Description:
<jats:p>Alteration of podocyte behavior is critically involved in the development and progression of many 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 <jats:italic toggle="yes">in vivo</jats:italic>. 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 <jats:italic toggle="yes">in vitro</jats:italic> coimmunoprecipitation experiments, we identified Rho GDP-dissociation inhibitor <jats:italic toggle="yes">α</jats:italic> (RhoGDI<jats:italic toggle="yes">α</jats:italic>) as a Kindlin-2–associated protein. Loss of Kindlin-2 in podocytes significantly reduced the expression of RhoGDI<jats:italic toggle="yes">α</jats:italic> and resulted in the dissociation of Rac1 from RhoGDI<jats:italic toggle="yes">α</jats:italic>, leading to Rac1 hyperactivation and increased motility of podocytes. Inhibition of Rac1 activation effectively suppressed podocyte motility and alleviated the podocyte defects and proteinuria induced by the loss of Kindlin-2 <jats:italic toggle="yes">in vivo</jats:italic>. Our results identify a novel Kindlin-2–RhoGDI<jats:italic toggle="yes">α</jats:italic>–Rac1 signaling axis that is critical for regulation of podocyte structure and function <jats:italic toggle="yes">in vivo</jats:italic> and provide evidence that it may serve as a useful target for therapeutic control of podocyte injury and associated glomerular diseases.</jats:p>