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.