title: N-wasp is required for stabilization of podocyte foot processes.
abstract: 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.
authors.affiliation: Renal Division, University Hospital Freiburg, Breisacher Str. 66, 79106 Freiburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schell
authors.forename: Lisa
authors.initials: L
authors.lastname: Baumhakl
authors.forename: Sarah
authors.initials: S
authors.lastname: Salou
authors.forename: Ann-Christin
authors.initials: AC
authors.lastname: Conzelmann
authors.forename: Charlotte
authors.initials: C
authors.lastname: Meyer
authors.forename: Martin
authors.initials: M
authors.lastname: Helmstädter
authors.forename: Christoph
authors.initials: C
authors.lastname: Wrede
authors.forename: Florian
authors.initials: F
authors.lastname: Grahammer
authors.forename: Stefan
authors.initials: S
authors.lastname: Eimer
authors.forename: Dontscho
authors.initials: D
authors.lastname: Kerjaschki
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
authors.forename: Scott
authors.initials: S
authors.lastname: Snapper
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
mesh_terms: D008841:Actin Cytoskeleton / Q000737:chemistry; D000199:Actins / Q000737:chemistry; D000818:Animals; D002478:Cells, Cultured; D051379:Mice; D018345:Mice, Knockout; D050199:Podocytes / Q000737:chemistry / Q000502:physiology* / Q000648:ultrastructure; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000032:analysis / Q000502:physiology*
chemical_list: D000199:Actins; C495772:Wasl protein, mouse; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal