論文 - 木内　謙一郎

Prorenin receptor is essential for normal podocyte structure and function

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

Journal of the American Society of Nephrology （Ovid Technologies (Wolters Kluwer Health)）  22 （ 12 ） 2203 - 2212 2011年12月

筆頭著者, 最終著者, 責任著者, 査読有り,  ISSN  1046-6673

　概要を見る

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 V0 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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Functional characterization of (pro)renin receptor in association with V-ATPase

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

Frontiers in Bioscience （IMR Press）  16 （ 8 ） 3216 - 3223 2011年06月

筆頭著者, 最終著者, 責任著者, 査読有り,  ISSN  1093-9946

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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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Involvement of activated prorenin in the pathogenesis of slowly progressive nephropathy in the non-clipped kidney of two kidney, one-clip hypertension

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

Hypertension Research （Springer Science and Business Media LLC）  34 （ 3 ） 301 - 307 2011年03月

筆頭著者, 最終著者, 責任著者, 査読有り,  ISSN  0916-9636

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The handle region peptide (HRP), a (pro)renin receptor (P)RR blocker, did not prevent the acute nephropathy occurring 2 weeks after clipping in renovascular hypertensive rats. This study was performed to examine the effects of HRP, its scramble peptide, or a saline vehicle on slowly progressive nephropathy occurring in the kidneys of two-kidney, one-clip Goldblatt hypertensive rats. At 2 weeks after clipping, the renal morphology in the clipped and non-clipped kidneys was similar in the three groups of rats. At 12 weeks after clipping, however, the glomerulosclerosis index (GI) and the tubulointerstitial damage (TD) of the non-clipped kidneys of the HRP-treated rats were significantly lower than those of vehicle-treated rats, although the GI and the TD were similar in the rats treated with scramble peptide and vehicle. The GI and the TD of the clipped kidneys were similar in the three groups of rats at 12 weeks after clipping. In the non-clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and transforming growth factor (TGF)-β mRNA levels of HRP-treated rats were significantly lower than those of vehicle-treated rats, although they were similar in the non-clipped kidneys from the rats treated with scramble peptide and vehicle. In the clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and TGF-β mRNA levels were similar in the three groups of rats. These results suggest that the ((P)RR)-dependent activation of prorenin contributes to the pathogenesis of slowly progressive nephropathy in the intact kidney in a rat model of renovascular hypertension.

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(Pro)renin receptor/ATP6AP2 and cell death

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

Japanese Journal of Nephrology 53 （ 7 ） 996 - 999 2011年

筆頭著者, 最終著者, 責任著者,  ISSN  03852385

(プロ)レニン受容体/ATP6AP2と細胞死

木内 謙一郎, 市原 淳弘, 伊藤 裕

日本腎臓学会誌 = The Japanese journal of nephrology （東京 : 日本腎臓学会）  53 （ 7 ） 996 - 999 2011年

筆頭著者, 最終著者, 責任著者, 査読有り,  ISSN  03852385

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コレクション : 国立国会図書館デジタルコレクション > 電子書籍・電子雑誌 > 学術機関 > 学協会

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[(Pro)renin receptor /ATP6AP2 and cell death].

Kinouchi K, Ichihara A, Ito H

Nihon Jinzo Gakkai shi （日本腎臓学会）  53 （ 7 ） 996 - 999 2011年

筆頭著者, 最終著者, 責任著者, 査読有り,  ISSN  0385-2385

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Differential effects in cardiovascular markers between high-dose angiotensin II receptor blocker monotherapy and combination therapy of ARB with calcium channel blocker in hypertension (DEAR Trial)

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

International Journal of Hypertension （Hindawi Limited）  2011   284823 - 11 2011年

筆頭著者, 最終著者, 責任著者, 査読有り,  ISSN  2090-0384

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<jats:p><jats:italic>Background/Aims</jats:italic>. Arterial stiffness is an independent risk factor for cardiovascular morbidity and mortality. This study was conducted to determine the effect of olmesartan (OLM) and azelnidipine (AZL) on arterial stiffness using the cardio-ankle vascular index (CAVI), which is a novel blood pressure (BP)-independent marker for arterial stiffness in hypertensive patients.<jats:italic>Methods</jats:italic>. Fifty-two consecutive hypertensive patients were randomly assigned either to a group treated with OLM monotherapy or to a group treated with OLM and AZL combination therapy. Clinical and biological parameters were measured before and 12 months after the start of this study.<jats:italic>Results</jats:italic>. Both therapies significantly and similarly reduced BP, augmentation index, and plasma aldosterone levels. The combination therapy significantly decreased CAVI and serum low-density lipoprotein (LDL-C) levels and these reductions were significantly greater than those produced with monotherapy. No significant differences in metabolic parameters were observed between the two therapies.<jats:italic>Conclusion</jats:italic>. The combination therapy with OLM and AZL had beneficial effects on arterial stiffness assessed by CAVI, LDL-C, and metabolism, despite the similar BP reduction, compared with OLM monotherapy. Since these markers are known to influence the future risk of cardiovascular events, combination therapy with OLM and AZL could be a useful choice for treating hypertensive patients.</jats:p>

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ATP6ap2/(Pro)renin receptor

佐野 元昭, 木内 謙一郎, 市原 淳弘, 和田 洋

心臓 （Japan Heart Foundation）  43 （ 5 ） 604 - 609 2011年

筆頭著者, 最終著者, 責任著者,  ISSN  0586-4488

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ATP6ATP2(pro)renin receptor is essential for the function of organella in murine cardiomycytes

K. Kinouchi, A. Ichihara, M. Sano, G.H. Sun-Wada, Y. Wada, A. Kurauchi-Mito, K. Bokuda, T. Narita, Y. Oshima, M. Sakoda, Y. Tama, H. Sato, K. Fukuda, H. Itoh

2010年12月

筆頭著者, 最終著者, 責任著者, 査読有り

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

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

Journal of Pharmacological Sciences 113 （ 4 ） 296 - 300 2010年08月

筆頭著者, 最終著者, 責任著者, 査読有り,  ISSN  1347-8613

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The (Pro)renin receptor/ATP6AP2 is essential for vacuolar H ⁺-ATPase assembly in murine cardiomyocytes

Kinouchi, K. and Ichihara, A. and Sano, M. and Sun-Wada, G.-H. and Wada, Y. and Kurauchi-Mito, A. and Bokuda, K. and Narita, T. and Oshima, Y. and Sakoda, M. and Tamai, Y. and Sato, H. and Fukuda, K. and Itoh, H.

Circulation Research （Ovid Technologies (Wolters Kluwer Health)）  107 （ 1 ） 30 - 34 2010年07月

筆頭著者, 最終著者, 責任著者,  ISSN  0009-7330

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<jats:p>
<jats:bold>
<jats:italic>
<jats:underline>Rationale</jats:underline>
:
</jats:italic>
</jats:bold>
The (pro)renin receptor [(P)RR], encoded in
<jats:italic>ATP6AP2</jats:italic>
, plays a key role in the activation of local renin-angiotensin system (RAS). A truncated form of (P)RR, termed M8.9, was also found to be associated with the vacuolar H
<jats:sup>+</jats:sup>
-ATPase (V-ATPase), implicating a non–RAS-related function of ATP6AP2.
</jats:p>
<jats:p>
<jats:bold>
<jats:italic>
<jats:underline>Objective</jats:underline>
:
</jats:italic>
</jats:bold>
We investigated the role of (P)RR/ATP6AP2 in murine cardiomyocytes.
</jats:p>
<jats:p>
<jats:bold>
<jats:italic>
<jats:underline>Methods and Results</jats:underline>
:
</jats:italic>
</jats:bold>
Cardiomyocyte-specific ablation of
<jats:italic>Atp6ap2</jats:italic>
resulted in lethal heart failure; the cardiomyocytes contained RAB7- and lysosomal-associated membrane protein 2 (LAMP2)-positive multivesicular vacuoles, especially in the perinuclear regions. The myofibrils and mitochondria remained at the cell periphery. Cardiomyocyte death was accompanied by numerous autophagic vacuoles that contained undigested cellular constituents, as a result of impaired autophagic degradation. Notably, ablation of
<jats:italic>Atp6ap2</jats:italic>
selectively suppressed expression of the V
<jats:sub>O</jats:sub>
subunits of V-ATPase, resulting in deacidification of the intracellular vesicles. Furthermore, the inhibition of intracellular acidification by treatment with bafilomycin A1 or chloroquine reproduced the phenotype observed for the (P)RR/ATP6AP2-deficient cardiomyocytes.
</jats:p>
<jats:p>
<jats:bold>
<jats:italic>
<jats:underline>Conclusions</jats:underline>
:
</jats:italic>
</jats:bold>
Genetic ablation of
<jats:italic>Atp6ap2</jats:italic>
created a loss-of-function model for V-ATPase. The gene product of
<jats:italic>ATP6AP2</jats:italic>
is considered to act as in 2 ways: (1) as (P)RR, exerting a RAS-related function; and (2) as the V-ATPase-associated protein, exerting a non–RAS-related function that is essential for cell survival.
</jats:p>

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Add-on blockade of (pro)renin receptor in imidapril-treated diabetic SHRsp

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

Frontiers in Bioscience - Elite 2 （ 3 ） 972 - 979 2010年06月

筆頭著者, 最終著者, 責任著者, 査読有り,  ISSN  1945-0494

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Aliskiren inhibits intracellular angiotensin ii levels without affecting (Pro)renin Receptor Signals in Human Podocytes

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

American Journal of Hypertension 23 （ 5 ） 575 - 580 2010年05月

筆頭著者, 最終著者, 責任著者, 査読有り,  ISSN  0895-7061

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Renoprotective effects of mineralocorticoid receptor blockade in heminephrectomized (pro)renin receptor transgenic rats.

Mizuguchi Y, Ichihara A, Seki Y, Sakoda M, Kurauchi-Mito A, Narita T, Kinouchi K, Bokuda K, Itoh H

Clinical and experimental pharmacology & physiology 37 （ 5-6 ） 569 - 73 2010年05月

筆頭著者, 最終著者, 責任著者,  ISSN  0305-1870

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Renoprotective effects of mineralocorticoid receptor blockade in heminephrectomized (pro)renin receptor transgenic rats

Yuki Mizuguchi, Atsuhiro Ichihara, Yasufumi Seki, Mariyo Sakoda, Asako Kurauchi-Mito, Tatsuya Narita, Kenichiro Kinouchi, Kanako Bokuda, Hiroshi Itoh

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY 37 （ 5-6 ） 569 - 573 2010年05月

筆頭著者, 最終著者, 責任著者, 査読有り,  ISSN  0305-1870

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Renoprotective effects of mineralocorticoid receptor blockade in heminephrectomized (pro)renin receptor transgenic rats

Kenichiro Kinouchi, Asako Kurauchi-Mito, Mariyo Sakoda, Yasufumi Seki, Yuki Mizuguchi, Kanako Bokuda, Tatsuya Narita, Atsuhiro Ichihara, Hiroshi Itoh

Clinical and Experimental Pharmacology and Physiology （Wiley）  37   569 - 573 2010年04月

筆頭著者, 最終著者, 責任著者,  ISSN  03051870

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<jats:title>Summary</jats:title><jats:p>1. Nephropathy and elevated plasma aldosterone concentrations (PAC) have been observed in (pro)renin receptor transgenic (TG) rats. In the present study, we hypothesized that PAC and/or mineralocorticoid receptor contribute to the nephropathy of TG rats. To test this hypothesis, the effects of a high‐sodium (8% NaCl) diet and heminephrectomy on PAC were examined.</jats:p><jats:p>2. Feeding of the high‐sodium diet for 12 weeks similarly decreased PAC in TG and wild‐type (WT) rats. Heminephrectomy further reduced PAC in TG rats fed a high‐sodium diet, but had no effect on PAC in WT rats fed a high‐sodium diet.</jats:p><jats:p>3. Next, the effects of eplerenone (125 mg/kg per day) and dietary salt restriction (0.36% NaCl diet) on proteinuria and renal morphology were examined in rats fed a high‐sodium diet or subjected to heminephrectomy. Both eplerenone and dietary sodium restriction significantly reduced the arterial pressure of TG rats, but had no effect in WT rats. In TG rats, treatment with eplerenone significantly decreased urinary protein excretion, but dietary sodium restriction did not.</jats:p><jats:p>4. Nephrin and podocin mRNA levels, as determined by real‐time quantitative reverse transcription–polymerase chain reaction, were significantly lower in TG rats than in WT rats. In TG rats, eplerenone treatment significantly increased nephrin mRNA levels, but not podocin mRNA levels. Dietary salt restriction significantly increased mRNA levels of both nephrin and podocin. Although zonula occludens (ZO)‐1 mRNA levels were similar in both WT and TG rats, eplerenone treatment significantly decreased ZO‐1 mRNA levels in TG rats.</jats:p><jats:p>5. The results of the present study suggest that the improvement in proteinuria following eplerenone treatment is independent of its effects on sodium balance and may be mediated by effects on the expression of slit diaphragm proteins.</jats:p>

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

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

Hypertension Research （Springer Science and Business Media LLC）  33 （ 3 ） 177 - 180 2010年03月

筆頭著者, 最終著者, 責任著者, 査読有り,  ISSN  0916-9636

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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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Recent advance in (Pro)renin receptor research

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

Respiration and Circulation （株式会社医学書院）  58 （ 3 ） 245 - 251 2010年03月

筆頭著者, 最終著者, 責任著者,  ISSN  0452-3458

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Blood pressure-independent effect of candesartan on cardio-ankle vascular index in hypertensive patients with metabolic syndrome

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

Vascular Health and Risk Management 6 （ 1 ） 571 - 578 2010年

筆頭著者, 最終著者, 責任著者, 査読有り,  ISSN  1176-6344

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

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

Kidney and Blood Pressure Research （S. Karger AG）  33 （ 4 ） 304 - 312 2010年

筆頭著者, 最終著者, 責任著者, 査読有り,  ISSN  1420-4096

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<jats:p><i>Background/Aims:</i> 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. <i>Methods:</i> 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. <i>Results:</i> 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. <i>Conclusion:</i> 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.</jats:p>

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