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Papers - Ito, Hiroshi

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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

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.

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 2009.12

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 2009.12

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 2009.12

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 2009.12

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 2009.11

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 2009.10

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 2009.08

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 2009.06

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 2009.05

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 2009.04

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 2009.03

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 2009.03

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 2009.03

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 2009.03

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 2009.02

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 2009.02

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 2009.02

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 2009.01

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 2009.01

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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