A molecular mechanism for angiotensin II receptor blocker-mediated slit membrane protection: Angiotensin II increases nephrin endocytosis via AT1-receptor-dependent ERK 1/2 activation
Eva Königshausen, Ulf M. Zierhut, Martin Ruetze, Lars C. Rump, Lorenz Sellin
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引用次数: 0
Abstract
Albuminuria is characterized by a disruption of the glomerular filtration barrier, which is composed of the fenestrated endothelium, the glomerular basement membrane, and the slit diaphragm. Nephrin is a major component of the slit diaphragm. Apart from hemodynamic effects, Ang II enhances albuminuria by β-Arrestin2-mediated nephrin endocytosis. Blocking the AT1 receptor with candesartan and irbesartan reduces the Ang II-mediated nephrin-β-Arrestin2 interaction. The inhibition of MAPK ERK 1/2 blocks Ang II-enhanced nephrin-β-Arrestin2 binding. ERK 1/2 signaling, which follows AT1 receptor activation, is mediated by G-protein signaling, EGFR transactivation, and β-Arrestin2 recruitment. A mutant AT1 receptor defective in EGFR transactivation and β-Arrestin2 recruitment reduces the Ang II-mediated increase in nephrin β-Arrestin2 binding. The mutation of β-Arrestin2K11,K12, critical for AT1 receptor binding, completely abrogates the interaction with nephrin, independent of Ang II stimulation. β-Arrestin2K11R,K12R does not influence nephrin cell surface expression. The data presented here deepen our molecular understanding of a blood-pressure-independent molecular mechanism of AT-1 receptor blockers (ARBs) in reducing albuminuria.
血管紧张素 II 受体阻滞剂介导裂隙膜保护的分子机制:血管紧张素 II 通过 AT1 受体依赖性 ERK 1/2 激活增加肾素内吞
肾小球滤过屏障由栅栏状内皮、肾小球基底膜和裂隙隔膜组成,白蛋白尿的特征是肾小球滤过屏障遭到破坏。肾素是裂隙隔膜的主要组成部分。除了血流动力学效应外,Ang II 还会通过 β-Arrestin2 介导的肾素内吞作用增加白蛋白尿。用坎地沙坦和厄贝沙坦阻断 AT1 受体可减少 Ang II 介导的肾素-β-阿restin2 相互作用。抑制 MAPK ERK 1/2可阻止 Ang II 增强的肾素-β-阿瑞斯汀2结合。AT1 受体激活后的 ERK 1/2 信号传导是由 G 蛋白信号传导、表皮生长因子受体转录激活和 β-Arrestin2 招募介导的。在表皮生长因子受体反式激活和 β-Arrestin2 招募方面存在缺陷的突变 AT1 受体可减少 Ang II 介导的肾素 β-Arrestin2 结合的增加。对 AT1 受体结合至关重要的 β-Arrestin2K11,K12 基因突变会完全终止与肾素的相互作用,与 Ang II 的刺激无关。β-Arrestin2K11R,K12R 不影响肾素细胞表面的表达。本文提供的数据加深了我们对AT-1受体阻滞剂(ARBs)降低白蛋白尿的不依赖于血压的分子机制的理解。
期刊介绍:
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