We report the following: (i) Pod-Vcl-KO mice develop proteinuria upon challenge; (ii) defects in podocyte cell protrusion/foot process morphology occur in Pod-Vcl-KO mice; (iii) altered adhesion signaling with impaired FAK phosphorylation occurs in Pod-Vcl-KO podocytes; (iv) disrupted intercellular junctions with mislocalization of the key junctional protein ZO-1 are detected in Pod-Vcl-KO podocytes; and (v) analysis of human kidney sections revealed that vinculin localization is altered in glomeruli of FSGS, MCD, and MN samples, compared with control samples. The gene discussed is VCL; the disease is focal segmental glomerulosclerosis.