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Papers - Ito, Hiroshi

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Vaccination against the angiotensin type 1 receptor for the prevention of L-NAME-induced nephropathy

Azegami, T., Sasamura, H., Hayashi, K. and Itoh, H.

Hypertens Res 35 ( 5 ) 492 - 9 2012.05

ISSN 0916-9636

Previous studies have shown that renin-angiotensin (Ang) system vaccines may be effective for the treatment of hypertension, but their efficacy for the prevention of renal disease is unclear. The aim of this study was to compare the effects of an Ang II type 1 (AT1) receptor vaccine with an Ang II receptor blocker (ARB) and a vasodilator on blood pressure (BP) and renal injury in the L-NAME nephropathy model. Male spontaneously hypertensive rats (SHRs) were divided into six groups and treated transiently with three injections of vehicle or AT1 receptor vaccine (0.1 mg) at age 4, 6 and 8 weeks, or continuously with candesartan cilexetil (0.1 mg kg(-1) per day) or hydralazine hydrochloride (5 mg kg(-1) per day), then administered NG-nitro-L-arginine methyl ester (L-NAME) from age 18 to 21 weeks to induce renal injury. Vaccination against the AT1 receptor caused a significant increase in AT1 receptor titers, and a sustained decrease in BP. L-NAME treatment resulted in a marked increase in proteinuria in the control groups, which was completely suppressed in the AT1 vaccine-treated group, and glomerular injury scores were also significantly decreased. Real-time RT-PCR and immunofluorescence studies revealed increased renin mRNA, and increased glomerular expression of nephrin. Comparable results were seen in rats treated continuously with the ARB candesartan, but not with hydralazine. These results suggest that transient AT1 vaccination is as effective as continuous treatment with ARB, not only for the attenuation of hypertension, but also for the prevention of L-NAME-induced nephropathy in SHR.

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Mineralocorticoid receptor-associated hypertension and its organ damage: clinical relevance for resistant hypertension

Shibata, H. and Itoh, H.

Am J Hypertens 25 ( 5 ) 514 - 23 2012.05

ISSN 0895-7061

The role of aldosterone in the pathogenesis of hypertension and cardiovascular diseases has been clearly shown in congestive heart failure and endocrine hypertension due to primary aldosteronism. In resistant hypertension, defined as a failure of concomitant use of three or more different classes of antihypertensive agents to control blood pressure (BP), add-on therapy with mineralocorticoid receptor (MR) antagonists is frequently effective, which we designate as "MR-associated hypertension". The MR-associated hypertension is classified into two subtypes, that with elevated plasma aldosterone levels and that with normal plasma aldosterone levels. The former subtype includes primary aldosteronism (PA), aldosterone-associated hypertension which exhibited elevated aldosterone-to-renin ratio and plasma aldosterone levels, but no PA, aldosterone breakthrough phenomenon elicited when angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB) is continued to be given, and obstructive sleep apnea. In contrast, the latter subtype includes obesity, diabetes mellitus, chronic kidney disease (CKD), and polycystic ovary syndrome (PCOS). The pathogenesis of MR-associated hypertension with normal plasma aldosterone levels is considered to be mediated by MR activation by pathways other than high aldosterone levels, such as increased MR levels, increased MR sensitivity, and MR overstimulation by other factors such as Rac1. For resistant hypertension with high plasma aldosterone levels, MR antagonist should be given as a first-line therapy, whereas for resistant hypertension with normal aldosterone levels, ARB or ACE-I should be given as a first-line therapy and MR antagonist would be given as an add-on agent.

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[The 39th scientific meeting: perspectives of internal medicine; the cutting edge of treatment of medical disorders encountered in clinical practice; 10. Summary]

Itoh, H.

Nihon Naika Gakkai Zasshi 101 ( 3 ) 654 - 5 2012.03

ISSN 0021-5384

'Memory' and 'legacy' in hypertension and lifestyle-related diseases

Sasamura, H. and Itoh, H.

Hypertens Res 35 ( 3 ) 272 - 3 2012.03

ISSN 0916-9636

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Regression of atherosclerosis in apolipoprotein E-deficient mice is feasible using high-dose angiotensin receptor blocker, candesartan

Hayashi, K., Sasamura, H., Azegami, T. and Itoh, H.

J Atheroscler Thromb 19 ( 8 ) 736 - 46 2012

ISSN 1340-3478

AIM: Clinical studies have suggested that renin-angiotensin inhibitors are effective for the prevention of atherosclerosis progression, but the results for the regression of established lesions are equivocal. The aim of this study was to examine the effects of different doses of the angiotensin receptor blocker (ARB) candesartan on the regression of atherosclerosis and lipid-induced nephropathy in apolipoprotein E (apoE)-deficient spontaneously hyperlipidemic (SHL) mice. METHODS AND RESULTS: Male SHL were given an atherogenic diet together with salt loading to induce atherosclerosis. The mice were then treated with various doses of candesartan (0-50 mg/kg/d) for 12 weeks. Treatment with high-dose candesartan caused clear regression of atherosclerotic plaques in the aorta, which was not observed with normal-dose candesartan. Biglycan and ACAT1 expression were significantly decreased, and aortic free cholesterol: cholesterol ester ratios were increased in these mice. Treatment of cultured THP-1 macrophages in vitro with candesartan resulted in a similar decrease in ACAT1 expression. In the kidney, glomerular lipid accumulation, mesangial expansion, and albuminuria were significantly regressed after treatment with high-dose candesartan, while biglycan and ACAT1 expressions were decreased. CONCLUSION: These results suggest that regression of established atherosclerosis lesions in ApoE-deficient mice is feasible using high-dose candesartan, by mechanisms involving (i) a decrease in the lipid-retaining proteoglycan biglycan, and (ii) suppression of ACAT1 expression resulting in increased free cholesterol for lipid release.

Bile acid binding resin improves metabolic control through the induction of energy expenditure

Watanabe, M., Morimoto, K., Houten, S. M., Kaneko-Iwasaki, N., Sugizaki, T., Horai, Y., Mataki, C., Sato, H., Murahashi, K., Arita, E., Schoonjans, K., Suzuki, T., Itoh, H. and Auwerx, J.

PLoS One 7 ( 8 ) e38286 2012

ISSN 1932-6203

BACKGROUND: Besides well-established roles of bile acids (BA) in dietary lipid absorption and cholesterol homeostasis, it has recently become clear that BA is also a biological signaling molecule. We have shown that strategies aimed at activating TGR5 by increasing the BA pool size with BA administration may constitute a significant therapeutic advance to combat the metabolic syndrome and suggest that such strategies are worth testing in a clinical setting. Bile acid binding resin (BABR) is known not only to reduce serum cholesterol levels but also to improve glucose tolerance and insulin resistance in animal models and humans. However, the mechanisms by which BABR affects glucose homeostasis have not been established. We investigated how BABR affects glycemic control in diet-induced obesity models. METHODS AND FINDINGS: We evaluated the metabolic effect of BABR by administrating colestimide to animal models for the metabolic syndrome. Administration of BABR increased energy expenditure, translating into significant weight reduction and insulin sensitization. The metabolic effects of BABR coincide with activation of cholesterol and BA synthesis in liver and thermogenesis in brown adipose tissue. Interestingly, these effects of BABR occur despite normal food intake and triglyceride absorption. Administration of BABR and BA had similar effects on BA composition and thermogenesis, suggesting that they both are mediated via TGR5 activation. CONCLUSION: Our data hence suggest that BABR could be useful for the management of the impaired glucose tolerance of the metabolic syndrome, since they not only lower cholesterol levels, but also reduce obesity and improve insulin resistance.

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Effect of obesity on declining beta cell function after diagnosis of type 2 diabetes: a possible link suggested by cross-sectional analysis

Saisho, Y., Tanaka, K., Abe, T., Shimada, A., Kawai, T. and Itoh, H.

Endocr J 59 ( 3 ) 187 - 95 2012

ISSN 0918-8959

It has been reported that beta cell function progressively declines in patients with type 2 diabetes. The objective of this study was to assess the effect of obesity on declining beta cell function after diagnosis of type 2 diabetes. We conducted a cross-sectional study of 689 consecutive subjects with type 2 diabetes who were admitted to our hospital from 2000 to 2007. Fasting and postprandial serum C-peptide immunoreactivity (CPR) and urinary CPR levels had been measured during admission. The subjects were stratified according to BMI and time since diagnosis. CPR index was calculated as CPR (ng/mL) / plasma glucose (mg/dL) x 100. All CPR measurements were significantly higher in the 263 obese (BMI >/=25) subjects compared to the 426 lean subjects (BMI <25). There was a significant negative correlation between CPR indices and duration of diabetes, suggesting a progressive decline in beta cell function after diagnosis of type 2 diabetes. However, this decline was more apparent in obese subjects (postprandial CPR index 0.059/year) compared to lean subjects (0.025/year). The significant difference in serum CPR indices between the lean and obese subjects was lost in subjects more than 10 years after diagnosis. In conclusion, our observations suggest that beta cell function shows a greater progressive decline in obese subjects than in lean subjects with type 2 diabetes. Treatment of obesity may be an important strategy to preserve beta cell function in patients with type 2 diabetes.

Factors Associated with the Decline of Kidney Function Differ among eGFR Strata in Subjects with Type 2 Diabetes Mellitus

Meguro, S., Tomita, M., Kabeya, Y., Katsuki, T., Oikawa, Y., Shimada, A., Kawai, T., Itoh, H. and Atsumi, Y.

Int J Endocrinol 2012 687867 2012

ISSN 1687-8337

Introduction. There is no report about risk factors for renal deterioration according to the clinical stage, divided by the estimated glomerular filtration rate (eGFR) in type 2 diabetes. Materials and Methods. We evaluated the factors correlated with the annual eGFR decline in 1303 subjects with type 2 diabetes whose eGFR was >/=30 mL/min/1.73 m(2). eGFR strata were defined by baseline eGFR value as follows: stratum 1: >/=90, stratum 2: >/=60, <90, and stratum 3: >/=30, <60. Results. The annual eGFR decline was 2.3 +/- 5.4 mL/min/1.73 m(2) in overall subjects. Multiple linear regression analysis demonstrated that age, male sex, systolic blood pressure, logarithmically transformed albumin excretion rate (AER), eGFR strata, and hemoglobin concentration were significantly correlated with the annual eGFR decline. When stratified by eGFR, the factors that showed a significant correlation were different among eGFR strata. AER was significantly correlated with annual eGFR decline in all eGFR strata. Hemoglobin concentration showed a significant correlation only in the advanced eGFR stratum. Conclusion. The factors correlated with the annual eGFR decline were different among eGFR strata in type 2 diabetes mellitus, and hemoglobin concentration and AER were important factors for renal deterioration, especially in the advanced eGFR stratum.

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A new preventive strategy for hypoglycemia incorporating added food diet in patients with type 2 diabetes who received sitagliptin therapy

Meguro, S., Sano, M., Kawai, T., Matsuhashi, T., Mogi, S., Fukuda, K., Itoh, H. and Suzuki, Y.

Endocr Res 37 ( 4 ) 175 - 81 2012

ISSN 0743-5800

There has been concern as to whether dipeptidyl peptidase-4 (DPP-4) inhibitors can be used safely in patients with relatively good glycemic control. This study, approved by the institutional review board of Hanzoumon Diabetes City Atlas Clinic, examined whether DPP-4 inhibitor sitagliptin could safely achieve good glycemic control without severe hypoglycemia by employing the "added food" concept. The subjects were 60 patients (46 men and 14 women) with type 2 diabetes who started sitagliptin therapy during a 1-month period from December 15, 2009 to January 15, 2010. They were recommended to have added food between meals to prevent hypoglycemia, while maintaining the same daily calorie intake. HbA(1c) decreased from 7.1 +/- 1.2% to 6.5 +/- 0.6% after 6 months of sitagliptin treatment (p < 0.001). In patients with a baseline HbA(1c) <7%, it decreased from 6.5 +/- 0.3% to 6.1 +/- 0.4% (p < 0.001). Systolic blood pressure was significantly reduced from 127.7 +/- 17.0 to 122.7 +/- 17.9 mmHg in the patients with a baseline HbA(1c) < 7% (p = 0.018). However, body weight increased by approximately 900 g and high-density lipoprotein cholesterol decreased significantly from 1.57 +/- 0.46 to 1.43 +/- 0.35 mmol/L (p < 0.01) in the patients concomitantly receiving sulfonylureas with sitagliptin. Excellent glycemic control was achieved by sitagliptin treatment together with the added food concept. However, combined use of sitagliptin with sulfonylureas requires attention to weight gain and the lipid profile. Further clinical studies will elucidate whether sitagliptin can decrease cardiovascular events as well as normalizing blood glucose and lowering the blood pressure.

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Prorenin receptor is essential for normal podocyte structure and function

Oshima, Y., Kinouchi, K., Ichihara, A., Sakoda, M., Kurauchi-Mito, A., Bokuda, K., Narita, T., Kurosawa, H., Sun-Wada, G. H., Wada, Y., Yamada, T., Takemoto, M., Saleem, M. A., Quaggin, S. E. and Itoh, H.

J Am Soc Nephrol 22 ( 12 ) 2203 - 12 2011.12

ISSN 1046-6673

The prorenin receptor is an accessory subunit of the vacuolar H(+)-ATPase, suggesting that it has fundamental functions beyond activation of the local renin-angiotensin system. Podocytes express the prorenin receptor, but its function in these cells is unknown. Here, podocyte-specific, conditional, prorenin receptor-knockout mice died of kidney failure and severe proteinuria within 4 weeks of birth. The podocytes of these mice exhibited foot process effacement with reduced and altered localization of the slit-diaphragm proteins nephrin and podocin. Furthermore, the podocytes contained numerous autophagic vacuoles, confirmed by enhanced accumulation of microtubule-associated protein 1 light chain 3-positive intracellular vesicles. Ablation of the prorenin receptor selectively suppressed expression of the V(0) c-subunit of the vacuolar H(+)-ATPase in podocytes, resulting in deacidification of intracellular vesicles. In conclusion, the prorenin receptor is important for the maintenance of normal podocyte structure and function.

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The role of microRNA-145 in human embryonic stem cell differentiation into vascular cells

Yamaguchi, S., Yamahara, K., Homma, K., Suzuki, S., Fujii, S., Morizane, R., Monkawa, T., Matsuzaki, Y., Kangawa, K. and Itoh, H.

Atherosclerosis 219 ( 2 ) 468 - 74 2011.12

ISSN 0021-9150

BACKGROUND: Recent studies have reported that microRNA-145 (miR-145) is a critical mediator in the regulation of proliferation, differentiation, and phenotype expression of smooth muscle cells (SMCs). Previously, we established a system for differentiating human ESCs into vascular cells including endothelial cells (ECs) and vascular smooth muscle cells (SMCs). In the present study, we investigated the role of miR-145 in the differentiation process from human ESCs into ECs and SMCs. METHODS AND RESULTS: Undifferentiated human ESCs were induced to differentiate into vascular lineage according to our established method. Quantitative RT-PCR analysis revealed that human ESC-derived precursor of SMCs (ES-pre-SMCs), similar to human aortic SMCs, expressed a significant amount of miR-145 as well as smooth muscle-specific proteins, compared to undifferentiated human ESCs, adult ECs, or ESC-derived ECs (ES-ECs). However, morphological analysis revealed that human ES-pre-SMCs appeared round and flattened in shape, though human aortic SMCs exhibited the typical spindle-like morphology of SMCs. In addition, Kruppel-like factor 4 and 5 (KLF4 and 5), direct targets of miR-145 and suppressors of smooth muscle differentiation, were upregulated in ES-pre-SMCs compared to aortic SMCs, indicating ES-pre-SMCs were not fully differentiated SMCs. Overexpression of miR-145 in ES-pre-SMCs upregulated the expression of smooth muscle markers, repressed KLF4 and 5 expressions, and changed their morphology into a differentiated spindle-like shape. Furthermore, by introduction of miR-145, ES-pre-SMC proliferation was significantly inhibited and carbachol-stimulated contraction of ES-pre-SMCs was significantly increased. In contrast, downregulation of miR-145 in ES-pre-SMCs upregulated KLF4 and 5 expressions, suppressed the expression of smooth muscle markers, and left unchanged their proliferation and contractility. In ES-ECs, miR-145 overexpression did not induce the synthesis of smooth muscle-related proteins nor suppress the expression of endothelial nitric oxide synthase. CONCLUSION: We showed that miR-145 can regulate the fate and phenotype of human ES-pre-SMCs as they become fully differentiated SMCs. Overexpression of miR-145 on human ES-pre-SMCs is a promising method to obtain functional mature SMCs from human ESCs, which are required for reliable experimental research in the fields of atherosclerosis, hypertension and other vascular diseases.

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A mimic of viral double-stranded RNA triggers fulminant type 1 diabetes-like syndrome in regulatory T cell-deficient autoimmune diabetic mouse

Tada, A., Shimada, A., Yamada, T., Oikawa, Y., Yamada, Y., Okubo, Y., Irie, J., Bluestone, J. A. and Itoh, H.

J Immunol 187 ( 10 ) 4947 - 53 2011.11

ISSN 0022-1767

Human fulminant type 1 diabetes (FT1D) is an extremely aggressive disease. The delay of proper diagnosis results in high mortality. However, the pathophysiology of this disease remains unclear. We took advantage of CD28-deficient NOD (CD28(-/-) NOD) mice, which have limited numbers of regulatory T cells and develop aggressive autoimmune diabetes, to create a FT1D model that mimicked the disease in humans. Young CD28(-/-) NOD mice were injected with polyinosinic-polycytidylic acid to activate innate immunity in an effort to induce diabetes onset. In this model, innate immune cell activation precedes the onset of diabetes similar to approximately 70% of FT1D patients. Eighty-three percent of CD28(-/-) NOD mice developed diabetes within 1-6 d after injection of polyinosinic-polycytidylic acid. Moreover, T cells infiltrated the pancreatic exocrine tissue and destroyed alpha cells, an observation characteristic of human FT1D. We conclude that an FT1D-like phenotype can be induced in the background of autoimmune diabetes by a mimic of viral dsRNA, and this model is useful for understanding human FT1D.

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Renal amyloidosis caused by apolipoprotein A-II without a genetic mutation in the coding sequence

Morizane, R., Monkawa, T., Konishi, K., Hashiguchi, A., Ueda, M., Ando, Y., Tokuyama, H., Hayashi, K., Hayashi, M. and Itoh, H.

Clin Exp Nephrol 15 ( 5 ) 774 - 9 2011.10

ISSN 1342-1751

Although the majority of renal amyloidosis is caused by either acquired monoclonal immunoglobulin light-chain amyloidosis or reactive systemic amyloid A, some cases are caused by hereditary amyloidosis. Apolipoprotein A-II (apoAII) amyloidosis is a rare form of hereditary amyloidosis and cannot be diagnosed by a routine examination. Thus, the prevalence and etiology of apoAII amyloidosis are uncertain. In humans, a genetic mutation in the stop codon of apoAII is considered to be a cause of amyloid fibril formation. We report on a 68-year-old man who presented with proteinuria by apoAII amyloidosis without family history. His proteinuria gradually increased to 6 g/day within 1 year. A renal biopsy showed amyloid deposition in the glomeruli, however, acquired monoclonal immunoglobulin light-chain amyloidosis and reactive systemic amyloid A were ruled out. Immunohistochemistry revealed apoAII deposition in the glomeruli, but DNA sequencing did not identify any genetic mutation in the coding sequence of apoAII. Here, we report a case of apoAII amyloidosis without a genetic mutation in the coding sequence and discuss the etiology of apoAII amyloidosis.

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[Obesity: visceral fat]

Mitsuishi, M., Miyashita, K. and Itoh, H.

Nihon Rinsho 69 Suppl 7 568 - 72 2011.09

ISSN 0047-1852

Rho-kinase inhibition ameliorates peritoneal fibrosis and angiogenesis in a rat model of peritoneal sclerosis

Washida, N., Wakino, S., Tonozuka, Y., Homma, K., Tokuyama, H., Hara, Y., Hasegawa, K., Minakuchi, H., Fujimura, K., Hosoya, K., Hayashi, K. and Itoh, H.

Nephrol Dial Transplant 26 ( 9 ) 2770 - 9 2011.09

ISSN 0931-0509

BACKGROUND: Peritoneal fibrosis (PF) and angiogenesis are typical morphological changes, leading to loss of peritoneal functions in patients undergoing peritoneal dialysis. The small G protein, Rho, and its downstream effector Rho-kinase have been shown to be involved in the tissue fibrosis process. This study was undertaken to investigate the role of Rho-kinase in the pathogenesis of these alterations. METHODS: PF was induced by intraperitoneal administration of chlorhexidine (CHX) in male rats (CHX group). These rats were treated with a Rho-kinase inhibitor, fasudil (Fas group). Human pleural mesothelial cells, MeT-5A cells, were stimulated by glucose with or without another Rho-kinase inhibitor, Y-27632. RESULTS: Peritoneal damage including peritoneal thickening, fibrous changes, macrophage migration and angiogenesis were evident in the CHX group and were ameliorated in the Fas group. The expression of markers of tissue fibrosis, such as transforming growth factor (TGF)-beta, fibronectin and alpha-smooth muscle cell actin, were increased in the CHX group and were downregulated by fasudil. Similar results were also seen with an inducer of angiogenesis, vascular endothelial growth factor (VEGF). Rho-kinase was activated in the peritoneum of the CHX group, which was inhibited by fasudil. In MeT-5A cells, high glucose increased TGF-beta expression and VEGF secretion, which were blocked by Y-27632. CONCLUSIONS: The activation of Rho-kinase is involved in peritoneal damage at multiple stages including tissue fibrosis and angiogenesis. The inhibition of Rho-kinase constitutes a novel strategy for the treatment of PF.

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Significance of adrenocorticotropin stimulation test in the diagnosis of an aldosterone-producing adenoma

Sonoyama, T., Sone, M., Miyashita, K., Tamura, N., Yamahara, K., Park, K., Oyamada, N., Taura, D., Inuzuka, M., Kojima, K., Honda, K., Fukunaga, Y., Kanamoto, N., Miura, M., Yasoda, A., Arai, H., Itoh, H. and Nakao, K.

J Clin Endocrinol Metab 96 ( 9 ) 2771 - 8 2011.09

ISSN 0021-972

CONTEXT: Adrenal venous sampling is the "gold standard" test in the diagnosis of an aldosterone-producing adenoma (APA) among patients with primary aldosteronism (PA) but is available only in specialized medical centers. Meanwhile, an APA is reported to be generally more sensitive to ACTH than idiopathic hyperaldosteronism. OBJECTIVE: The aim was to evaluate the diagnostic accuracy of the ACTH stimulation test in the diagnosis of an APA among those with suspicion of PA. PATIENTS AND SETTING: Fifty-nine patients admitted to Kyoto University Hospital on suspicion of PA were included in the study. INTERVENTIONS: ACTH stimulation tests with 1-mg dexamethasone suppression were performed. MAIN OUTCOME MEASURE: Plasma aldosterone concentrations (PAC) were examined every 30 min after ACTH stimulation. Receiver-operated characteristics curve analysis was used to evaluate the diagnostic accuracy. RESULTS: PAC after ACTH stimulations were significantly higher in patients with an APA than in patients with idiopathic hyperaldosteronism or non-PA. Receiver-operated characteristics curve analyses showed that the PAC after ACTH stimulation was effective for the diagnosis of an APA among patients suspected of PA. The diagnostic accuracy was highest at 90 min after ACTH injection, with the optimal cutoff value greater than 37.9 ng/dl corresponding with sensitivity and specificity of 91.3 and 80.6% for the diagnosis of an APA. CONCLUSIONS: Our study indicates that the ACTH stimulation test is useful in the diagnosis of an APA among patients suspected of PA. This test can be used to select patients who are highly suspected of an APA and definitely require adrenal venous sampling.

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[Angiotensin receptor vaccines]

Sasamura, H., Azegami, T. and Itoh, H.

Nihon Rinsho 69 ( 9 ) 1633 - 8 2011.09

ISSN 0047-1852

Recent clinical studies have shown that RAS inhibitors are effective not only for the prevention of end-organ damage in hypertensive patients, but also for prevention of new-onset hypertension, diabetes mellitus, and atrial fibrillation. Vaccines against the RAS have been developed since the 1950s, and a recent phase IIa placebo-controlled study has confirmed that an angiotensin vaccine causes a significant decrease in blood pressure in hypertensive patients. The results of animal experiments from our and other laboratories have suggested that vaccination against the angiotensin type 1 (AT1) receptor causes a significant decrease in blood pressure in animal models of hypertension, and also ameliorates hypertensive end-organ damage. The angiotensin receptor may therefore be an important target for the development of vaccines for the prevention of hypertension and related complications.

Human C-reactive protein exacerbates metabolic disorders in association with adipose tissue remodelling

Kaneko, H., Anzai, T., Nagai, T., Anzai, A., Takahashi, T., Mano, Y., Morimoto, K., Maekawa, Y., Itoh, H., Yoshikawa, T., Ogawa, S. and Fukuda, K.

Cardiovasc Res 91 ( 3 ) 546 - 55 2011.08

ISSN 0008-6363

AIMS: C-reactive protein (CRP) expression is increased with metabolic alterations. We sought to clarify the effect of CRP on the development of obesity-induced metabolic disorders using human CRP-overexpressing transgenic mice (CRPTG). METHODS AND RESULTS: CRPTG and their non-transgenic littermates (CON) were fed a standard diet (STD) or a high-fat diet (HFD) from 6 weeks of age. Oral glucose tolerance and intraperitoneal insulin tolerance tests 12 weeks after starting the diets showed deterioration of glucose tolerance and insulin sensitivity in HFD/CRPTG compared with HFD/CON. Hepatocellular ballooning, oil droplets, and peri-sinusoidal fibrosis were more prominent in HFD/CRPTG than in HFD/CON. In HFD/CRPTG, hepatic triglyceride content was higher and serum adiponectin levels lower than in HFD/CON. Epididymal adipose tissue mRNA expression of mucin-like, hormone receptor-like 1, monocyte chemotactic protein-1, and tumour necrosis factor-alpha in HFD/CRPTG was up-regulated compared with that in HFD/CON. Immunohistochemical staining of epididymal adipose tissue showed that the number of Mac-3(+) macrophages was higher in HFD/CRPTG than in HFD/CON. CONCLUSION: Human CRP overexpression facilitated the development of insulin resistance and hepatosteatosis with HFD in association with adiponectin down-regulation and enhancement of macrophage infiltration and expression of pro-inflammatory cytokines in epididymal adipose tissue, suggesting its pathogenic role in the development of obesity-induced metabolic disorders.

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Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure

Watanabe, M., Horai, Y., Houten, S. M., Morimoto, K., Sugizaki, T., Arita, E., Mataki, C., Sato, H., Tanigawara, Y., Schoonjans, K., Itoh, H. and Auwerx, J.

J Biol Chem 286 ( 30 ) 26913 - 20 2011.07

ISSN 0021-9258

We evaluated the metabolic impact of farnesoid X receptor (FXR) activation by administering a synthetic FXR agonist (GW4064) to mice in which obesity was induced by a high fat diet. Administration of GW4064 accentuated body weight gain and glucose intolerance induced by the high fat diet and led to a pronounced worsening of the changes in liver and adipose tissue. Mechanistically, treatment with GW4064 decreased bile acid (BA) biosynthesis, BA pool size, and energy expenditure, whereas reconstitution of the BA pool in these GW4064-treated animals by BA administration dose-dependently reverted the metabolic abnormalities. Our data therefore suggest that activation of FXR with synthetic agonists is not useful for long term management of the metabolic syndrome, as it reduces the BA pool size and subsequently decreases energy expenditure, translating as weight gain and insulin resistance. In contrast, expansion of the BA pool size, which can be achieved by BA administration, could be an interesting strategy to manage the metabolic syndrome.

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Functional characterization of (pro)renin receptor in association with V-ATPase

Kinouchi, K., Ichihara, A. and Itoh, H.

Front Biosci (Landmark Ed) 16 3216 - 23 2011.06

ISSN 1093-4715

The (pro)renin receptor ((P)RR) is a unique molecule that binds prorenin and renin in tissues, not only leading to their activation, but also inducing intracellular signaling. As a key player in the local renin-angiotensin system, (P)RR activation plays an important role in the development of cardiac fibrosis and proteinuria in hypertension and diabetes. Intriguingly, the fragment (P)RR is also called ATP6AP2 because it has been shown to be associated with vacuolar-type H(+)-ATPase (V-ATPase). The V-ATPase is a multi-subunit proton pump involved in diverse and fundamental cellular processes, including receptor-mediated endocytosis, processing of proteins and signaling molecules, membrane sorting and trafficking, and activation of lysosomal enzymes. The role of (P)RR in the function of the V-ATPase is implicated in the previous findings and vigorously investigated in the recent studies. Furthermore, the novel function of the (P)RR as an adaptor protein between the Wnt receptor complex and the V-ATPase was discovered. Thus, the (P)RR is a multi-functional molecule that shows the complex structure and behaviour. This review highlights the current insights and the future perspectives in research regarding the (P)RR and mammalian V-ATPase.

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