Erythropoietin ameliorates podocyte injury in advanced diabetic

26 Podocyte damage and accumulation of advanced glycation end-products (AGEs) are 27 characteristic of diabetic nephropathy (DN). The pathophysiology of AGE-challenged 28 podocytes such as hypertrophy, apoptosis and reduced cell migration is closely 29 related to the induction of cell cycle inhibitor p27 and to the inhibition of neuropilin 30 1 (NRP1). We previously demonstrated that treatment with erythropoietin is 31 associated with protective effects for podocytes in vitro. db/db mice with overt DN 32 aged 15-16 weeks were treated with either placebo, or epoetin-β, or CERA 33 (continuous erythropoietin receptor activator) for 2 weeks. db/db mice compared with 34 non-diabetic db/m controls revealed the expected increases in body weight, blood 35 glucose, albumin-to-creatinine ratio (ACR) and AGE-accumulation. Whereas no 36 differences in body weight, hyperglycemia and AGEs were observed among the 37 diabetic groups receiving epoetin-β resp. CERA and placebo indicating that epoetin38 β /CERA treatment does not interfere with the development of diabetes in this model. 39 However, the ACR were significantly lower in db/db mice treated with epoetin-β or 40 CERA. Furthermore, kidney weights in db/db mice were increased compared with the 41 db/m controls indicating renal hypertrophy, whereas the increase in renal weight in 42 epoetin-βor CERA-treated db/db was significantly lower than in the placebo-treated 43 controls. Induction of p27 and suppression of NRP1 were significantly reduced in 44 the epoetin-β resp. CERA treatment group. Furthermore, erythropoietin treatment 45 diminished the diabetes-induced podocyte loss. Together, independently from 46 hematopoetic effects, epoetin-β or CERA treatment was associated with protective 47 changes in DN, especially that the NRP1 and p27 expressions as well as the 48 number of podocytes returned to normal level. Our data show for the first time that 49