title: Angiotensin II increases glomerular permeability by β-arrestin mediated nephrin endocytosis.
abstract: Glomerular permeability and subsequent albuminuria are early clinical markers for glomerular injury in hypertensive nephropathy. Albuminuria predicts mortality and cardiovascular morbidity. AT1 receptor blockers protect from albuminuria, cardiovascular morbidity and mortality. A blood pressure independent, molecular mechanism for angiotensin II (Ang II) dependent albuminuria has long been postulated. Albuminuria results from a defective glomerular filter. Nephrin is a major structural component of the glomerular slit diaphragm and its endocytosis is mediated by β-arrestin2. Ang II stimulation increases nephrin-β-arrestin2 binding, nephrin endocytosis and glomerular permeability in mice. This Ang II effect is mediated by AT1-receptors. AT1-receptor mutants identified G-protein signaling to be essential for this Ang II effect. Gαq knockdown and phospholipase C inhibition block Ang II mediated enhanced nephrin endocytosis. Nephrin Y1217 is the critical residue controlling nephrin binding to β-arrestin under Ang II stimulation. Nephrin Y1217 also mediates cytoskeletal anchoring to actin via nck2. Ang II stimulation decreases nephrin nck2 binding. We conclude that Ang II weakens the structural integrity of the slit diaphragm by increased nephrin endocytosis and decreased nephrin binding to nck2, which leads to increased glomerular permeability. This novel molecular mechanism of Ang II supports the use of AT1-receptor blockers to prevent albuminuria even in normotensives.
authors.affiliation: Nephrology, Medical School Duesseldorf, Heinrich Heine University, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Königshausen
authors.affiliation: Nephrology, Medical School Duesseldorf, Heinrich Heine University, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Ulf M
authors.initials: UM
authors.lastname: Zierhut
authors.affiliation: Nephrology, Medical School Duesseldorf, Heinrich Heine University, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Ruetze
authors.affiliation: Nephrology, Medical School Duesseldorf, Heinrich Heine University, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Potthoff
authors.affiliation: Nephrology, Medical School Duesseldorf, Heinrich Heine University, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Stegbauer
authors.affiliation: Nephrology, Medical School Duesseldorf, Heinrich Heine University, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Woznowski
authors.affiliation: Nephrology, Medical School Duesseldorf, Heinrich Heine University, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Ivo
authors.initials: I
authors.lastname: Quack
authors.affiliation: Nephrology, Medical School Duesseldorf, Heinrich Heine University, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Lars C
authors.initials: LC
authors.lastname: Rump
authors.affiliation: Nephrology, Medical School Duesseldorf, Heinrich Heine University, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Sellin
mesh_terms: D000419:Albuminuria / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D019921:Biotinylation; D001794:Blood Pressure; D003599:Cytoskeleton / Q000378:metabolism; D004705:Endocytosis; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D010539:Permeability; D050199:Podocytes / Q000166:cytology; D011485:Protein Binding; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071557:beta-Arrestins / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D000071557:beta-Arrestins; C113267:nephrin; D000804:Angiotensin II; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins