Dept. of Internal Medicine III, Univ. Hospital Jena, Univ. of Jena, Erlanger Allee 101, Jena D-07740, Germany.
Am J Physiol Renal Physiol. 2013 Sep 15;305(6):F911-8. doi: 10.1152/ajprenal.00643.2012. Epub 2013 Jul 3.
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.
足细胞损伤和晚期糖基化终产物 (AGEs) 的积累是糖尿病肾病 (DN) 的特征。AGE 挑战足细胞的病理生理学，如肥大、凋亡和细胞迁移减少，与细胞周期抑制剂 p27(Kip1) 的诱导和神经纤毛蛋白 1 (NRP1) 的抑制密切相关。我们之前已经证明，促红细胞生成素的治疗与体外足细胞的保护作用有关。15-16 周龄患有明显 DN 的 db/db 小鼠接受安慰剂、促红细胞生成素-β或持续促红细胞生成素受体激活剂 (CERA) 治疗 2 周。与非糖尿病 db/m 对照小鼠相比，db/db 小鼠的体重、血糖、白蛋白/肌酐比值和 AGE 积累均有预期增加。然而，与 CERA 和安慰剂治疗相比，接受促红细胞生成素-β治疗的糖尿病小鼠的体重没有差异，高血糖和 AGEs 也没有差异，表明促红细胞生成素-β/CERA 治疗不会干扰该模型中糖尿病的发展。然而，促红细胞生成素-β或 CERA 治疗的 db/db 小鼠的白蛋白/肌酐比值显著降低。此外，与 db/m 对照小鼠相比，db/db 小鼠的肾脏重量增加，表明肾肥大，而接受促红细胞生成素-β或 CERA 治疗的 db/db 小鼠的肾脏重量增加明显低于接受安慰剂治疗的对照小鼠。与 CERA 治疗组相比，促红细胞生成素-β治疗组 p27(Kip1) 的诱导和 NRP1 的抑制明显降低。此外，促红细胞生成素治疗可减少糖尿病引起的足细胞丢失。总之，促红细胞生成素-β或 CERA 治疗与 DN 的保护变化有关，特别是 NRP1 和 p27(Kip1) 的表达以及足细胞的数量恢复正常水平，这与造血作用无关。我们的数据首次表明，促红细胞生成素短期治疗明显 DN 可改善蛋白尿和足细胞丢失。
