Manabu Hayata

Publications (3)11.27 Total impact

• Article: Effect of a serine protease inhibitor on the progression of chronic renal failure.

  Manabu Hayata, Yutaka Kakizoe, Kohei Uchimura, Jun Morinaga, Rika Yamazoe, Teruhiko Mizumoto, Tomoaki Onoue, Miki Ueda, Naoki Shiraishi, Masataka Adachi, Taku Miyoshi, Yoshiki Sakai, Kimio Tomita, Kenichiro Kitamura
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  ABSTRACT: The number of the chronic renal failure (CRF) patients is increasing explosively. Hypertension, proteinuria, inflammation, fibrosis, and oxidative stress are intertwined in a complicated manner that leads to the progression of CRF. However, the therapeutic strategies to delay its progression are limited. Since serine proteases are involved in many processes that contribute to these risk factors, we investigated the effects of a synthetic serine protease inhibitor, camostat mesilate (CM), on the progression of CRF in 5/6 nephrectomized (Nx) rats. Eighteen male Sprague-Dawley rats were divided into three groups: a sham-operated group (n = 6), a vehicle-treated Nx group (n = 6), and a CM-treated Nx group (n = 6). Following the 9-wk study period, both proteinuria and serum creatinine levels were substantially increased in the vehicle-treated Nx group, and treatment with CM significantly reduced proteinuria and serum creatinine levels. The levels of podocyte-associated proteins in glomeruli, such as nephrin and synaptopodin, were markedly decreased by 5/6 nephrectomy, and this was significantly ameliorated by CM. CM also suppressed the levels of inflammatory and fibrotic marker mRNAs including transforming growth factor-β1, TNF-α, collagen types I, III, and IV, and reduced glomerulosclerosis, glomerular hypertrophy, and interstitial fibrosis in histological studies. Furthermore, CM decreased the expression of NADPH oxidase component mRNAs, as well as reactive oxygen species generation and advanced oxidative protein product levels. Our present results strongly suggest the possibility that CM could be a useful therapeutic agent against the progression of CRF.
  AJP Renal Physiology 07/2012; 303(8):F1126-35. · 4.42 Impact Factor
• Article: In vivo contribution of serine proteases to the proteolytic activation of γENaC in aldosterone-infused rats.

  Kohei Uchimura, Yutaka Kakizoe, Tomoaki Onoue, Manabu Hayata, Jun Morinaga, Rika Yamazoe, Miki Ueda, Teruhiko Mizumoto, Masataka Adachi, Taku Miyoshi, Naoki Shiraishi, Yoshiki Sakai, Kimio Tomita, Kenichiro Kitamura
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  ABSTRACT: Aldosterone plays an important role in the regulation of blood pressure by modulating the activity of the epithelial sodium channel (ENaC) that consists of α-, β-, and γ-subunits. Aldosterone induces a molecular weight shift of γENaC from 85 to 70 kDa that is necessary for the channel activation. In vitro experiments demonstrated that a dual cleavage mechanism is responsible for this shift. It has been postulated that furin executes the primary cleavage in the Golgi and that the second cleavage is provided by other serine proteases such as prostasin or plasmin at the plasma membrane. However, the in vivo contribution of serine proteases to this cleavage remains unclear. To address this issue, we administered the synthetic serine protease inhibitor camostat mesilate (CM) to aldosterone-infused rats. CM decreased the abundance of the 70-kDa form of ENaC and led to a new 75-kDa form with a concomitant increase in the urinary Na-to-K ratio. Because CM inhibits the protease activity of serine proteases such as prostasin and plasmin, but not furin, our findings strongly indicate that CM inhibited the second cleavage of γENaC and subsequently suppressed ENaC activity. The results of our current studies also suggest the possibility that the synthetic serine protease inhibitor CM might represent a new strategy for the treatment of salt-sensitive hypertension in humans.
  AJP Renal Physiology 07/2012; 303(7):F939-43. · 4.42 Impact Factor
• Source

  Available from: Shizuka Aritomi

  Article: Regulation of adrenal aldosterone production by serine protease prostasin.

  Takehiro Ko, Yutaka Kakizoe, Naoki Wakida, Manabu Hayata, Kohei Uchimura, Naoki Shiraishi, Taku Miyoshi, Masataka Adachi, Shizuka Aritomi, Tomoyuki Konda, Kimio Tomita, Kenichiro Kitamura
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  ABSTRACT: A serine protease prostasin has been demonstrated to have a pivotal role in the activation of the epithelial sodium channel. Systemic administration of adenovirus carrying human prostasin gene in rats resulted in an increase in plasma prostasin and aldosterone levels. However, the mechanism by which the elevation of prostasin levels in the systemic circulation stimulated the plasma aldosterone levels remains unknown. Therefore, we examined if prostasin increases the aldosterone synthesis in a human adrenocortical cell line (H295R cells). Luciferase assay using CYP11B2 promoter revealed that prostasin significantly increased the transcriptional activity of CYP11B2. Prostasin significantly increased both CYP11B2 mRNA expression and aldosterone production in a dose-dependent manner. Surprisingly, treatment with camostat mesilate, a potent prostasin inhibitor, had no effect on the aldosterone synthesis by prostasin and also a protease-dead mutant of prostasin significantly stimulated the aldosterone production. A T-type/L-type calcium channel blocker and a protein kinase C (PKC) inhibitor significantly reduced the aldosterone synthesis by prostasin. Our findings suggest a stimulatory effect of prostasin on the aldosterone synthesis by adrenal gland through the nonproteolytic action and indicate a new role of prostasin in the systemic circulation.
  Journal of Biomedicine and Biotechnology 01/2010; 2010:793843. · 2.44 Impact Factor