Contribution of TNF receptor 1 to retinal neural cell death induced by elevated glucose
Contribution of TNF receptor 1 to retinal neural cell death induced by elevated glucose
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DOI：
10.1016/j.mcn.2012.04.003
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发表时间：
2012-05-01
影响因子：
3.5
通讯作者：
Santos, P. F.
中科院分区：
文献类型：
--
作者：
Costa, G. N.;Vindeirinho, J.;Santos, P. F.
糖尿病视网膜病变 (DR) 是工作年龄成年人视力丧失和失明的主要原因，具有多种炎症性疾病的特征。神经视网膜细胞死亡的增加是糖尿病视网膜的早期事件，发生在微血管细胞损失之前。由于肿瘤坏死因子-α (TNF-α) 已被证明会引发周细胞和内皮细胞的死亡以及血-视网膜屏障的破坏，因此我们着手研究 TNF-α 通过肿瘤坏死因子受体 1 (TNFR1)（负责介导 TNF 诱导的细胞死亡的主要受体）发挥作用，是否也可能是 DR 中观察到的早期神经元细胞死亡的原因。我们使用暴露于高葡萄糖条件下的视网膜神经细胞培养物来模拟高血糖，并评估 TNFR1 在神经细胞死亡中的作用。人们发现 TNFR1 在很大程度上存在于视网膜神经元中，并且这种受体的水平在高葡萄糖条件下培养的细胞中发生了改变。高葡萄糖诱导细胞活力早期下降、细胞凋亡增加以及裂解的 caspase-3 的免疫反应性更高，表明高葡萄糖诱导 caspase 依赖性细胞死亡。这些观察结果与 TNF-α 表达的增加相关。尽管如此，抑制 TNFR1 的激活足以防止细胞活力下降和细胞凋亡导致的视网膜细胞死亡增加。总之，我们的数据表明，TNF-α 通过 TNFR1 发挥作用，是高葡萄糖诱导的细胞死亡的原因，而阻断该受体的活性是避免这种情况下细胞损失的充分策略。 (c) 2012 Elsevier Inc. 保留所有权利。
Diabetic retinopathy (DR), a leading cause of vision loss and blindness among working-age adults, holds several hallmarks of an inflammatory disease. The increase in cell death in neural retina is an early event in the diabetic retina, preceding the loss of microvascular cells. Since tumor necrosis factor-alpha (TNF-alpha) has been shown to trigger the death of perycites and endothelial cells as well as the breakdown of the blood-retinal barrier, we set out to investigate whether TNF-alpha acting through tumor necrosis factor receptor 1 (TNFR1), the major receptor responsible for mediating TNF-induced cell death, could also be responsible for the early neuronal cell death observed in DR. We used retinal neural cell cultures exposed to high glucose conditions, to mimic hyperglycaemia, and evaluated the contribution of TNFR1 in neural cell death. TNFR1 was found to be present to a great extent in retinal neurons and the levels of this receptor were found to be altered in cells cultured in high glucose conditions. High glucose induced an early decrease in cell viability, an increase in apoptosis and a higher immunoreactivity for the cleaved caspase-3, indicating a high glucose-induced caspase-dependent cell death. These observations were correlated with an increase in TNF-alpha expression. Nonetheless, inhibiting the activation of TNFR1 was sufficient to prevent the decrease in cell viability and the increase in retinal cell death by apoptosis. In conclusion, our data indicate that TNF-alpha acting through TNFR1 is responsible for the high glucose-induced cell death and that blocking the activity of this receptor is an adequate strategy to avoid cell loss in such conditions. (c) 2012 Elsevier Inc. All rights reserved.