Podocyte damage and accumulation of advanced glycation end-products (AGEs) are characteristic of diabetic nephropathy (DN). The pathophysiology of AGE-challenged podocytes is closely related to the induction of cell cycle inhibitor p27^Kip1 and to the inhibition of neuropilin 1 (NRP1). We previously demonstrated that treatment with erythropoietin is associated with protective effects for podocytes in vitro. db/db mice with overt DN aged 15-16 weeks were treated with either placebo, or epoetin-β, or CERA (continuous erythropoietin receptor activator) for 2 weeks. db/db mice compared with non-diabetic db/m controls revealed the expected increases in body weight, blood glucose, albumin-to-creatinine ratio (ACR) and AGE-accumulation. Whereas no differences in body weight, hyperglycemia and AGEs were observed among the diabetic groups receiving epoetin-β resp, The ACR were significantly lower in db/db mice treated with epoetin-β or CERA. Furthermore, kidney weights in db/db mice were increased compared with the db/m controls indicating renal hypertrophy, whereas the increase in renal weight in epoetin-β- or CERA-treated db/db was significantly lower than in the placebo-treated controls. Induction of p27^Kip1 and suppression of NRP1 were significantly reduced in the epoetin-β resp. CERA treatment group. Furthermore, erythropoietin treatment diminished the diabetes-induced podocyte loss. Together, independently from hematopoetic effects, epoetin-β or CERA treatment was associated with protective changes in DN, especially that the NRP1 and p27Kip1 expressions as well as the number of podocytes returned to normal level. Our data show for the first time that medication of overt DN with erythropoietin for a short time can ameliorate albuminuria and podocyte loss.