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The anti-fibrotic effect of a serine protease inhibitor in the kidney.

Authors: Morinaga, J  Kakizoe, Y  Miyoshi, T  Onoue, T  Ueda, M  Mizumoto, T  Yamazoe, R  Uchimura, K  Hayata, M  Shiraishi, N  Adachi, M  Sakai, Y  Tomita, K  Kitamura, K 
Citation: Morinaga J, etal., Am J Physiol Renal Physiol. 2013 May 22.
Pubmed: (View Article at PubMed) PMID:23698112
DOI: Full-text: 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)-beta1 is a major activator of fibroblasts. Since previous reports indicate that serine protease inhibitors have a potential to inhibit TGF-beta1 signaling in vitro, we hypothesized that a synthetic serine protease inhibitor, camostat mesilate (CM), could slow the progression of renal fibrosis. TGF-beta1 markedly increased the phosphorylation of TGF-beta type I receptor (TbetaIR), ERK 1/2 and smad2/3, and the levels of pro-fibrotic markers, such as alphaSMA, CTGF, and PAI-1, in renal fibroblast (NRK-49F cells), and they were all significantly reduced by CM. In protocol 1, eight-week-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 the renal fibrosis that was determined by sirius red staining, collagen expression, and hydroxyproline levels. The phosphorylation of ERK1/2 and smad2/3, and the levels of alphaSMA, CTGF, proMMP-2, and MMP-2 were substantially increased by UUO, and they were all significantly attenuated by CM. These anti-fibrotic effects of CM were also observed in protocol 2. Our current results suggest the possibility that CM might represent a new class of therapeutic drugs for the treatment of renal fibrosis through the suppression of the TGF-beta1 signaling.

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CRRD Object Information
CRRD ID: 7244171
Created: 2013-05-24
Species: All species
Last Modified: 2013-05-24
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.