Erythropoietin ameliorates podocyte injury in advanced diabetic nephropathy in thedb/dbmouse

Abstract

Podocyte damage and accumulation of advanced glycation end products (AGEs) are characteristics of diabetic nephropathy (DN). The pathophysiology of AGE-challenged podocytes, such as hypertrophy, apoptosis, and reduced cell migration, is closely related to the induction of the cell cycle inhibitor p27^Kip1and to the inhibition of neuropilin 1 (NRP1). We have previously demonstrated that treatment with erythropoietin is associated with protective effects for podocytes in vitro. db/ db mice with overt DN aged 15–16 wk were treated with either placebo, epoetin-β, or continuous erythropoietin receptor activator (CERA) for 2 wk. db/ db mice compared with nondiabetic db/ m control mice revealed the expected increases in body weight, blood glucose, albumin-to-creatinine ratio, and AGE accumulation. Whereas there were no differences in body weight, hyperglycemia and AGEs were observed among diabetic mice that received epoetin-β compared with CERA and placebo treatment, indicating that epoetin-β/CERA treatment does not interfere with the development of diabetes in this model. However, the albumin-to-creatinine ratio was significantly lower in db/ db mice treated with epoetin-β or CERA. Furthermore, kidney weights in db/ db mice were increased compared with db/ m control mice, indicating renal hypertrophy, whereas the increase in renal weight in epoetin-β- or CERA-treated db/ db mice was significantly lower than in placebo-treated control mice. Induction of p27^Kip1and suppression of NRP1 were significantly reduced in the epoetin-β treatment group versus the 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 NRP1 and p27^Kip1expressions as well as numbers of podocytes returned to normal levels. Our data show, for the first time, that medication of overt DN with erythropoietin for a short time can ameliorate albuminuria and podocyte loss.