Dept. of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, Japan.
Am J Physiol Renal Physiol. 2012 Oct 15;303(8):F1126-35. doi: 10.1152/ajprenal.00706.2011. Epub 2012 Jul 25.
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.
慢性肾衰竭（CRF）患者的数量正在呈爆炸式增长。高血压、蛋白尿、炎症、纤维化和氧化应激以复杂的方式相互交织，导致 CRF 的进展。然而，延缓其进展的治疗策略有限。由于丝氨酸蛋白酶参与导致这些危险因素的许多过程，我们研究了一种合成丝氨酸蛋白酶抑制剂卡莫司他（CM）对 5/6 肾切除（Nx）大鼠 CRF 进展的影响。18 只雄性 Sprague-Dawley 大鼠分为三组：假手术组（n = 6）、 vehicle 处理的 Nx 组（n = 6）和 CM 处理的 Nx 组（n = 6）。在 9 周的研究期间，vehicle 处理的 Nx 组的蛋白尿和血清肌酐水平显著升高，而 CM 治疗显著降低了蛋白尿和血清肌酐水平。肾小球中足细胞相关蛋白，如nephrin 和 synaptopodin 的水平因 5/6 肾切除而显著降低，CM 显著改善了这一点。CM 还抑制了包括转化生长因子-β1、TNF-α、胶原类型 I、III 和 IV 在内的炎症和纤维化标志物 mRNAs 的水平，并在组织学研究中减少了肾小球硬化、肾小球肥大和间质纤维化。此外，CM 降低了 NADPH 氧化酶成分 mRNAs 的表达以及活性氧的产生和高级氧化蛋白产物水平。我们目前的结果强烈表明，CM 可能是一种对抗 CRF 进展的有用治疗剂。
