The antifibrotic effect of a serine protease inhibitor in the kidney

• Published in: American journal of physiology. Renal physiology 2013-07, Vol.305 (2), p.F173-F181
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Cells; Chemokine CCL2 - metabolism; Fibroblasts - metabolism; Gabexate - analogs & derivatives; Gabexate - pharmacology; Gabexate - therapeutic use; Kidney diseases; Macrophages - drug effects; Nephrosclerosis - etiology; Nephrosclerosis - metabolism; Nephrosclerosis - therapy; Phosphorylation; Phosphorylation - drug effects; Protease inhibitors; Rats; Rats, Sprague-Dawley; Rodents; Serine Proteinase Inhibitors - pharmacology; Serine Proteinase Inhibitors - therapeutic use; Tissues; Transforming Growth Factor beta1 - metabolism; Tumor Necrosis Factor-alpha - metabolism; Ureteral Obstruction - complications
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00586.2012

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)-β₁ is a major activator of fibroblasts. Since previous reports have indicated that serine protease inhibitors have a potential to inhibit TGF-β₁ signaling in vitro, we hypothesized that a synthetic serine protease inhibitor, camostat mesilate (CM), could slow the progression of renal fibrosis. TGF-β₁ markedly increased the phosphorylation of TGF-β type I receptor, ERK 1/2, and Smad2/3 and the levels of profibrotic markers, such as α-smooth muscle actin (α-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 α-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-β₁ signaling.