Within the glomerulus, the scaffolding protein nephrin bridges the actin-rich foot processes that extend from adjacent podocytes to form the slit diaphragm. Mutations affecting a number of slit diaphragm proteins, including nephrin, cause glomerular disease through rearrangement of the actin cytoskeleton and disruption of the filtration barrier. We recently established that the Nck family of Src homology 2 (SH2)/SH3 cytoskeletal adaptor proteins can mediate nephrin-dependent actin reorganization. Formation of foot processes requires expression of Nck in developing podocytes, but it is unknown whether Nck maintains podocyte structure and function throughout life. Here, we used an inducible transgenic strategy to delete Nck expression in adult mouse podocytes and found that loss of Nck expression rapidly led to proteinuria, glomerulosclerosis, and altered morphology of foot processes. We also found that podocyte injury reduced phosphorylation of nephrin in adult kidneys. These data suggest that Nck is required to maintain adult podocytes and that phosphotyrosine-based interactions with nephrin may occur in foot processes of resting, mature podocytes. 20: 153320: -154320: , 200920: . doi: 10.1681 Podocytes are unique epithelial cells within the kidney glomerulus that comprise the outermost layer of the blood filtration barrier. 1 Upon differentiation, podocytes extend numerous actin-based foot processes from their cell bodies that interdigitate and surround the glomerular capillary wall. At the interface of adjacent foot processes, a specialized intercellular junction known as the slit diaphragm is formed. The slit diaphragm apparently contributes to the morphology of foot processes through physical connection to the underlying actin cytoskeleton, as mutations affecting numerous slit diaphragm-associated proteins lead to actin rearrangement and foot process effacement. 2 In addition to genetic alterations, injury to podocytes as a consequence of diseases such as diabetes and hypertension as well as inflammation may also result in impaired slit diaphragm filtration leading to loss of protein in the urine (proteinuria) and subsequent renal failure. 3 Nephrin, encoded by NPHS1, is a transmembrane protein of the Ig superfamily that forms a key structural component of the slit diaphragm. Nephrin also functions as an intracellular signaling scaffold to recruit proteins such as podocin and CD2AP J Am Soc Nephrol