BACKGROUND: Studies have confirmed that the occurrence and development of diabetic nephropathy are related to tubular epithelial cell transdifferentiation and renal interstitial fibrosis. OBJECTIVE: To investigate the protective effect of erythropoietin preconditioned adipose-derived mesenchymal stem cells on diabetic nephropathy rat's kidney and to evaluate its potential mechanisms. METHODS: Human adipose-derived mesenchymal stem cells were harvested and identified for cell multilineage differentiation. TranswelI migration system was used to observe the effects of erythropoietin of different concentrations (0, 5, 20, 50 IU/mL) on the migration of adipose-derived mesenchymal stem cells to high glucose-induced rat renal tubular epithelial cell lines. Forty-eight Sprague-Dawley rats (provided by the Animal Experimental Center of Xuzhou Medical University in China) were randomly divided into normal control, diabetic model group, cell transplantation group and erythropoietin preconditioning group (n=12 per group). Adipose-derived mesenchymal stem cells (3.5×105, 150 μL) alone or erythropoietin (20 IU/mL) preconditioned adipose-derived mesenchymal stem cells were injected into the tail vein of rats in the latter two groups, respectively. The protein levels of transforming growth β1, α-smooth muscle actin, E-cadherin, matrix metalloproteinase-9 and matrix metalloproteinase inhibitor-1 in the renal tissues were detected by western blot assay at 14 weeks after cell transplantation. RESULTS AND CONCLUSION: Erythropoietin preconditioning markedly increased the number of migrated adipose-derived mesenchymal stem cells in a concentration-dependent manner (P < 0.05) , and the ability peaked at a concentration of 20 IU/ml. The expression of stromal cell-derived factor-1 protein in NRK-52 E cells was consistent with the migration trend of adipose-derived mesenchymal stem cells. Compared with the diabetic model group, the levels of transforming growth β1, α-smooth muscle actin, and matrix metalloproteinase inhibitor-1 were increased dramatically, while the levels of E-cadherin and matrix metalloproteinase-9 decreased remarkably in the other groups (P < 0.05) , especially in erythropoietin preconditioning group (P < 0.05). In conclusion, erythropoietin could promote the directional chemotaxis of adipose-derived mesenchymal stem cells, and moreover, adipose-derived mesenchymal stem cells could inhibit the transdifferentiation of renal tubular epithelial cells, reduce the deposition of extracellular matrix and delay the progression of diabetic renal fibrosis under the action of erythropoietin.