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.

GAPVD1 and ANKFY1 Mutations Implicate RAB5 Regulation in Nephrotic Syndrome

“…79 From these findings we derived a hypothetic working model (shown in Supplemental Figure 10). In line with previous reports, [43][44][45][46][47][48]51,80,81 our data thus underscore the importance of the endocytic pathway for nephrin trafficking. This pathway may further be involved in the delivery of nephrin to the slit diaphragm and/or slit diaphragm maintenance by endocytic turnover.…”

“…A role of endocytosis for podocyte biology has previously been proposed: The slit diaphragm protein nephrin is subject to endocytosis utilizing different branches of the endocytosis pathway. [43][44][45][46][47][48] In mice, phosphoinositide 3-kinases 49,50 and effectors of vesicular fission and clathrin uncoating are essential for the glomerular filtration barrier. Knockout of the murine isoforms of dynamin, synaptojanin, or endophilin each resulted in severe proteinuria.…”

ShcA Adaptor Protein Promotes Nephrin Endocytosis and Is Upregulated in Proteinuric Nephropathies

“…10 Loss of Y1217 phosphorylation (and thus nephrin-Nck binding) was recently reported to induce b-arrestin binding to nephrin and subsequent endocytosis. 36 By contrast, phosphorylation of Y1193 increases during PSinduced damage and declines again during recovery. 10,34 It is therefore tempting to speculate that in the prolonged PAN model, the rise in Y1193 (and Y1217) phosphorylation could promote recruitment of ShcA, and trigger a parallel switch-like mechanism to sustain clathrin-dependent removal of nephrin from the cell surface.…”

Is the kidney a target of SARS-CoV-2?

“…If a F1457 SARS-CoV-2 AFFECTS KIDNEY CELLS pathological process increases glomerular levels of angiotensin II, podocytes acquire a dysfunctional phenotype mediated by cellular responses to this octapeptide due to shear stress and resulting in single nephron hyperfiltration. This phenotype involves Ca 2ϩ signaling, cytoskeleton restructure, and nephrin internalization, which finally is manifested by proteinuria (38,65). The actual tropism of SARS-CoV-2 to podocytes has been recently determined, and it is reasonable to hypothesize that proteinuria is a partial consequence of direct podocyte infection with potential RAAS alterations, which together would affect the glomerular filtration barrier and result in increased filtration of plasmatic proteins.…”