Podocytes are highly differentiated cells that have a complex cytoskeletal architecture. They extend numerous protrusions — primary processes and terminally branched protrusions called secondary (or foot) processes — which interdigitate and anchor the podocyte to the glomerular basement membrane. Appropriate formation of podocyte processes is critical for the functioning of the glomerular filtration barrier; however, the pathways underlying podocyte process formation are unclear. New research has identified a key role for the N-WASP–ARP2–ARP3 axis in regulating podocyte morphology. “Analyses revealed that ARP3 has an important role in the development of secondary processes,” say Christoph Schell, Manuel Rogg and Tobias B. Huber. “Combining these findings with primary podocyte culture systems helped us to identify a central role for actomyosin machinery in podocyte foot process development and showed that ARP3 is also involved in controlling the adhesion and mechanoadaptation of podocytes.”

On the basis of the hypothesis that the adhesion machinery of podocytes is in tight interplay with cytoskeletal components, Schell and colleagues used a proteomics approach to identify involvement of N-WASP–ARP2–ARP3 — a complex that is involved in the nucleation and assembly of branched actin networks — in both biological processes. To assess the relevance of N-WASP–ARP2–ARP3-generated actin networks to podocyte development, the researchers used a series of conditional knockout mouse models and primary podocyte culture systems to show that loss of either N-WASP or ARP3 disturbed the development of podocyte foot processes. Cells deficient in Arp3 showed distorted focal adhesions characterized by a hypermaturated, plaque-like appearance, associated with overactivation of actomyosin machinery and increased inherent tension. These cells were also unable to adapt to mechanical stress, promoting podocyte detachment. “We can now more precisely describe the events leading to foot process effacement,” says Huber. “We aim to assess how this understanding can be used to predict and halt podocyte cytoskeletal alterations in glomerular diseases.”