Abstract
Podocytes are specialized actin-rich epithelial cells that line the kidney glomerular filtration barrier. The interface between the pod.ocyte and the glomerular basement membrane requires integrins, and defects in either alpha(3) or beta(1) integrin, or the alpha(3)beta(1) ligand laminin result in nephrotic syndrome in murine models. The large cytoskeletal protein talinl is not only pivotal for integrin activation, but also directly links integrins to the actin cytoskeleton. Here, we found that mice lacking talinl specifically in pod.ocytes display severe proteinuria, foot process effacement, and kidney failure. Loss of talinl in pod.ocytes caused only a modest reduction in beta(1) integrin activation, pod.ocyte cell adhesion, and cell spreading; however, the actin cytoskeleton of pod.ocytes was profoundly altered by the loss of talinl. Evaluation of marine models of glomerular injury and patients with nephrotic syndrome revealed that calpain-induced talinl cleavage in pod.ocytes might promote pathogenesis of nephrotic syndrome. Furthermore, pharmacologic inhibition of calpain activity following glomerular injury substantially reduced talinl cleavage, albuminuria, and foot process effacement. Collectively, these findings indicate that pod.ocyte talinl is critical for maintaining the integrity of the glomerular filtration barrier and provide insight into the pathogenesis of nephrotic syndrome.
