Significance MAGUK Inverted 2 (MAGI-2) is a scaffold protein with a putative tumor-suppressor role and also interacts with nephrin in the glomerular slit diaphragm protein complex. To gain insight into its function, we generated Magi-2 –KO mice and found that loss of MAGI-2 expression leads to slit diaphragm disruption, podocyte foot process effacement, and severe podocyte loss. Magi-2 –null mice develop rapidly progressive glomerular disease and renal failure. Our findings suggest that MAGI-2 is essential for kidney filter function and podocyte survival, thereby providing insights into the pathogenesis of proteinuric kidney disease. Moreover, Magi-2 –null mice can serve as an excellent model system for studying glomerular disease progression and identification of new treatment targets for the difficult-to-treat spectrum of primary podocytopathies.