Protective Role of Insulin-Like Growth Factor-1 Receptor in Endothelial Cells against Unilateral Ureteral Obstruction-Induced Renal Fibrosis
Protective Role of Insulin-Like Growth Factor-1 Receptor in Endothelial Cells against Unilateral Ureteral Obstruction-Induced Renal Fibrosis
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DOI：
10.1016/j.ajpath.2015.01.027
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发表时间：
2015-05-01
影响因子：
6
通讯作者：
Cheng, Jizhong
中科院分区：
文献类型：
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作者：
Liang, Ming;Woodard, Lauren E.;Cheng, Jizhong
胰岛素样生长因子-1 受体 (IGF-1R) 可以调节血管稳态和内皮功能。我们研究了 IGF-1R 在氧化应激诱导的内皮功能障碍中的作用。在野生型 (WT) 小鼠和内皮细胞 (EC) 特异性 IGF-1R 敲除 (KO) 小鼠中进行单侧输尿管梗阻 (UUO)。内皮 IGF-1R KO 小鼠 UUO 后，内皮屏障功能障碍比 WT 小鼠更严重，如炎症细胞浸润增加和血管内皮 (VE) 钙粘蛋白磷酸化增加所示。与 WT 小鼠相比，内皮 IGF-1R KO 小鼠中的 UUO 增加了间质成纤维细胞的积累并增强了细胞外蛋白沉积。通过响应过氧化氢 (H2O2) 的跨内皮迁移测量内皮屏障功能在 EC 中受损。沉默 IGF-1R 增强了 H2O2 在破坏 VE 蛋白酪氨酸磷酸酶/VE-钙粘蛋白相互作用方面的影响。 IGF-1R 的过度表达抑制 H2O2 诱导的内皮屏障功能障碍。此外，通过使用piggyBac转座子系统，我们在小鼠的VE细胞中表达IGF-1R。 ECs中IGF-1R的表达也抑制了UUO诱导的炎症细胞浸润和肾纤维化。与对照小鼠相比，骨髓细胞VE-钙粘蛋白谱系中的IGF-1R KO对UUO诱导的纤维化没有显着影响。我们的结果表明，内皮细胞中的 IGF-1R 通过稳定 VE 蛋白酪氨酸磷酸酶/VE-钙粘蛋白复合物来维持内皮屏障功能。 IGF-1R 表达减少会损害内皮功能并增加肾脏疾病的纤维化。
Insulin-Like growth factor-1 receptor (IGF-1R) can regulate vascular homeostasis and endothelial function. We studied the role of IGF-1R in oxidative stress induced endothelial dysfunction. Unilateral ureteral obstruction (UUO) was performed in wild-type (WT) mice and mice with endothelial cell (EC) specific IGF-1R knockout (KO). After UUO in endothelial IGF-1R KO mice, endothelial barrier dysfunction was more severe than in WT mice, as seen by increased inflammatory cell infiltration and vascular endothelial (VE) cadherin phosphorylation. UUO in endothelial IGF-1R KO mice increased interstitial fibroblast accumulation and enhanced extracellular protein deposition as compared with the WT mice. Endothelial barrier function measured by transendothelial migration in response to hydrogen peroxide (H2O2) was impaired in ECs. Silencing IGF-1R enhanced the influence of H2O2 in disrupting the VE protein tyrosine phosphatase/VE-cadherin interaction. Overexpression of IGF-1R suppressed H2O2-induced endothelial barrier dysfunction. Furthermore, by using the piggyBac transposon system, we expressed IGF-1R in VE cells in mice. The expression of IGF-1R in ECs also suppressed the inflammatory cell infiltration and renal fibrosis induced by UUO. IGF-1R KO in the VE-cadherin Lineage of bone marrow cells had no significant effect on the UUO-induced fibrosis, as compared with control mice. Our results indicate that IGF-1R in the endothelium maintains the endothelial barrier function by stabilization of the VE protein tyrosine phosphatase/VE-cadherin complex. Decreased expression of IGF-1R impairs endothelial function and increases the fibrosis of kidney disease.