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

Abstract

AbstractAlbuminuria 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.