Effect of a serine protease inhibitor on the progression of chronic renal failure

• Published in: American journal of physiology. Renal physiology 2012-10, Vol.303 (8), p.F1126-F1135
• Main Authors: Hayata, Manabu, Kakizoe, Yutaka, Uchimura, Kohei, Morinaga, Jun, Yamazoe, Rika, Mizumoto, Teruhiko, Onoue, Tomoaki, Ueda, Miki, Shiraishi, Naoki, Adachi, Masataka, Miyoshi, Taku, Sakai, Yoshiki, Tomita, Kimio, Kitamura, Kenichiro
• Format: Article
• Language: English
• Subjects: Animals; Creatinine - blood; Disease Progression; Gabexate - analogs & derivatives; Gabexate - pharmacology; Gabexate - therapeutic use; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidney diseases; Kidney Failure, Chronic - drug therapy; Kidney Failure, Chronic - metabolism; Kidney Failure, Chronic - pathology; Male; Membrane Proteins - metabolism; Microfilament Proteins - metabolism; Nephrectomy; Oxidative stress; Oxidative Stress - drug effects; Proteins; Proteinuria - drug therapy; Proteinuria - metabolism; Proteinuria - pathology; Rats; Rats, Sprague-Dawley; Ribonucleic acid; Risk factors; RNA; Rodents; Serine Proteinase Inhibitors - pharmacology; Serine Proteinase Inhibitors - therapeutic use; Treatment Outcome
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00706.2011

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.