Abstract: Objective To investigate the potential mechanism of urine albumin reduction by the application of tacrolimus in rats with type 2diabetic mellitus（T2DM）. Methods The T2 DM rat models were established by feeding them with high fat and high sugar food for 8weeks combining with the intraperitoneal injection of low-dose streptozotocin. These model rats were randomly selected and then divided into the diabetic mellitus group（DM group,n=10）and FK506 treatment group（FK group,n=10）. The normal control group（n=10）was also established.The rats in the FK group were exposed to FK506 by intragastric administration for 8weeks,while the rats in the DM group and the normal control group were given the same amount of citrate buffer solution by intragastric administration for 8 weeks. Kidney hypertrophy index（kidney mass/body mass,KM/BM）,systolic blood pressure,24-hour urinary albumin/urine creatinine,fasting blood glucose,endogenous creatinine clearance rate（CCr）,total cholesterol,triglyceride,alanine transaminase（ALT）,aspartate aminotransferase（AST）and white blood cells were determined before and after the intervention in all groups. Renal pathological changes were observed by light and electron microscopy,nephrin protein expression was detected by immunohistochemical method,and the podocyte apoptosis was observed by TUNEL assay. The expression of cleaved-caspase-3and the ratio of bax/bcl-2 were detected by Western blot. Results Compared with the normal control group,KM/BM,systolic blood pressure,fasting blood glucose,CCr,total cholesterol,triglyceride and urinary albumin/urine creatinine in the DM group were significantly increased（P＜0.05）. Compared with the DM group,KM/BM and urinary albumin/urine creatinine were decreased in FK group（P＜0.05）,while there were no significant differences in systolic blood pressure,fasting blood glucose,CCr,ALT,AST and white blood cells between these two groups. While the increased glomerular volume,mesangial cell proliferation and thickened basement membrane were observed by light microscopy in the DM group,these aboved pathological changes were markedly attenuated in the FK group. Under an electron microscope,the glomerular basement membrane was significantly thickened,and foot processes were in disorder and the fusion rate was significantly increased in the DM group compared to the normal control group（73.50±3.60）% vs（4.20±1.91）%,P＜0.05. Compared to the DM group,these aboved pathological changes of FK group attenuated,and the fusion rate was decreased significantly（33.80±1.93）% vs（73.50±3.60）%,P＜0.05. Immunohistochemical assay showed that the expression of nephrin protein was significantly decreased in the DM group compared with the normal control group,which was increased after treatment with FK506（P＜0.05）. TUNEL assay showed that the number of podocyte apoptosis was significantly increased in the DM group compared with the normal control group（P＜0.05）,which was significantly decreased after treatment with FK506（P＜0.05）. Western blot showed that the expression of cleaved-caspase-3and the ratio of bax to bcl-2increased in the DM group when was compared with the normal control group（P＜0.05）,which were significantly decreased in the FK group（P＜0.05）. Conclusion Tacrolimus could reduce urine albumin and delay the progression of nephropathy by reducing podocyte apoptosis in T2 DM rats.