Effect of a serine protease inhibitor on the progression of chronic renal failure
Effect of a serine protease inhibitor on the progression of chronic renal failure
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DOI：
10.1152/ajprenal.00706.2011
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发表时间：
2012-10-01
影响因子：
4.2
通讯作者：
Kitamura, Kenichiro
中科院分区：
文献类型：
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作者：
Hayata, Manabu;Kakizoe, Yutaka;Kitamura, Kenichiro
Hayata M，Kakizoe Y，Uchimura K，Morinaga J，Yamazoe R，Mizumoto T，Onoue T，Ueda M，Shiraishi N，Adachi M，Miyoshi T，Sakai Y，Tomita K，Kitamura K。丝氨酸蛋白酶抑制剂对慢性肾功能衰竭进展的影响。 Am J Physiol Renal Physiol 303：F1126-F1135，2012。首次发表于 2012 年 7 月 25 日； doi:10.1152/ajprenal.00706.2011.-慢性肾衰竭（CRF）患者的数量呈爆炸式增长。高血压、蛋白尿、炎症、纤维化和氧化应激以复杂的方式交织在一起，导致 CRF 的进展。然而，延缓其进展的治疗策略是有限的。由于丝氨酸蛋白酶参与了导致这些危险因素的许多过程，因此我们研究了合成丝氨酸蛋白酶抑制剂甲磺酸卡莫司他 (CM) 对 5/6 肾切除 (Nx) 大鼠 CRF 进展的影响。将 18 只雄性 Sprague-Dawley 大鼠分为三组：假手术组 (n = 6)、载体治疗的 Nx 组 (n = 6) 和 CM 治疗的 Nx 组 (n = 6)。在 9 周的研究期之后，媒介物治疗的 Nx 组的蛋白尿和血清肌酐水平均显着增加，而 CM 治疗则显着降低了蛋白尿和血清肌酐水平。 5/6 肾切除术显着降低了肾小球中足细胞相关蛋白的水平，例如去氧肾上腺素和突触蛋白，而 CM 则显着改善了这种情况。 CM 还抑制炎症和纤维化标志物 mRNA 的水平，包括转化生长因子-β 1、TNF-α、I、III 和 IV 型胶原蛋白，并在组织学研究中减少肾小球硬化、肾小球肥大和间质纤维化。此外，CM 降低了 NADPH 氧化酶成分 mRNA 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 可能成为对抗 CRF 进展的有用治疗剂。
Hayata M, Kakizoe Y, Uchimura K, Morinaga J, Yamazoe R, Mizumoto T, Onoue T, Ueda M, Shiraishi N, Adachi M, Miyoshi T, Sakai Y, Tomita K, Kitamura K. Effect of a serine protease inhibitor on the progression of chronic renal failure. Am J Physiol Renal Physiol 303: F1126-F1135, 2012. First published July 25, 2012; 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-beta 1, TNF-alpha, 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.