研究者詳細 - 伊藤　裕

論文 - 伊藤　裕

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Adrenocortical zonation in humans under normal and pathological conditions

Nishimoto, K., Nakagawa, K., Li, D., Kosaka, T., Oya, M., Mikami, S., Shibata, H., Itoh, H., Mitani, F., Yamazaki, T., Ogishima, T., Suematsu, M. and Mukai, K.

J Clin Endocrinol Metab 95 （ 5 ） 2296 - 305 2010年05月

ISSN 0021-972

CONTEXT: Aldosterone synthase (CYP11B2) and steroid 11 beta-hydroxylase (CYP11B1) catalyze the terminal steps for aldosterone and cortisol syntheses, respectively, thereby determining the functional differentiation of human adrenocortical cells. Little is known, however, about how the cells expressing the enzymes are actually distributed in the adrenals under normal and pathological conditions. OBJECTIVE: The objective of the study was to determine the localization of CYP11B2 and -B1 in human adrenal specimens by using developed antibodies capable of distinguishing the two enzymes from each other. RESULTS: Under normal conditions, CYP11B2 was sporadically detected in the zona glomerulosa, whereas CYP11B1 was entirely detected in the zonae fasciculata-reticularis. Adrenocortical cells lacking both enzymes were observed in the outer cortical regions. In addition to conventional zonation, we found a variegated zonation consisting of a subcapsular cell cluster expressing CYP11B2, which we termed aldosterone-producing cell cluster, and a CYP11B1-expressing area. Aldosterone-producing adenomas differed in cell populations expressing CYP11B2 from one another, whereas CYP11B1-expressing and double-negative cells were also intermingled. Adenomas from patients with Cushing's syndrome expressed CYP11B1 entirely but not CYP11B2, resulting in atrophic nontumor glands. The nontumor portions of both types of adenomas bore frequently one or more aldosterone-producing cell clusters, which sustained CYP11B2 expression markedly under the conditions of the suppressed renin-angiotensin system. CONCLUSION: Immunohistochemistry of the human normal adrenal cortex for CYP11B2 and CYP11B1 revealed a variegated zonation with cell clusters constitutively expressing CYP11B2. This technique may provide a pathological confirmatory diagnosis of adrenocortical adenomas.

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Kidney-specific overexpression of Sirt1 protects against acute kidney injury by retaining peroxisome function

Hasegawa, K., Wakino, S., Yoshioka, K., Tatematsu, S., Hara, Y., Minakuchi, H., Sueyasu, K., Washida, N., Tokuyama, H., Tzukerman, M., Skorecki, K., Hayashi, K. and Itoh, H.

J Biol Chem 285 （ 17 ） 13045 - 56 2010年04月

ISSN 0021-9258

Sirt1, a NAD-dependent protein deacetylase, is reported to regulate intracellular metabolism and attenuate reactive oxidative species (ROS)-induced apoptosis leading to longevity and acute stress resistance. We created transgenic (TG) mice with kidney-specific overexpression of Sirt1 using the promoter sodium-phosphate cotransporter IIa (Npt2) driven specifically in proximal tubules and investigated the kidney-specific role of Sirt1 in the protection against acute kidney injury (AKI). We also elucidated the role of number or function of peroxisome and mitochondria in mediating the mechanisms for renal protective effects of Sirt1 in AKI. Cisplatin-induced AKI decreased the number and function of peroxisomes as well as mitochondria and led to increased local levels of ROS production and renal tubular apoptotic cells. TG mice treated with cisplatin mitigated AKI, local ROS, and renal tubular apoptotic tubular cells. Consistent with these results, TG mice treated with cisplatin also exhibited recovery of peroxisome number and function, as well as rescued mitochondrial function; however, mitochondrial number was not recovered. Immunoelectron microscopic findings consistently demonstrated that the decrease in peroxisome number by cisplatin in wild type mice was restored in transgenic mice. In HK-2 cells, a cultured proximal tubule cell line, overexpression of Sirt1 rescued the cisplatin-induced cell apoptosis through the restoration of peroxisome number, although the mitochondria number was not restored. These results indicate that Sirt1 overexpression in proximal tubules rescues cisplatin-induced AKI by maintaining peroxisomes number and function, concomitant up-regulation of catalase, and elimination of renal ROS levels. Renal Sirt1 can be a potential therapeutic target for the treatment of AKI.

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NF-YC functions as a corepressor of agonist-bound mineralocorticoid receptor

Murai-Takeda, A., Shibata, H., Kurihara, I., Kobayashi, S., Yokota, K., Suda, N., Mitsuishi, Y., Jo, R., Kitagawa, H., Kato, S., Saruta, T. and Itoh, H.

J Biol Chem 285 （ 11 ） 8084 - 93 2010年03月

ISSN 0021-9258

The role of aldosterone has been implicated in the metabolic syndrome and cardiovascular diseases. The biological actions of aldosterone are mediated through mineralocorticoid receptor (MR). Nuclear receptor-mediated gene expression is regulated by dynamic and coordinated recruitment of coactivators and corepressors. To identify new coregulators of the MR, full-length MR was used as bait in yeast two-hybrid screening. We isolated NF-YC, one of the subunits of heterotrimeric transcription factor NF-Y. Specific interaction between MR and NF-YC was confirmed by yeast two-hybrid, mammalian two-hybrid, coimmunoprecipitation assays, and fluorescence subcellular imaging. Transient transfection experiments in COS-7 cells demonstrated that NF-YC repressed MR transactivation in a hormone-sensitive manner. Moreover, reduction of NF-YC protein levels by small interfering RNA potentiated hormonal activation of endogenous target genes in stably MR-expressing cells, indicating that NF-YC functions as an agonist-dependent MR corepressor. The corepressor function of NF-YC is selective for MR, because overexpression of NF-YC did not affect transcriptional activity mediated by androgen, progesterone, or glucocorticoid receptors. Chromatin immunoprecipitation experiments showed that endogenous MR and steroid receptor coactivator-1 were recruited to an endogenous ENaC gene promoter in a largely aldosterone-dependent manner, and endogenous NF-YC was sequentially recruited to the same element. Immunohistochemistry showed that endogenous MR and NF-YC were colocalized within the mouse kidney. Although aldosterone induces interaction of the N and C termini of MR, NF-YC inhibited the N/C interaction. These findings indicate that NF-YC functions as a new corepressor of agonist-bound MR via alteration of aldosterone-induced MR conformation.

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Possible roles of human (pro)renin receptor suggested by recent clinical and experimental findings

Ichihara, A., Sakoda, M., Kurauchi-Mito, A., Narita, T., Kinouchi, K., Murohashi-Bokuda, K. and Itoh, H.

Hypertens Res 33 （ 3 ） 177 - 80 2010年03月

ISSN 0916-9636

Numerous in vitro and in vivo animal studies using the (pro)renin receptor (P)RR blocker handle region peptide have suggested an important role of (P)RR in the pathogenesis of end-stage organ damage in patients with diabetes and hypertension. In addition, a limited number of clinical studies have suggested an association between (P)RR gene polymorphisms and blood pressure levels and between (P)RR mRNA levels and angiotensin-converting enzyme mRNA levels in human arteries. However, recent studies have shown that the (P)RR is divided into its soluble form and a residual hydrophobic part, which includes ATPase 6 associated protein 2, within cells. Therefore, the (P)RR may have a more complex function than previously thought. In addition, the physiological roles of the (P)RR remain undetermined, because the construction of (P)RR null mice has not been successful. As a next step for research in this area, a method for determining the soluble (P)RR levels in plasma and urine and the construction of tissue-specific (P)RR-knockout mice are needed to elucidate the roles of the (P)RR in physiology and pathophysiology.

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Brachial-ankle pulse wave velocity predicts silent cerebrovascular diseases in patients with end-stage renal diseases

Washida, N., Wakino, S., Hayashi, K., Kuwahara, T. and Itoh, H.

J Atheroscler Thromb 17 （ 2 ） 165 - 72 2010年02月

ISSN 1340-3478

AIM: Cerebrovascular disease (CVD) is a major determinant of the prognosis in end-stage renal diseases (ESRD). The purpose of this study was to examine whether factors associated with arterial stiffness contributed to the development of CVD in patients with ESRD. METHODS: CVD (lacunes and carotid/intracranial artery stenosis) was evaluated with brain magnetic resonance imaging (MRI), and carotid/intracranial artery magnetic resonance angiography (MRA) in 44 pre-dialytic patients. The severity of CVD was evaluated by the number of lacunes and the degree of stenosis, respectively. The association between CVD and atherosclerotic parameters was evaluated. RESULTS: Patients with severe lacunes (n=18) manifested older age, lower diastolic blood pressure, serum creatinine and albumin, and higher CRP and serum calcium than those with absent-moderate lacunes (n=26). When assessed by multivariate analysis, only baPWV was adopted as an independent risk factor for severe lacunes. Furthermore, baPWV and i-PTH were associated with the severity of carotid/intracranial artery stenosis, both of which were independent of other risk factors, including age and diabetes. CONCLUSIONS: Arterial stiffness may constitute a novel determinant predicting the severity of CVD in pre-dialytic patients besides classical risk factors.

[Anti-atherosclerotic effects by PPARgamma and its ligands through the activation of reverse cholesterol transport system]

Wakino, S. and Itoh, H.

Nihon Rinsho 68 （ 2 ） 217 - 23 2010年02月

ISSN 0047-1852

Peroxisome proliferator-activated receptor gamma (PPARgamma) belongs to a nuclear receptor superfamily which agonists were in clinical use for anti-diabetic therapy. Recent studies both in vivo and in vitro revealed that PPARgamma agonists have anti-atherosclerotic effects which is also demonstrated by a large clinical trial including PROactive study. One of the mechanisms for this effect is the activation of reverse cholesterol transport through the induction of ABCA1 transporter by PPARgamma agonists. The transporter exports cholesterol from macrophages migrating in the vasculature and inhibits the formation of foam cell which contains lipid droplet in the cytosol as cholesterol ester. Clinical application of PPARgamma agonists have beneficial effects by preventing the cardiovascular events in diabetic patients.

T-type Ca channel blockade as a determinant of kidney protection

Hayashi, K., Homma, K., Wakino, S., Tokuyama, H., Sugano, N., Saruta, T. and Itoh, H.

Keio J Med 59 （ 3 ） 84 - 95 2010年

ISSN 0022-9717

Voltage-dependent Ca channels are classified into several subtypes based on the isoform of their alpha1 subunits. Traditional Ca channels blockers (CCBs), including nifedipine and amlodipine, act predominantly on L-type Ca channels, whereas novel CCBs such as efonidipine, benidipine and azelnidipine inhibit both L-type and T-type Ca channels. Furthermore, cilnidipine blocks L-type and N-type Ca channels. These CCBs exert divergent actions on renal microvessels. L-type CCBs preferentially dilate afferent arterioles, whereas both L-/T-type and L-/N-type CCBs potently dilate afferent and efferent arterioles. The distinct actions of CCBs on the renal microcirculation are reflected by changes in glomerular capillary pressure and subsequent renal injury: L-type CCBs favor an increase in glomerular capillary pressure, whereas L-/T-type and L-/N-type CCBs alleviate glomerular hypertension. The renal protective action of L-/T-type CCBs is also mediated by non-hemodynamic mechanisms, i.e., inhibition of the inflammatory process and inhibition of Rho kinase and aldosterone secretion. Finally, a growing body of evidence indicates that T-type CCBs offer more beneficial action on proteinuria and renal survival rate than L-type CCBs in patients with chronic kidney disease (CKD). Similarly, in CKD patients treated with renin-angiotensin blockers, add-on therapy with N-type CCBs is more potent in reducing proteinuria than that with L-type CCBs, although no difference is found in the subgroup with diabetic nephropathy. Thus, the strategy for hypertension treatment with CCBs has entered a new era: treatment selection depends not only on blood pressure control but also on the subtypes of CCBs.

Absence of gelatinase (MMP-9) or collagenase (MMP-13) attenuates adriamycin-induced albuminuria and glomerulosclerosis

Sakamaki, Y., Sasamura, H., Hayashi, K., Ishiguro, K., Takaishi, H., Okada, Y., D'Armiento, J. M., Saruta, T. and Itoh, H.

Nephron Exp Nephrol 115 （ 2 ） e22 - 32 2010年

ISSN 1660-2129

BACKGROUND/AIMS: The role of matrix metalloproteinases (MMPs) in the pathogenesis of glomerular injury appears to be complex. To investigate the role of individual MMPs, we examined the course of Adriamycin-induced albuminuria and glomerulosclerosis in mice lacking either a gelatinase (MMP-9) or a collagenase (MMP-13). METHODS: Adriamycin was administered to MMP-9 or MMP-13 knockout (KO) mice. Glomerular injury was assessed by the quantification of albuminuria, the glomerular injury score and type IV collagen immunostaining. RESULTS: Treatment of mice with Adriamycin (18 mg/kg i.v.) resulted in marked albuminuria and glomerulosclerosis reaching a peak at 4-8 weeks. The albuminuria and glomerulosclerosis were significantly (p < 0.05) attenuated in both the MMP-9 KO and MMP-13 KO mice compared to controls. In contrast, treatment of wild-type mice with the broad-spectrum MMP inhibitor doxycycline did not have a beneficial effect on the albuminuria and glomerulosclerosis. CONCLUSION: These results support a role for both gelatinase (MMP-9) and collagenase (MMP-13) in the pathogenesis of glomerular injury in the Adriamycin-induced glomerulosclerosis model. MMP inhibitors with high specificity towards MMP-9 and/or MMP-13 may be potential future candidates to provide more effective therapies to inhibit the development of glomerulosclerosis.

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Beta cell dysfunction and its clinical significance in gestational diabetes

Saisho, Y., Miyakoshi, K., Tanaka, M., Shimada, A., Ikenoue, S., Kadohira, I., Yoshimura, Y. and Itoh, H.

Endocr J 57 （ 11 ） 973 - 80 2010年

ISSN 0918-8959

The aim of this study is to explore beta cell dysfunction and its clinical significance in gestational diabetes mellitus (GDM). We assessed insulin sensitivity and insulin secretion in a total of 277 Japanese women between 24 and 27 weeks of pregnancy who underwent a 2 h, 75 g oral glucose tolerance test (OGTT) because of an abnormal result on a 1 h 50 g oral glucose challenge conducted as part of a standard screening for GDM. Insulin sensitivity was evaluated by an insulin sensitivity index derived from OGTT (IS(OGTT)), whereas insulin secretion was calculated as a ratio of the total area under the insulin curve to the total area under the glucose curve (AUC(ins/glu)). Beta cell function in relation to insulin sensitivity (i.e. disposition index) was derived from the product of insulin sensitivity and insulin secretion (i.e. AUC(ins/glu) x IS(OGTT)). In women diagnosed with GDM (n=57), the disposition index was significantly lower than that in those without GDM, irrespective of obesity. The disposition index in women with GDM was significantly correlated with levels of fasting and mean preprandial capillary glucose and HbA1c before initiating insulin therapy (r = -0.45, -0.38, -0.49, respectively). Furthermore, there was a significant correlation between the disposition index and total insulin dosage to achieve glycemic goal (r = -0.41). In conclusion, we demonstrated beta cell dysfunction in Japanese women with GDM irrespective of obesity. The level of beta cell dysfunction in GDM was associated with the severity of glucose intolerance and total insulin dosage required. These findings underpin clinical significance of beta cell dysfunction in GDM.

CXC chemokine ligand 10 DNA vaccination plus Complete Freund's Adjuvant reverses hyperglycemia in non-obese diabetic mice

Oikawa, Y., Shimada, A., Yamada, Y., Okubo, Y., Katsuki, T., Shigihara, T., Miyazaki, J., Narumi, S. and Itoh, H.

Rev Diabet Stud 7 （ 3 ） 209 - 24 2010年

ISSN 1613-6071

OBJECTIVE: Complete Freund's Adjuvant (CFA) is known to arrest autoimmune diabetes development in non-obese diabetic (NOD) mice. However, CFA alone cannot induce effective remission in diabetic NOD mice. Previously, we reported that anti-CXC chemokine ligand 10 (CXCL10) antibody can promote beta-cell proliferation in NOD mice. In the present study, we aimed to examine whether anti-CXCL10 plus CFA treatment can effectively reverse autoimmune diabetes development. METHODS: Systemic supply of anti-CXCL10 antibody by CXCL10 DNA vaccination in combination with CFA injection was performed in new-onset diabetic NOD mice. Remission rate of diabetes, histological characteristics of residual insulitis lesions, residual beta-cell mass, and regulatory T cell population in local pancreas were examined. RESULTS: A high frequency of diabetes reversal was observed after combination treatment with anti-CXCL10 plus CFA. In mice showing diabetes reversal, residual beta-cell mass was significantly increased, and some beta-cells were in a proliferative state. Although systemic cytokine profiles were unaffected, the frequency of "hybrid regulatory T cells", i.e. regulatory T cells expressing CXCR3, was significantly increased in local pancreatic lesions. This was possibly associated with the regulation of anti-islet autoimmunity. CONCLUSIONS: Anti-CXCL10 plus appropriate immune adjuvant therapy arrested, and reversed, type 1 diabetes development.

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Effects of telmisartan on arterial stiffness assessed by the cardio-ankle vascular index in hypertensive patients

Kinouchi, K., Ichihara, A., Sakoda, M., Kurauchi-Mito, A., Murohashi-Bokuda, K. and Itoh, H.

Kidney Blood Press Res 33 （ 4 ） 304 - 12 2010年

ISSN 1420-4096

BACKGROUND/AIMS: This study was conducted to determine the effect of telmisartan on the cardio-ankle vascular index (CAVI), a novel blood pressure (BP)-independent marker for arterial stiffness in hypertensive patients. METHODS: One hundred consecutive hypertensive patients were randomly assigned either to a group treated with calcium channel blocker (CCB)-based therapy or a group treated with telmisartan-based therapy. Clinical and biological parameters were then measured before and 12 months after the start of this study. RESULTS: CAVI, the logarithm of urinary albumin excretion, and BP were reduced significantly after telmisartan-based therapy. The decreases in 24-hour diastolic BP and daytime systolic BP associated with telmisartan-based therapy were significantly greater than those associated with CCB-based therapy. Both therapies significantly and similarly decreased the clinical BP, 24-hour systolic BP, daytime diastolic BP and serum levels of low-density lipoprotein cholesterol. No significant differences in the metabolic parameters were observed between the two therapies. CONCLUSION: Telmisartan-based therapy had beneficial effects on arterial stiffness assessed by CAVI, albuminuria, 24-hour BP and metabolism compared with CCB-based therapy. Since these markers are known to influence the future risk of cardiovascular events, telmisartan could be a useful drug for hypertensive patients.

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New approaches to blockade of the renin-angiotensin-aldosterone system: characteristics and usefulness of the direct renin inhibitor aliskiren

Ichihara, A., Sakoda, M., Kurauchi-Mito, A., Narita, T., Kinouchi, K., Bokuda, K. and Itoh, H.

J Pharmacol Sci 113 （ 4 ） 296 - 300 2010年

ISSN 1347-8613

Since renin inhibition interferes with the first and rate-limiting steps in the renin-angiotensin system, the renin step is a very attractive target for lowering blood pressure and minimizing target-organ damage. The newly developed direct renin inhibitor aliskiren has several attractive characteristics: it definitively reduces plasma renin activity among inhibitors of the renin-angiotensin system, is remarkably specific for human renin, exhibits a long half-life in plasma comparable to that of amlodipine, and has a high affinity for renal glomeruli and vasculature. Although these characteristics suggest the clinical usefulness and safety of aliskiren, several problems remain unsolved. Why does aliskiren have beneficial effects on the heart and kidneys of patients treated with angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II type 1-receptor blockers (ARBs)? Is the blood-pressure-lowering effect of aliskiren dependent on the plasma renin activity? Does aliskiren exert a possible adverse effect via (pro)renin receptor-dependent intracellular signals? Here, we review the characteristics and usefulness of aliskiren and discuss the current issues associated with this direct renin inhibitor.

Differentiation of murine embryonic stem and induced pluripotent stem cells to renal lineage in vitro

Morizane, R., Monkawa, T. and Itoh, H.

Biochem Biophys Res Commun 390 （ 4 ） 1334 - 9 2009年12月

ISSN 0006-291

Embryonic stem (ES) cells which have the unlimited proliferative capacity and extensive differentiation potency can be an attractive source for kidney regeneration therapies. Recent breakthroughs in the generation of induced pluripotent stem (iPS) cells have provided with another potential source for the artificially-generated kidney. The purpose of this study is to know how to differentiate mouse ES and iPS cells into renal lineage. We used iPS cells from mouse fibroblasts by transfection of four transcription factors, namely Oct4, Sox2, c-Myc and Klf4. Real-time PCR showed that renal lineage markers were expressed in both ES and iPS cells after the induction of differentiation. It also showed that a tubular specific marker, KSP progressively increased to day 18, although the differentiation of iPS cells was slower than ES cells. The results indicated that renal lineage cells can be differentiated from both murine ES and iPS cells. Several inducing factors were tested whether they influenced on cell differentiation. In ES cells, both of GDNF and BMP7 enhanced the differentiation to metanephric mesenchyme, and Activin enhanced the differentiation of ES cells to tubular cells. Activin also enhanced the differentiation of iPS cells to tubular cells, although the enhancement was lower than in ES cells. ES and iPS cells have a potential to differentiate to renal lineage cells, and they will be an attractive resource of kidney regeneration therapy. This differentiation is enhanced by Activin in both ES and iPS cells.

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Safety and benefits of a tablet combining losartan and hydrochlorothiazide in Japanese diabetic patients with hypertension

Kinouchi, K., Ichihara, A., Sakoda, M., Kurauchi-Mito, A. and Itoh, H.

Hypertens Res 32 （ 12 ） 1143 - 7 2009年12月

ISSN 0916-9636

This study was conducted to determine the effects of a tablet combining losartan/hydrochlorothiazide (L/HCTZ) in comparison with losartan alone in Japanese diabetic patients with hypertension. Thirty consecutive Japanese diabetic patients with hypertension were randomly assigned to group A, receiving losartan alone for the first 3 months, then L/HCTZ for the next 3 months, or group B, receiving L/HCTZ for the first 3 months, then losartan alone for the next 3 months. Clinical and biological parameters were obtained before, and 3 and 6 months after the start of this study. The decreases in systolic and diastolic blood pressure (BP) during treatment with L/HCTZ were significantly greater than in treatment with losartan alone. Both treatments significantly and similarly decreased urinary albumin excretion, the cardio-ankle vascular index (CAVI) and augmentation index (AI). There was no significant difference in metabolic change during both the mono- and combination pharmacotherapies. The tablet combining L/HCTZ significantly reduced systolic and diastolic BP compared with the losartan monotherapy, and offered benefits similar to losartan monotherapy for albuminuria, arterial stiffness assessed by the CAVI and AI, and metabolic effects. Thus, the L/HCTZ tablet could be a useful drug for Japanese diabetic patients with hypertension.

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MCP-1 gene A-2518G polymorphism and carotid artery atherosclerosis in patients with type 2 diabetes

Yuasa, S., Maruyama, T., Yamamoto, Y., Hirose, H., Kawai, T., Matsunaga-Irie, S. and Itoh, H.

Diabetes Res Clin Pract 86 （ 3 ） 193 - 8 2009年12月

ISSN 0168-8227

AIMS: Cardiovascular diseases are the major cause of mortality in patients with diabetes mellitus. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine and plays an important role in cardiovascular diseases. The objective of this study was to evaluate the relation between the genotypes of the MCP-1 A-2518G polymorphism and the development of carotid atherosclerosis in patients with type 2 diabetes. METHODS: The subjects were 303 unrelated patients who were diagnosed with type 2 diabetes mellitus. To evaluate macroangiopathy, we measured carotid artery intima-media thickness (IMT) by ultrasonography. The MCP-1 A-2518G polymorphism was determined by TaqMan PCR method. RESULTS: IMT in patients with the MCP-1 -2518 AG or GG genotype was significantly greater than the AA-genotype (P=0.007). Simple regression analysis showed that age, systolic blood pressure, LDL-cholesterol, the MCP-1 -2518 AG+GG polymorphism, and HbA1c level were correlated with IMT (P<0.0001, <0.0001, 0.006, 0.007, 0.025, respectively). In multiple regression analysis, the MCP-1 -2518 AG+GG polymorphism was the third strongest independent determinant of IMT in patients with type 2 diabetes (P=0.021), subsequent to age and systolic blood pressure. CONCLUSION: Assessment of the MCP-1 A-2518G polymorphism would be useful in identifying the risk of developing carotid atherosclerosis in patients with type 2 diabetes.

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Natriuretic peptides/cGMP/cGMP-dependent protein kinase cascades promote muscle mitochondrial biogenesis and prevent obesity

Miyashita, K., Itoh, H., Tsujimoto, H., Tamura, N., Fukunaga, Y., Sone, M., Yamahara, K., Taura, D., Inuzuka, M., Sonoyama, T. and Nakao, K.

Diabetes 58 （ 12 ） 2880 - 92 2009年12月

ISSN 0012-1797

OBJECTIVE: Natriuretic peptides (NPs) have been characterized as vascular hormones that regulate vascular tone via guanylyl cyclase (GC), cyclic GMP (cGMP), and cGMP-dependent protein kinase (cGK). Recent clinical studies have shown that plasma NP levels were lower in subjects with the metabolic syndrome. The present study was conducted to elucidate the roles for NP/cGK cascades in energy metabolism. RESEARCH DESIGN AND METHODS: We used three types of genetically engineered mice: brain NP (BNP) transgenic (BNP-Tg), cGK-Tg, and guanylyl cyclase-A (GCA) heterozygous knockout (GCA(+/-)) mice and analyzed the metabolic consequences of chronic activation of NP/cGK cascades in vivo. We also examined the effect of NPs in cultured myocytes. RESULTS: BNP-Tg mice fed on high-fat diet were protected against diet-induced obesity and insulin resistance, and cGK-Tg mice had reduced body weight even on standard diet; surprisingly, giant mitochondria were densely packed in the skeletal muscle. Both mice showed an increase in muscle mitochondrial content and fat oxidation through upregulation of peroxisome proliferator-activated receptor (PPAR)-gamma coactivator (PGC)-1alpha and PPARdelta. The functional NP receptors, GCA and guanylyl cyclase-B, were downregulated by feeding a high-fat diet, while GCA(+/-) mice showed increases in body weight and glucose intolerance when fed a high-fat diet. NPs directly increased the expression of PGC-1alpha and PPARdelta and mitochondrial content in cultured myocytes. CONCLUSIONS: The findings together suggest that NP/cGK cascades can promote muscle mitochondrial biogenesis and fat oxidation, as to prevent obesity and glucose intolerance. The vascular hormone, NP, would contribute to coordinated regulation of oxygen supply and consumption.

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Cyclic GMP kinase and RhoA Ser188 phosphorylation integrate pro- and antifibrotic signals in blood vessels

Sawada, N., Itoh, H., Miyashita, K., Tsujimoto, H., Sone, M., Yamahara, K., Arany, Z. P., Hofmann, F. and Nakao, K.

Mol Cell Biol 29 （ 22 ） 6018 - 32 2009年11月

ISSN 0270-7306

Vascular fibrosis is a major complication of hypertension and atherosclerosis, yet it is largely untreatable. Natriuretic peptides (NPs) repress fibrogenic activation of vascular smooth muscle cells (VSMCs), but the intracellular mechanism mediating this effect remains undetermined. Here we show that inhibition of RhoA through phosphorylation at Ser188, the site targeted by the NP effector cyclic GMP (cGMP)-dependent protein kinase I (cGK I), is critical to fully exert antifibrotic potential. cGK I(+/-) mouse blood vessels exhibited an attenuated P-RhoA level and concurrently increased RhoA/ROCK signaling. Importantly, cGK I insufficiency caused dynamic recruitment of ROCK into the fibrogenic programs, thereby eliciting exaggerated vascular hypertrophy and fibrosis. Transgenic expression of cGK I-unphosphorylatable RhoA(A188) in VSMCs augmented ROCK activity, vascular hypertrophy, and fibrosis more prominently than did that of wild-type RhoA, consistent with the notion that RhoA(A188) escapes the intrinsic inhibition by cGK I. Additionally, VSMCs expressing RhoA(A188) became refractory to the antifibrotic effects of NPs. Our results identify cGK I-mediated Ser188 phosphorylation of RhoA as a converging node for pro- and antifibrotic signals and may explain how diminished cGMP signaling, commonly associated with vascular malfunction, predisposes individuals to vascular fibrosis.

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Serum bile acid along with plasma incretins and serum high-molecular weight adiponectin levels are increased after bariatric surgery

Nakatani, H., Kasama, K., Oshiro, T., Watanabe, M., Hirose, H. and Itoh, H.

Metabolism 58 （ 10 ） 1400 - 7 2009年10月

ISSN 0026-0495

Bariatric surgery has been shown to improve glucose tolerance, although the mechanism has not been fully elucidated. Animal studies have suggested important roles of bile acid (BA) as a regulator of energy homeostasis and glucose metabolism. However, little is known about its role in humans. We investigated the longitudinal changes of BA, incretins, and adipokines after significant weight reduction in 34 Japanese adults with morbid obesity who underwent laparoscopic bariatric surgery. In subjects who underwent malabsorptive or restrictive surgery, body mass index had markedly decreased from 43.0 +/- 6.5 (SD) to 37.8 +/- 5.7 kg/m(2) and from 45.3 +/- 11.2 to 41.5 +/- 10.5 kg/m(2), respectively, at 1 month after surgery. Glycated hemoglobin decreased from 6.1% +/- 1.5% to 5.2% +/- 0.4% and from 6.2% +/- 1.3% to 5.4% +/- 0.7%, and total BA level increased from 3.1 +/- 3.5 to 7.2 +/- 5.3 mumol/L and from 3.2 +/- 2.6 to 9.4 +/- 10.0 mumol/L, respectively. At baseline, serum concentration of primary BA was positively correlated with plasma gastric inhibitory polypeptide level (r = 0.548, P = .001); and change in primary BA level was positively correlated with changes in plasma gastric inhibitory polypeptide (r = 0.626, P = .001) and serum immunoreactive insulin level (r = 0.592, P = .002) at 1 month after surgery. Furthermore, plasma glucagon-like peptide-1 and serum high-molecular weight adiponectin levels increased in both surgeries. These hormonal changes might explain the mechanism(s) of improved glucose tolerance after bariatric surgery in morbidly obese subjects.

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Prevention and regression of hypertension: role of renal microvascular protection

Sasamura, H., Hayashi, K., Ishiguro, K., Nakaya, H., Saruta, T. and Itoh, H.

Hypertens Res 32 （ 8 ） 658 - 64 2009年08月

ISSN 0916-9636

Hypertension is a disease which affects over 26.4% of the world adult population, therefore novel approaches to the prevention and treatment of this disease need to be examined. Previous studies from our and other laboratories have shown that treatment of spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats with a renin-angiotensin system (RAS) inhibitor during the 'critical period' in hypertension development results in prevention of the later development of hypertension. In humans, Julius et al. reported similar findings in the landmark TROPHY study. Recently, we reported that 'pulse' treatment of SHR with high-dose angiotensin receptor blocker (ARB) is effective in causing sustained reduction of already established hypertension, even when the treatment was started after the 'critical period'. These results suggest the possibility that 'regression' of established hypertension may become feasible, and we have started a prospective, multicenter clinical study (STAR CAST study) to examine this possibility. In our animal studies, we found that treatment of rats during the 'critical period' with an ARB inhibits the development of renal arteriolar hypertrophy. Moreover, a high-dose angiotensin blocker caused a remarkable reversal of renal arteriolar hypertrophy in SHR, which was associated with changes in microvascular MMP expression. These results suggest that changes in the renal microvasculature may have an important role in the mechanisms of hypertension prevention and regression by ARB.

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Clinical importance of Stenotrophomonas maltophilia nosocomial pneumonia due to its high mortality in hemodialysis patients

Wakino, S., Imai, E., Yoshioka, K., Kamayachi, T., Minakuchi, H., Hayashi, K., Inamoto, H. and Itoh, H.

Ther Apher Dial 13 （ 3 ） 193 - 8 2009年06月

ISSN 1744-9979

Patients undergoing hemodialysis are immunocompromised and can suffer from pneumonia with various pathogens in nosocomial conditions. We investigated the fundamental information on the characteristics of hemodialysis inpatients and nosocomial pneumonia. We surveyed 1803 hemodialysis patients admitted to our university hospital between 2001 and 2007. The mean patient age was 64.8 years and the average period of hospitalization was 28.1 days, which was considerably longer than the average stay in our hospital (14.2 days). Patients were admitted to many different departments and for various reasons. We isolated 391 microorganisms from the sputum of 120 pneumonia patients undergoing hemodialysis, including Candida albicans, methicillin-resistant Staphylococcus aureus, and Staphylococcus epidermidis, which were the leading three isolates. From these 120 patients, a total of 199 pathogens were identified as being responsible for the pneumonia. Multi-drug resistant Stenotrophomonas maltophilia was found to be susceptible to a new fluoroquinolone, but is resistant to older generation quinolones. Out of the 120 patients with pneumonia, 12 out of 18 patients infected with S. maltophilia died, indicating the highest fatality rate for this pathogen. In this survey, we found that hemodialysis patients were hospitalized for long periods, and for various reasons in many departments. They suffered from nosocomial pneumonia caused by multi-drug resistant pathogens, including S. maltophilia. For pneumonia due to S. maltophilia, new generation fluoroquinolones can be the treatment of choice, although S. maltophilia-related pneumonia should be treated very carefully because of its high fatality rate.

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伊藤 裕

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伊藤　裕

論文 - 伊藤　裕