In the present study, Sestrin2 overexpression or TSP-1 blockade effectively inhibited HG-induced activation of TGF-β1/Smad3 pathway in podocytes, and Pirfenidone, a TGF-β/Smad inhibitor, mitigated HG-induced podocyte injury, indicating that Sestrin2 inhibits podocyte phenotypic alterations and podocyte apoptosis by modulating the activation of TSP-1/TGF-β1/Smad3 pathway in DKD. The gene discussed is SMAD3; the disease is diabetic kidney disease.