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Papers - ITOH Hiroshi

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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

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

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

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

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

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

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

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

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

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 2010.11

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 2010.10

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 2010.09

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 2010.09

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 2010.08

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 2010.07

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 2010.07

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 2010.06

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 2010.06

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 2010.05

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 2010.05

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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