Podocyte injury and loss contribute to progressive glomerulosclerosis. Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear hormone receptor, which we have found to be increased in podocytes in a variety of kidney diseases. It is not known if PPAR-γ contributes to renal injury or if it serves as a countermeasure to limit renal injury during disease progression. We tested these possibilities utilizing the puromycin aminonucleoside (PAN) model of renal injury in immortalized mouse podocytes. The cultured podocytes expressed PPAR-γ mRNA at baseline but this was decreased by PAN. Pioglitazone, a pharmacologic agonist of PPAR-γ, increased both PPAR-γ mRNA and activity in injured podocytes, as assessed by a reporter plasmid assay. Further, pioglitazone significantly decreased PAN-induced podocyte apoptosis and necrosis while restoring podocyte differentiation. The PPAR-γ agonist significantly restored expression of the cyclin-dependent kinase inhibitor p27 and the antiapoptotic molecule Bcl-xL while significantly decreasing proapoptotic caspase-3 activity. Pioglitazone tended to decrease PAN-induced transforming growth factor-β (TGF-β) mRNA expression. Our study shows that PPAR-γ is normally expressed by podocytes and its activation is protective against PAN-induced apoptosis and necrosis. We postulate that this protective effect may be mediated in part by effects on p27 and TGF-β expression.