Nishiyama Akira, Abe Youichi
Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan.
J Pharmacol Sci. 2006 Jan;100(1):9-16. doi: 10.1254/jphs.fmj05003x3. Epub 2006 Jan 6.
Recent clinical and pre-clinical studies have indicated the utility of mineralocorticoid receptor (MR) antagonists in renal injury. We have demonstrated in rats that chronic treatment with aldosterone results in severe proteinuria and renal injury, characterized by glomerular changes, tubulointerstitial fibrosis, and collagen accumulation. We also observed increased reactive oxygen species (ROS) generation and mitogen-activated protein kinases (MAPKs) activity in renal cortical tissues. Treatment with a selective MR antagonist, eplerenone, prevented elevation of ROS levels and MAPK activity, as well as ameliorating renal injury. In vitro studies revealed that MRs are highly expressed in rat glomerular mesangial cells (RMC) and rat renal fibroblasts. In RMC, aldosterone induces cellular injuries through NADPH oxidase-dependent ROS production and/or MAPK activation. Aldosterone-induced renal cellular injuries were markedly attenuated by treatment with eplerenone. These data suggest that aldosterone induces renal injury through activation of MRs and support the notion that MR blockade has beneficial effects on aldosterone-dependent renal injury through mechanisms that cannot be simply explained by hemodynamic changes. In this review, we summarized our recent findings pertaining to the roles of aldosterone and MRs in the pathogenesis of renal injury. Potential molecular mechanisms responsible for aldosterone/MR-induced renal injury were also discussed.
近期的临床和临床前研究表明，盐皮质激素受体（MR）拮抗剂在肾损伤中具有应用价值。我们在大鼠中已证实，长期使用醛固酮治疗会导致严重蛋白尿和肾损伤，其特征为肾小球改变、肾小管间质纤维化和胶原蛋白积聚。我们还观察到肾皮质组织中活性氧（ROS）生成增加以及丝裂原活化蛋白激酶（MAPK）活性增强。使用选择性MR拮抗剂依普利酮进行治疗可防止ROS水平升高和MAPK活性增强，同时改善肾损伤。体外研究显示，MR在大鼠肾小球系膜细胞（RMC）和大鼠肾成纤维细胞中高度表达。在RMC中，醛固酮通过NADPH氧化酶依赖性ROS生成和/或MAPK激活诱导细胞损伤。依普利酮治疗可显著减轻醛固酮诱导的肾细胞损伤。这些数据表明，醛固酮通过激活MR诱导肾损伤，并支持以下观点：MR阻断通过无法简单用血流动力学变化解释的机制，对醛固酮依赖性肾损伤具有有益作用。在本综述中，我们总结了我们最近关于醛固酮和MR在肾损伤发病机制中作用的研究发现。还讨论了醛固酮/MR诱导肾损伤的潜在分子机制。
