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

Abstract

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.

Membrane-anchored Serine Protease Matriptase Is a Trigger of Pulmonary Fibrogenesis

“…CM has successfully been used in experimental models of liver, pancreatic, and renal fibrosis (36)(37)(38), and the antifibrogenic effects of CM were attributable (at least partly) to reduced TGF-b expression and signaling. So far, CM efficiency had never been assessed in pulmonary fibrosis, and our results are consistent with these findings.…”

“…However, CM treatment in the present study was delayed and so is unlikely to interfere with the course of events triggered by bleomycin immediately after its delivery. Moreover, CM is efficient in the abovementioned experimental models of fibrosis affecting other organs, where fibrosis was induced by the administration of different agents (36,37,39,40), surgical procedures (38,41), or even spontaneously (42). Third, the collagen content might be overestimated in the Sircol assay (43).…”

The Serine Protease Inhibitor Camostat Mesilate Attenuates the Progression of Chronic Kidney Disease through its Antioxidant Effects

“…The fibrotic area was measured as the percentage of blue collagen staining in the tubulointerstitum with the exception of the tubular lumens and vessel walls using the Hybrid Cell Count image analysis (Keyence All-in-One Microscope BZ-X700, Osaka, Japan). To detect the ROS production in the kidney, frozen sections were incubated with DHE as previously described [7]. The images were obtained by an Olympus BX50 with BH2-RFL-T3 (Olympus, Tokyo, Japan).…”

“…Oxidative stress underlies as a common pathogenic component and accelerates the disease progression and complications [4,5,6]. Previously, we demonstrated that camostat mesilate (CM), an orally active synthetic serine protease inhibitor, has renoprotective effects in 5/6 nephrectomized rats [7]. CM showed an antioxidant effect and an antifibrotic effect in the remnant kidney, which resulted in the improvement of the renal function.…”

“…Oxidative stress is regulated by the balance between pro-oxidant and antioxidant systems. CM suppressed the expression of NADPH oxidase components, which comprise the main source of ROS production [7]. However, the effect of CM on the antioxidant system such as free scavenging activity is poorly understood.…”