Wang Ziying, Wei Xinbing, Zhang Yan, Ma Xuelian, Li Boqin, Zhang Shuya, Du Pengchao, Zhang Xiumei, Yi Fan
Department of Pharmacology, Shandong University School of Medicine, Jinan, PR China.
Cell Physiol Biochem. 2009;24(5-6):619-26. doi: 10.1159/000257517. Epub 2009 Nov 4.
Recent studies have demonstrated upregulation of transient receptor potential cation channel 6 (TRPC6) contributes to podocyte injury in acquired forms of proteinuric kidney diseases, such as focal segmental glomerulosclerosis (FSGS). However, under these pathophysiological conditions, the mechanisms of regulation of TRPC6 expression and activity remain unknown. The present study tested the hypothesis that NADPH oxidase-mediated redox signaling importantly participates in the development of podocyte injury by regulation of TRPC6 expression and activity. Injection of puromycin aminonucleoside (PAN) to rats produced severe proteinuria and mimics the lesions of FSGS. Podocyte effacement, NADPH oxidase subunit NOX4 expression, enzyme activity and TRPC6 expression were significant increased in glomeruli from PAN nephrosis rats. Inhibition of NADPH oxidase activity by apocynin ameliorated proteinuria and podocyte effacement and reduced TRPC6 expression. In in vitro study, PAN significantly increased NOX4 and TRPC6 expression levels in cultured podocytes. This increased TRPC6 expression was attenuated by apocynin or siRNA-NOX4. Our results provide direct evidence for the first time that NADPH oxidase-derived reactive oxygen species (ROS) is one of critical components of a signal transduction pathway that links PAN nephrosis to TRPC6-mediated Ca(2+) signaling.
近期研究表明，瞬时受体电位阳离子通道6（TRPC6）的上调促成了诸如局灶节段性肾小球硬化症（FSGS）等获得性蛋白尿性肾病中足细胞的损伤。然而，在这些病理生理条件下，TRPC6表达及活性的调控机制仍不清楚。本研究检验了以下假设：NADPH氧化酶介导的氧化还原信号通过调控TRPC6的表达及活性，在足细胞损伤的发展过程中起重要作用。给大鼠注射嘌呤霉素氨基核苷（PAN）可导致严重蛋白尿，并模拟FSGS的病变。PAN肾病大鼠肾小球中的足细胞足突消失、NADPH氧化酶亚基NOX4表达、酶活性及TRPC6表达均显著增加。阿朴吗啡抑制NADPH氧化酶活性可改善蛋白尿和足细胞足突消失，并降低TRPC6表达。在体外研究中，PAN显著增加了培养的足细胞中NOX4和TRPC6的表达水平。阿朴吗啡或siRNA-NOX4可减弱这种TRPC6表达的增加。我们的结果首次提供了直接证据，表明NADPH氧化酶衍生的活性氧（ROS）是将PAN肾病与TRPC6介导的Ca（2+）信号联系起来的信号转导途径的关键组成部分之一。
