The antifibrotic effect of a serine protease inhibitor in the kidney

作者：Morinaga Jun; Kakizoe Yutaka; Miyoshi Taku; Onoue Tomoaki; Ueda Miki; Mizumoto Teruhiko; Yamazoe Rika; Uchimura Kohei; Hayata Manabu; Shiraishi Naoki; Adachi Masataka; Sakai Yoshiki; Tomita Kimio; Kitamura Kenichiro^*

来源：American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 2013, 305(2): F173-F181.

DOI：10.1152/ajprenal.00586.2012

• renal fibrosis
• camostat mesilate
• transforming growth factor-beta(1)
• unilateral ureteral obstruction

Interstitial fibrosis is a final common pathway for the progression of chronic kidney diseases. Activated fibroblasts have an extremely important role in the progression of renal fibrosis, and transforming growth factor (TGF)-beta(1) is a major activator of fibroblasts. Since previous reports have indicated that serine protease inhibitors have a potential to inhibit TGF-beta(1) signaling in vitro, we hypothesized that a synthetic serine protease inhibitor, camostat mesilate (CM), could slow the progression of renal fibrosis. TGF-beta(1) markedly increased the phosphorylation of TGF-beta type I receptor, ERK 1/2, and Smad2/3 and the levels of profibrotic markers, such as alpha-smooth muscle actin (alpha-SMA), connective tissue growth factor (CTGF), and plasminogen activator inhibitor-1, in renal fibroblasts (NRK-49F cells), and they were all significantly reduced by CM. In protocol 1, 8-wk-old male Sprague-Dawley rats were subjected to unilateral ureteral obstruction (UUO) and were concurrently treated with a slow-release pellet of CM or vehicle for 14 days. Protocol 2 was similar to protocol 1 except that CM was administered 7 days after UUO. CM substantially improved renal fibrosis as determined by sirius red staining, collagen expression, and hydroxyproline levels. The phosphorylation of ERK1/2 and Smad2/3 and the levels of alpha-SMA, CTGF, promatrix metalloproteinase-2, and matrix metalloproteinase-2 were substantially increased by UUO, and they were all significantly attenuated by CM. These antifibrotic effects of CM were also observed in protocol 2. Our present results suggest the possibility that CM might represent a new class of therapeutic drugs for the treatment of renal fibrosis through the suppression of TGF-beta(1) signaling.

• 出版日期2013-7