa Yamashita, Hiroshi Itoh, Mototsugu Oya

Renal failure 42 ( 1 ) 799 - 806 2020.11

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 2020.10

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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.

Shigeru Shibata, Hisatomi Arima, Kei Asayama, Satoshi Hoshide, Atsuhiro Ichihara, Toshihiko Ishimitsu, Kazuomi Kario, Takuya Kishi, Masaki Mogi, Akira Nishiyama, Mitsuru Ohishi, Takayoshi Ohkubo, Kouichi Tamura, Masami Tanaka, Eiichiro Yamamoto, Koichi Yamamoto, Hiroshi Itoh

Hypertension research : official journal of the Japanese Society of Hypertension 43 ( 10 ) 1028 - 1046 2020.10

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.

Anna Nakamura, Yoko Yokoyama, Kazuki Tanaka, Giorgia Benegiamo, Akiyoshi Hirayama, Qi Zhu, Naho Kitamura, Taichi Sugizaki, Kohkichi Morimoto, Hiroshi Itoh, Shinji Fukuda, Johan Auwerx, Kazuo Tsubota, Mitsuhiro Watanabe

iScience 23 ( 9 ) 101522 - 101522 2020.09

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.

Kiyotaka Uchiyama, Shu Wakino, Junichiro Irie, Junki Miyamoto, Ayumi Matsui, Takaya Tajima, Tomoaki Itoh, Yoichi Oshima, Ayumi Yoshifuji, Ikuo Kimura, Hiroshi Itoh

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 35 ( 9 ) 1501 - 1517 2020.09

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.

Hiroshi Itoh

Hypertension research : official journal of the Japanese Society of Hypertension 43 ( 9 ) 857 - 858 2020.09

ISSN 0916-9636

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