ARP3 Controls the Podocyte Architecture at the Kidney Filtration Barrier

• Published in: Developmental cell 2018-12, Vol.47 (6), p.741-757.e8
• Main Authors: Schell, Christoph, Sabass, Benedikt, Helmstaedter, Martin, Geist, Felix, Abed, Ahmed, Yasuda-Yamahara, Mako, Sigle, August, Maier, Jasmin I., Grahammer, Florian, Siegerist, Florian, Artelt, Nadine, Endlich, Nicole, Kerjaschki, Dontscho, Arnold, Hans-Henning, Dengjel, Jörn, Rogg, Manuel, Huber, Tobias B.
• Format: Article
• Language: English
• Subjects: Actin Cytoskeleton - metabolism; actin networks; Actin-Related Protein 3 - metabolism; Actin-Related Protein 3 - physiology; Actins - metabolism; actomyosin; Actomyosin - metabolism; Animals; Arp2/3; Cell Adhesion; cell process generation; focal adhesion; Focal Adhesions - metabolism; glomerular epithelial cells; Glomerular Filtration Barrier - metabolism; Glomerular Filtration Barrier - physiology; Humans; Kidney - metabolism; Kidney - physiology; kidney filtration barrier; Mice; Mice, Knockout; N-WASP; podocytes; Podocytes - metabolism; Podocytes - physiology; Signal Transduction; Wiskott-Aldrich Syndrome Protein, Neuronal - metabolism
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2018.11.011

Podocytes, highly specialized epithelial cells, build the outer part of the kidney filtration barrier and withstand high mechanical forces through a complex network of cellular protrusions. Here, we show that Arp2/3-dependent actin polymerization controls actomyosin contractility and focal adhesion maturation of podocyte protrusions and thereby regulates formation, maintenance, and capacity to adapt to mechanical requirements of the filtration barrier. We find that N-WASP-Arp2/3 define the development of complex arborized podocyte protrusions in vitro and in vivo. Loss of dendritic actin networks results in a pronounced activation of the actomyosin cytoskeleton and the generation of over-maturated but less efficient adhesion, leading to detachment of podocytes. Our data provide a model to explain podocyte protrusion morphology and their mechanical stability based on a tripartite relationship between actin polymerization, contractility, and adhesion. [Display omitted] •ARP3-dependent actin assembly is required for podocyte process formation•Arp2/3 thereby links process formation, podocyte adhesion and mechano-adaptation•Arp2/3 function is regulated by a reciprocal interplay with actomyosin Glomerular podocytes maintain the kidney filtration barrier. Schell et al. show that the Arp2/3 machinery is required for podocyte process formation and adaptation to filtration barrier mechanical requirements via reciprocal interplay with the actomyosin network. Dendritic actin network loss results in actomyosin cytoskeleton activation and decreased adhesion, leading to podocyte detachment.