Objective To investigate whether umbilical cord mesenchymal stem cells (UC-MSCs) can exert kidney protection in diabetes rats through regulating autophagy. Methods Type 2 diabetes rats model was induced by a high-fat diet combined with a low dosage of streptozotocin (STZ) intraperitoneal injection. After successful modeling, those rats were fed with a high-fat diet for another eight weeks, and the control group (10) was given a normal chow diet. The treatment group (MSCs group, 10) was infused UC-MSCs (3x106 suspended in 0.5 ml PBS) via tail vein once every two weeks, for a total of eight weeks of treatment. The diabetes control group (T2DM group, 10) was infused 0.5 ml PBS solution via tail vein and the control group did not receive any treatment at the same time. Random blood glucose and body weight were monitored every two weeks. One week after the fourth treatment, intraperitoneal glucose tolerance test (IPGTT) was performed in all rats, and later on they were sacrificed and their kidneys were collected for histopathological examinations and autophagy-related protein examinations. Data was measured using two independent sample mean t tests, one-way ANOVA and repeated measures analysis of variance. Results Compared to T2DM group, random blood glucose decreased [(23.9±3.7) vs (28.7±2.1) mmol/L, t=3.568, P<0.01], and glucose tolerance improved (t=3.07-6.64, P<0.01) in MSCs group. The pathological results showed that in the MSCs group the degree of glomerular sclerosis was reduced (P<0.01, t=17.28), the glomerular basement membrane thickening was relieved (P<0.01, t=12.00),and the degree of renal interstitial fibrosis was improved (P<0.01, t=2.83-17.28). Examinations of autophagy-related proteins showed that the MSCs group exhibited increased expression of LC3[(78.3±5.3)% vs(33.4±8.3)%,t=10.22, P<0.01] and reduced expression of P62[(24.1±4.2)% vs (93.3±4.9)%, t=24.13, P<0.01],which indicated that the level of autophagy in rat kidneys were significantly increased after MSCs infusion. Conclusion UC-MSCs therapy has the function of kidney protection and delay the development of diabetic nephropathy, which may be related to the enhancement of autophagy in renal tissues. [ABSTRACT FROM AUTHOR]