Kindlin-2 association with rho GDP-dissociation inhibitor a suppresses rac1 activation and podocyte injury

Abstract

Alteration of podocyte behavior is critically involved in the development and progression ofmany forms of human glomerular diseases. The molecular mechanisms that control podocyte behavior, however, are not well understood. Here, we investigated the role of Kindlin-2, a component of cell-matrix adhesions, in podocyte behavior in vivo. Ablation of Kindlin-2 in podocytes resulted in alteration of actin cytoskeletal organization, reduction of the levels of slit diaphragm proteins, effacement of podocyte foot processes, and ultimately massive proteinuria and death due to kidney failure. Through proteomic analyses and in vitro coimmunoprecipitation experiments, we identified Rho GDP-dissociation inhibitor a (RhoGDIa) as a Kindlin-2-associated protein. Loss of Kindlin-2 in podocytes significantly reduced the expression of RhoGDIa and resulted in the dissociation of Rac1 from RhoGDIa, leading to Rac1 hyperactivation and increasedmotility of podocytes. Inhibition of Rac1 activation effectively suppressed podocytemotility and alleviated the podocyte defects and proteinuria induced by the loss of Kindlin-2 in vivo. Our results identify a novel Kindlin-2-RhoGDIa-Rac1 signaling axis that is critical for regulation of podocyte structure and function in vivo and provide evidence that it may serve as a useful target for therapeutic control of podocyte injury and associated glomerular diseases.