N-wasp is required for stabilization of podocyte foot processes

TY - JOUR

T1 - N-wasp is required for stabilization of podocyte foot processes

AU - Schell, Christoph

AU - Baumhakl, Lisa

AU - Salou, Sarah

AU - Conzelmann, Ann-Christin

AU - Meyer, Charlotte

AU - Helmstädter, Martin

AU - Wrede, Christoph

AU - Grahammer, Florian

AU - Eimer, Stefan

AU - Kerjaschki, Dontscho

AU - Walz, Gerd

AU - Snapper, Scott

AU - Huber, Tobias B

PY - 2013/4

Y1 - 2013/4

N2 - Alteration of cortical actin structures is the common final pathway leading to podocyte foot process effacement and proteinuria. The molecular mechanisms that safeguard podocyte foot process architecture and maintain the three-dimensional actin network remain elusive. Here, we demonstrate that neuronal Wiskott-Aldrich syndrome protein (N-WASP), which promotes actin nucleation, is required to stabilize podocyte foot processes. Mice lacking N-WASP specifically in podocytes were born with normal kidney function but developed significant proteinuria 3 weeks after birth, suggesting an important role for N-WASP in maintaining foot processes. In addition, inducing deletion of N-WASP in adult mice resulted in severe proteinuria and kidney failure. Electron microscopy showed an accumulation of electron-dense patches of actin and strikingly altered morphology of podocyte foot processes. Although basic actin-based processes such as cell migration were not affected, primary cultures of N-WASP-deficient podocytes revealed significant impairment of dynamic actin reorganization events, including the formation of circular dorsal ruffles. Taken together, our findings suggest that N-WASP-mediated actin nucleation of branched microfilament networks is specifically required for the maintenance of foot processes, presumably sustaining the mechanical resistance of the filtration barrier.

AB - Alteration of cortical actin structures is the common final pathway leading to podocyte foot process effacement and proteinuria. The molecular mechanisms that safeguard podocyte foot process architecture and maintain the three-dimensional actin network remain elusive. Here, we demonstrate that neuronal Wiskott-Aldrich syndrome protein (N-WASP), which promotes actin nucleation, is required to stabilize podocyte foot processes. Mice lacking N-WASP specifically in podocytes were born with normal kidney function but developed significant proteinuria 3 weeks after birth, suggesting an important role for N-WASP in maintaining foot processes. In addition, inducing deletion of N-WASP in adult mice resulted in severe proteinuria and kidney failure. Electron microscopy showed an accumulation of electron-dense patches of actin and strikingly altered morphology of podocyte foot processes. Although basic actin-based processes such as cell migration were not affected, primary cultures of N-WASP-deficient podocytes revealed significant impairment of dynamic actin reorganization events, including the formation of circular dorsal ruffles. Taken together, our findings suggest that N-WASP-mediated actin nucleation of branched microfilament networks is specifically required for the maintenance of foot processes, presumably sustaining the mechanical resistance of the filtration barrier.

KW - Actin Cytoskeleton

KW - Actins

KW - Animals

KW - Cells, Cultured

KW - Mice

KW - Mice, Knockout

KW - Podocytes

KW - Wiskott-Aldrich Syndrome Protein, Neuronal

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1681/ASN.2012080844

DO - 10.1681/ASN.2012080844

M3 - SCORING: Journal article

C2 - 23471198

VL - 24

SP - 713

EP - 721

JO - J AM SOC NEPHROL

JF - J AM SOC NEPHROL

SN - 1046-6673

IS - 5

ER -