1. 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.
- Author
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Königshausen E, Zierhut UM, Ruetze M, Rump LC, and Sellin L
- Subjects
- Animals, Humans, MAP Kinase Signaling System drug effects, Angiotensin II Type 1 Receptor Blockers pharmacology, Mice, Albuminuria metabolism, Podocytes metabolism, Podocytes drug effects, Mitogen-Activated Protein Kinase 3 metabolism, Mitogen-Activated Protein Kinase 3 genetics, Biphenyl Compounds pharmacology, Irbesartan pharmacology, HEK293 Cells, beta-Arrestin 2 metabolism, beta-Arrestin 2 genetics, Benzimidazoles, Tetrazoles, Endocytosis drug effects, Endocytosis physiology, Membrane Proteins metabolism, Membrane Proteins genetics, Angiotensin II pharmacology, Angiotensin II metabolism, Receptor, Angiotensin, Type 1 metabolism, Receptor, Angiotensin, Type 1 genetics
- 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-Arrestin2
K11,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., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)- Published
- 2024
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