title: A serine protease inhibitor attenuates aldosterone-induced kidney injuries via the suppression of plasmin activity.
abstract: Emerging evidence has suggested that aldosterone has direct deleterious effects on the kidney independently of its hemodynamic effects. However, the detailed mechanisms of these direct effects remain to be elucidated. We have previously reported that camostat mesilate (CM), a synthetic serine protease inhibitor, attenuated kidney injuries in Dahl salt-sensitive rats, remnant kidney rats, and unilateral ureteral obstruction rats, suggesting that some serine proteases would be involved in the pathogenesis of kidney injuries. The current study was conducted to investigate the roles of serine proteases and the beneficial effects of CM in aldosterone-related kidney injuries. We observed a serine protease that was activated by aldosterone/salt in rat kidney lysate, and identified it as plasmin with liquid chromatography-tandem mass spectrometry. Plasmin increased pro-fibrotic and inflammatory gene expressions in rat renal fibroblast cells. CM inhibited the protease activity of plasmin and suppressed cell injury markers induced by plasmin in the fibroblast cells. Furthermore, CM ameliorated glomerulosclerosis and interstitial fibrosis in the kidney of aldosterone/salt-treated rats. Our findings indicate that plasmin has important roles in kidney injuries that are induced by aldosterone/salt, and that serine protease inhibitor could provide a new strategy for the treatment of aldosterone-associated kidney diseases in humans.
authors: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors: Yutaka
authors: Y
authors: Kakizoe
authors: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors: Yoshikazu
authors: Y
authors: Miyasato
authors: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors: Tomoaki
authors: T
authors: Onoue
authors: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors: Terumasa
authors: T
authors: Nakagawa
authors: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors: Manabu
authors: M
authors: Hayata
authors: Third Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo-City, Yamanashi, 409-3898, Japan.
authors: Kohei
authors: K
authors: Uchimura
authors: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors: Jun
authors: J
authors: Morinaga
authors: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors: Teruhiko
authors: T
authors: Mizumoto
authors: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors: Masataka
authors: M
authors: Adachi
authors: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors: Taku
authors: T
authors: Miyoshi
authors: Ono Pharmaceutical Co. Ltd., 1-8-2 Kyutaromachi Chuo-ku, Osaka, 541-8564, Japan.
authors: Yoshiki
authors: Y
authors: Sakai
authors: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors: Kimio
authors: K
authors: Tomita
authors: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors: Masashi
authors: M
authors: Mukoyama
authors: Third Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo-City, Yamanashi, 409-3898, Japan. Electronic address: kkenichiro@yamanashi.ac.jp.
authors: Kenichiro
authors: K
authors: Kitamura
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D000450:Aldosterone / Q000633:toxicity*; D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005341:Fibrinolysin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000933:Antifibrinolytic Agents; D015842:Serine Proteinase Inhibitors; D000450:Aldosterone; D005341:Fibrinolysin
keywords: Aldosterone; Kidney injury; Plasmin; Serine protease; Serine protease inhibitor