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Objective To explore potential mechanisms involved in the reduction of podocyte apoptosis and oxidative stress induced by high glucose (HG) by tanshinone ⅡA (Tan ⅡA). Methods CCK-8 method was used to screen the appropriate interference concentration of Tan ⅡA. The MPC-5 cells were divided into NC group (5.5 mmol/L D-glucose), MA group(5.5 mmol/L D-glucose and 22.5 mmol/L mannitol), HG group(25 mmol/L D-glucose), HG+Tan ⅡA group(25 mmol/L D-glucose and 10 μmol/L Tan ⅡA), and HG+Tan ⅡA+SIRT1 inhibitors(sirtinol) group (25 mmol/L D-glucose, 10 μmol/L Tan ⅡA and 20 μmol/L sirtinol). Determina- tion of oxidative stress markers malondialdehyde(MDA), superoxide dismutase (SOD) and catalase (CAT) were made by microplate method, WST-1 method and visible light method. Flow cytometry was used to measure cell apoptosis. Western blot was used to evaluate the expression of apoptosis-related proteins and silent information regulator 1 (SIRT1)/endothelial nitric oxide synthase (eNOS) pathway proteins. Results Tan ⅡA improved the viability of MPC-5 cells induced by HG (P＜0.05). Compared with the MA group, the level of cell apoptosis in the HG group increased, the expression of B-cell lymphoma-2 gene (Bcl-2), phosphorylated SIRT1 (p-SIRT1) and phosphorylated eNOS(p-eNOS) in the cells, and the activity of SOD and of CAT were reduced, the expression of Bcl-2-associated X protein (Bax) and cleaved caspase-3, and the content of MDA in cells were increased(P＜0.05). Compared with the HG group, the level of cell apoptosis in the Tan ⅡA group reduced, the expressions of Bcl-2, p-SIRT1 and p-eNOS in the cells, and the activity of SOD and CAT were increased, the expression of Bax and cleaved caspase-3, and the content of MDA in cells were reduced(P＜0.05). The SIRT1 inhibitor sirtinol attenuated the inhibitory effect of Tan ⅡA on HG-induced podocyte apoptosis and oxidative stress (P＜0.05). Conclusions Tan ⅡA may reduce HG-induced apoptosis and oxidative stress in podocytes with a potential mechanism of activating the SIRT1/eNOS pathway.