Li Zhao-Dong, Bork Jens Peter, Krueger Bettina, Patsenker Eleonora, Schulze-Krebs Anja, Hahn Eckhart G, Schuppan Detlef
Department of Medicine I, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
Biochem Biophys Res Commun. 2005 Sep 9;334(4):1049-60. doi: 10.1016/j.bbrc.2005.07.005.
The role of glomerular endothelial cells in kidney fibrosis remains incompletely understood. While endothelia are indispensable for repair of acute damage, they can produce extracellular matrix proteins and profibrogenic cytokines that promote fibrogenesis. We used a murine cell line with all features of glomerular endothelial cells (glEND.2), which dissected the effects of vascular endothelial growth factor (VEGF) on cell migration, proliferation, and profibrogenic cytokine production. VEGF dose-dependently induced glEND.2 cell migration and proliferation, accompanied by up-regulation of VEGFR-2 phosphorylation and mRNA expression. VEGF induced a profibrogenic gene expression profile, including up-regulation of TGF-beta1 mRNA, enhanced TGF-beta1 secretion, and bioactivity. VEGF-induced endothelial cell migration and TGF-beta1 induction were mediated by the phosphatidyl-inositol-3 kinase pathway, while proliferation was dependent on the Erk1/2 MAP kinase pathway. This suggests that differential modulation of glomerular angiogenesis by selective inhibition of the two identified VEGF-induced signaling pathways could be a therapeutic approach to treat kidney fibrosis.
肾小球内皮细胞在肾纤维化中的作用仍未完全明确。虽然内皮细胞对于急性损伤的修复不可或缺，但它们可产生促进纤维化的细胞外基质蛋白和促纤维化细胞因子。我们使用了具有肾小球内皮细胞所有特征的小鼠细胞系（glEND.2），以剖析血管内皮生长因子（VEGF）对细胞迁移、增殖和促纤维化细胞因子产生的影响。VEGF以剂量依赖方式诱导glEND.2细胞迁移和增殖，同时伴有VEGFR-2磷酸化和mRNA表达上调。VEGF诱导了促纤维化基因表达谱，包括TGF-β1 mRNA上调、TGF-β1分泌增加及生物活性增强。VEGF诱导的内皮细胞迁移和TGF-β1诱导由磷脂酰肌醇-3激酶途径介导，而增殖则依赖于Erk1/2丝裂原活化蛋白激酶途径。这表明，通过选择性抑制两个已确定的VEGF诱导信号通路来差异调节肾小球血管生成可能是治疗肾纤维化的一种治疗方法。
