Investigation of Dok1 and Dok2 as novel modulators of focal adhesion dynamics in kidney podocytes

Abstract

Podocyte adhesion to the underlying glomerular basement membrane is required for proper filtration and is mediated by dynamic signalling events. Integrins are a major component of focal adhesions, and their activity is negatively regulated by Dok1. Dok is a member of the Dok family of adaptor proteins and though its expression has been detected in podocytes, its function therein has yet to be investigated. Here, we show that expression of Dok1 and the highly related Dok2 increases in human kidney disease. Using Dok1/2 knockout mice, we demonstrate an attenuated response to podocyte injury. We further show in glomerular protein lysates that Dok1/2 knockout animals display higher surface levels of integrin β1 relative to WT controls, and that phosphorylation of focal adhesion proteins are significantly increased. Based on these findings, we conclude that Dok1/2 regulate integrin signaling in podocytes, which may have implications in adhesion and maintenance of glomerular filtration.