Department of Internal Medicine III, Friedrich Schiller University, Jena, Germany.
Nephron Exp Nephrol. 2011;117(1):e21-30. doi: 10.1159/000319653. Epub 2010 Aug 4.
Podocyte damage and accumulation of advanced glycation end-products (AGEs) are implicated in the development and progression of diabetic nephropathy. We have previously shown that changes in podocyte pathophysiology, such as hypertrophy and reduced migration, are closely linked with the induction of the cell cycle inhibitor p27(Kip1) and a decrease in neuropilin-1 (NRP1) expression. We investigated whether the erythropoietin receptor activators CERA and epoetin-β may prevent AGE-mediated changes in podocytes.
Differentiated mouse podocytes in culture were challenged by AGE-modified bovine serum albumin (BSA) or control BSA in the presence or absence of CERA as well as epoetin-β. Cell cycle analysis and determination of apoptosis markers were performed. p27(Kip1) and NRP1 expression was measured by RT-PCR and Western blots.
Differentiated mouse podocytes in culture expressed erythropoietin receptors which were phosphorylated after incubation with CERA or epoetin-β. CERA or epoetin-β prevented the p27(Kip1)-dependent cell cycle arrest and cellular hypertrophy induced by AGE-BSA incubation. Furthermore, the p27(Kip1)-dependent AGE-BSA-induced decrease in cell viability and decrease in cell proliferation was ameliorated in the presence of CERA or epoetin-β. Following erythropoietin treatment, AGE-BSA failed to further reduce NRP1 expression, resulting in improved podocyte migration.
Treatment with the erythropoietin receptor activators epoetin-β or CERA protected podocytes from AGE-BSA-mediated damage via an effect on p27(Kip1) and NRP1 expression. Consequently, early treatment with erythropoietin may help to prevent diabetic nephropathy.
足细胞损伤和晚期糖基化终产物（AGEs）的积累与糖尿病肾病的发生和发展有关。我们之前已经表明，足细胞病理生理学的变化，如肥大和迁移减少，与细胞周期抑制剂 p27（Kip1）的诱导和神经纤毛蛋白-1（NRP1）表达的降低密切相关。我们研究了促红细胞生成素受体激动剂 CERA 和 epoetin-β 是否可以预防 AGE 介导的足细胞变化。
在存在或不存在 CERA 以及 epoetin-β的情况下，用 AGE 修饰的牛血清白蛋白（BSA）或对照 BSA 挑战培养的分化小鼠足细胞。进行细胞周期分析和凋亡标志物测定。通过 RT-PCR 和 Western blot 测定 p27（Kip1）和 NRP1 的表达。
培养的分化小鼠足细胞表达了促红细胞生成素受体，在用 CERA 或 epoetin-β孵育后被磷酸化。CERA 或 epoetin-β 可预防 AGE-BSA 孵育诱导的 p27（Kip1）依赖性细胞周期阻滞和细胞肥大。此外，在存在 CERA 或 epoetin-β的情况下，p27（Kip1）依赖性 AGE-BSA 诱导的细胞活力降低和细胞增殖减少得到改善。在用促红细胞生成素治疗后，AGE-BSA 未能进一步降低 NRP1 的表达，从而改善了足细胞的迁移。
促红细胞生成素受体激动剂 epoetin-β或 CERA 的治疗通过对 p27（Kip1）和 NRP1 的表达的影响，保护足细胞免受 AGE-BSA 介导的损伤。因此，早期使用促红细胞生成素治疗可能有助于预防糖尿病肾病。
