Objective To investigate the effects of Zuogui Jiangtang Yishen decoction (ZGJTYS) on the expression of nephrin and podocin in podocyte of MKR mice with diabetic nephropathy (DN), and explore its mechanism. Methods Forty MKR mice (8 weeks old) were randomly divided into four groups as follows:negative control group (group A), DN model group (group B), ZGJTYS group (group C) and positive control group (group D, Gliquidone and benazepri). All mice from group B, C and D were received high-fat diet feed and unilateral nephrectomy. Four weeks after operation, all mice were received drug intervention, and four weeks later, all mice were put to death. The levels of UmAlb were observed by ELISA, the serum BUN and Cr by biochemical, and the FBG by electrochemical detection method. The nephrin and podocin mRNA expression were measured by RT-PCR and the protein expression by western blotting. The morphological structure changes of the podocytes were observed by transmission electron microscopes. Results As compared with group A, FBG, BUN, SCr and urine UmAlb in the mice of group B increased significantly (P<0.01), the expression level of nephrin and podocin mRNA and protein were markedly decreased (P<0.01). After intervention of drugs, all biochemical indicators above in the mice of group C and D significantly decreased (P<0.01), the expression level of nephrin and podocin mRNA and protein were markedly increased (P<0.01, P<0.05), compared with group B. The renal pathological lesions of group C and D were significantly improved compared with group B. Conclusion ZGJTYS decoction exerts reno-protective effect via reinstating nephrin and podocin expression to repair the damaged podocyte.