TNFα and SOCS3 regulate IRS-1 to increase retinal endothelial cell apoptosis.
TNFα and SOCS3 regulate IRS-1 to increase retinal endothelial cell apoptosis.
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TNFα和SOCS3调节IRS-1以增加视网膜内皮细胞凋亡。
DOI：
10.1016/j.cellsig.2012.01.003
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发表时间：
2012-05
影响因子：
4.8
通讯作者：
Steinle JJ
中科院分区：
文献类型：
--
作者：
Jiang Y;Zhang Q;Soderland C;Steinle JJ
糖尿病的发病率正在达到流行水平。1型和2型糖尿病的关键问题都是胰岛素信号转导功能障碍，这要么是由于分泌不足，要么是由于胰岛素敏感性受损。在动物模型中，糖尿病视网膜病变的一个关键特征是退行性毛细血管形成。本研究的目的是探讨高血糖引起视网膜内皮细胞凋亡的可能机制。该假说认为高血糖诱导的肿瘤坏死因子α通过抑制胰岛素信号转导导致视网膜内皮细胞凋亡。为了验证这一假设，原代培养的人视网膜内皮细胞在正常葡萄糖(5 MM)或高糖(25 MM)中培养，并用外源性肿瘤坏死因子α、肿瘤坏死因子αsiRNA或细胞因子信号转导抑制物3(SOCS3siRNA)处理。细胞裂解产物进行Western blotting和ELISA分析，以验证肿瘤坏死因子α和SOCS3基因敲除，以及关键的促和抗凋亡因子IRS-1和Akt。数据表明，高糖培养条件显著提高了肿瘤坏死因子α和SOCS3蛋白水平。敲除肿瘤坏死因子α和SOCS3显著增加了抗凋亡蛋白，而减少了促凋亡蛋白。下调肿瘤坏死因子α导致胰岛素受体-1Ser307的磷酸化水平降低，从而促进正常的胰岛素信号转导。SOCS3基因敲除后，总IRS-1水平升高，IRTyr960降低，两者均通过增加胰岛素信号转导途径抑制视网膜内皮细胞的凋亡。综上所述，我们的研究结果表明，增加的肿瘤坏死因子α通过两种方式抑制胰岛素信号转导：1)增加胰岛素受体1Ser307的磷酸化；2)增加SOCS3水平以降低总胰岛素受体1和增加胰岛素受体960，两者均阻断正常的胰岛素信号转导。解决高血糖诱导的视网膜内皮细胞肿瘤坏死因子α水平可能通过解除对胰岛素受体信号转导的抑制来防止细胞凋亡。
Rates of diabetes are reaching epidemic levels. The key problem in both type 1 and type 2 diabetes is dysfunctional insulin signaling, either due to lack of production or due to impaired insulin sensitivity. A key feature of diabetic retinopathy in animal models is degenerate capillary formation. The goal of this present study was to investigate a potential mechanism for retinal endothelial cell apoptosis in response to hyperglycemia. The hypothesis was that hyperglycemia-induced TNFα leads to retinal endothelial cell apoptosis through inhibition of insulin signaling. To test the hypothesis, primary human retinal endothelial cells were grown in normal glucose (5 mM) or high glucose (25 mM) and treated with exogenous TNFα, TNFα siRNA or suppressor of cytokine signaling 3 (SOCS3) siRNA. Cell lysates were processed for Western blotting and ELISA analyses to verify TNFα and SOCS3 knockdown, as well as key pro- and anti-apoptotic factors, IRS-1, and Akt. Data indicate that high glucose culturing conditions significantly increase TNFα and SOCS3 protein levels. Knockdown of TNFα and SOCS3 significantly increases anti-apoptotic proteins, while decreasing pro-apoptotic proteins. Knockdown of TNFα leads to decreased phosphorylation of IRS-1Ser307, which would promote normal insulin signaling. Knockdown of SOCS3 increased total IRS-1 levels, as well as decreased IRTyr960, both of which would inhibit retinal endothelial cell apoptosis through increased insulin signaling. Taken together, our findings suggest that increased TNFα inhibits insulin signaling in 2 ways: 1) increased phosphorylation of IRS-1Ser307, 2) increased SOCS3 levels to decrease total IRS-1 and increase IRTyr960, both of which block normal insulin signal transduction. Resolution of the hyperglycemia-induced TNFα levels in retinal endothelial cells may prevent apoptosis through disinhibition of insulin receptor signaling.
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影响因子：
15.9
作者：
Mizutani, M;Kern, TS;Lorenzi, M
通讯作者：
Lorenzi, M
影响因子：
15.9
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