WNK1 Kinase Activity Is Required for the Functional Maintenance of Podocyte Structure

Abstract

The filtration function of glomeruli requires slit diaphragms formed by interdigitating podocyte foot processes, which are actin-based membrane protrusions. Failure in the maintenance of these cytoskeletal structures leads to foot process effacement, proteinuria, and progression to chronic kidney disease. We report WNK1 kinase activity is required for normal glomerular function in vivo and test the hypothesis that WNK1 kinase activity affects the structure of podocyte foot processes through modulation of actomyosin activity and focal adhesion complexes. Perturbation of cytoskeletal structure and focal adhesion signalosomes with WNK1 kinase inhibition supports a role for WNK1 in the maintenance of podocyte foot processes and sarcomere-like structures (SLSs) that are induced in models of podocyte injury. Applicability of WNK1 kinase activity modulation toward treatment of podocyte injury was assessed using primary and immortalized podocyte cell lines developed from control and Col4a3^-/- Alport Syndrome model mice. Collectively, the results provide compelling evidence that WNK1 kinase signalosome activity, which includes regulation of nascent focal adhesion formation and NMII activity at membrane protrusions and extensions, is necessary for physiological maintenance of slit diaphragms.

Keywords: Alport syndrome; NMII; WNK1; actomyosin; cytoskeleton; podocytes; vinculin.