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(Kip1) and 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(Kip1) and 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(Kip1) expressions 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.

A Possible Mechanism for Renoprotective Effect of Sodium-Glucose Cotransporter 2 Inhibitor: Elevation of Erythropoietin Production

“…Erythropoietin protected mouse podocytes from damage by advanced glycation end-products [7]. Furthermore, erythropoietin ameliorated podocyte injury in advanced diabetic nephropathy in the db/db mouse [8]. In humans, serum erythropoietin transiently increased from baseline in the dapagliflozin group up to week 4, followed by a gradual decline until week 12 [9].…”

Erythropoietin Action in Stress Response, Tissue Maintenance and Metabolism

“…EPO and leptin share some structural similarities as members of the class-I cytokine superfamily and both signal through JAK/STAT pathways. EPO treatment in db / db mice was reported to promote VEGF expression, which could stimulate angiogenesis, and improved wound healing, stimulated podocyte survival, and, particularly with low dose administration, reduced albuminuria and diabetic kidney damage [152,153,154]. EPO treatment in db / db mice was also reported to reduce damage in cardiomyopathy, inhibiting transforming growth factor-β (TGF-β) and activating AKT signaling pathways as observed in kidney, and reduce injury to insulin producing pancreatic β-cells via antiapoptotic, anti-inflammatory and angiogenic effects in the islets [154,155,156].…”

The role of hypoxia and Morg1 in renal injury

“…Several studies have demonstrated that HIF signalling protects the kidney against AKI [30,76,[78][79][80][81]. In addition, increasing evidence suggests that EPO has organ protective effects, which may be useful in the prevention of renal disease [82][83][84]. For example, renoprotective effects of EPO have been shown in IR injury via activation of the Akt/ endothelial NOS -dependent pathway and in DN via amelioration of podocyte damage [80,84].…”