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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.
- Source :
-
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2024 Sep 15; Vol. 38 (17), pp. e70018. - Publication Year :
- 2024
-
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 <superscript>K11,K12</superscript> , critical for AT1 receptor binding, completely abrogates the interaction with nephrin, independent of Ang II stimulation. β-Arrestin2 <superscript>K11R,K12R</superscript> 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.<br /> (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1530-6860
- Volume :
- 38
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publication Type :
- Academic Journal
- Accession number :
- 39212304
- Full Text :
- https://doi.org/10.1096/fj.202400369R