Objective To investigate the effect of early injection of umbilical cord mesenchymal stem cells (UC-MSCs)on the progression of diabetic nephropathy (DN) in type 2 diabetes mellitus (T2DM) mice and its mechanism. Methods Twenty 5-week-old male db/db mice were used to establish T2DM model and randomly divided into stem cell treatment group(MSCs group, n=10) and T2DM group (DM group, n=10); In addition, age-matched db/m mice were set as normal control group(NC group, n=10). Human UC-MSCs (1×10⁶/0.2 ml saline) were infused into the tail vein of mice in MSCs group for 6 weeks,while the same volume of saline was infused into the tail vein of mice in NC and T2DM groups once a week for 6 consecutive times. Blood glucose and body weight of mice in each group were monitored weekly. At the end of the sixth treatment, the mice in each group were killed by heart perfusion, and the blood and kidney tissues were collected for biochemical and histopathological examination. Western blotting was used to detect the expression of silent information regulator 2 homolog 1 (SIRT1) and Claudin-1,and immunohistochemistry was used to detect the expression of SIRT1, Claudin-1, type 1 collagen (Col Ⅰ) and Col Ⅳ. The morphology of glomeruli was observed by electron microscope. HK-2 cells in logarithmic growth phase were divided into control group, high glucose induced model group (HG group), high glucose induced siRNA group (HG+siRNA group), MSC groups(HG+MSC group) and SIRT-1 siRNA group (HG+MSC+siRNA group). The expression levels of apoptosis-related proteins were detected by Western blotting. Results After the sixth treatment, compared with NC group [(7.66±0.37) mmol/L], the levels of blood glucose increased significantly (P<0.01) in T2DM group and MSCS group [(32.54±0.36) mmol/L, (29.74±1.04)respectively]; Compared with T2DM group, the level of blood glucose in MSCs group decreased significantly (P<0.05).Pathological results showed that compared with NC group, glomerular sclerosis, diffuse thickening of basement membrane and renal interstitial fibrosis were significantly increased in T2DM group; compared with T2DM group, glomerular sclerosis, deposition of mesangial extracellular matrix and renal interstitial fibrosis were alleviated in MSCs group. The results of Western blotting and immunohistochemistry showed that compared with T2DM group, the expression level of SIRT1 protein in MSCs group increased significantly (P<0.01), the expression of Claudin-1 protein decreased significantly (P<0.01), and of α-smooth muscle actin (α-SMA)protein decreased significantly in MSCs group (P<0.05). In addition, the immunohistochemical results showed that the percentage of Col Ⅰ and Col Ⅳ positive area in MSCs group was significantly lower than that in T2DM group (P<0.01). Compared with NC group, T2DM group showed marked destruction of glomerular filtration barrier, diffuse thickening of basement membrane, and extensive fusion and disappearance of foot processes. Compared with T2DM group, the structure of glomerular foot process in MSCs group was regular and complete. Western blotting results showed that SIRT-1 protein content was significantly lower in HG group than that in control group (P<0.01), while apoptosis-related Cytochrome-C protein contents were significantly higher in HG group than that in control group (P<0.01). Compared with HG group, the protein content of SIRT-1 in HG+MSC group was significantly higher (P<0.01), and the content of apoptosis-related Bax and Cytochrome-C protein decreased significantly (P<0.01).Compared with HG+MSC group, the protein content of SIRT-1 in HG+MSC+siRNA group was significantly decreased (P<0.01),while the protein content of apoptosis-related Bax and Cytochrome-C increased significantly (P<0.01). Conclusion UC-MSCs treatment may play a protective role for kidney of T2DM mice and delay the development of DN by up-regulating the expression of SIRT1 and down-regulating the expression of Claudin-1.