Oxidative stress-mediated TXNIP loss causes RPE dysfunction
Oxidative stress-mediated TXNIP loss causes RPE dysfunction
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DOI：
10.1038/s12276-019-0327-y
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发表时间：
2019-10-15
影响因子：
12.8
通讯作者：
Min, Jeong-Ki
中科院分区：
文献类型：
--
作者：
Cho, Min Ji;Yoon, Sung-Jin;Min, Jeong-Ki
例如，由于氧化损伤，视网膜色素上皮(RPE)的破坏是老年性黄斑变性(AMD)的常见因素。自噬的异常也有助于AMD的病理，因为自噬维持RPE的动态平衡，以确保血-视网膜屏障(BRB)的完整性，并保护光感受器。硫氧还蛋白相互作用蛋白(TXNIP)通过抑制硫氧还蛋白还原能力促进细胞氧化应激，并反过来受活性氧水平的反向调节；然而，它在氧化应激诱导的RPE细胞功能障碍中的作用以及TXNIP与自噬之间的机制联系在很大程度上是未知的。在这里，我们观察到在氧化应激下，RPE细胞中TXNIP的表达迅速下调，RPE细胞的增殖减少。TXNIP基因敲除表明，TXNIP耗竭诱导的自噬通量抑制了细胞的增殖，通过核定位增加了P53的激活，进而增强了AMPK的磷酸化和激活。此外，TXNIP下调还破坏了RPE细胞的紧密连接，并通过磷酸化从而激活了Src激酶，从而增强了细胞的运动性，从而进一步负面影响了BRB的完整性。最后，我们还发现，TXNIP基因敲除上调了HIF-1α，导致RPE细胞分泌VEGF的增加，并刺激了共培养的人视网膜微血管内皮细胞的血管生成。这表明RPE细胞暴露在持续的氧化应激下可能促进脉络膜新生血管，这是AMD的另一种病理。综上所述，这些发现揭示了TXNIP下调扰乱RPE细胞功能从而加重AMD发病的三种不同机制。因此，通过靶向TXNIP来加强或恢复BRB的完整性可能是预防或减轻AMD光感受器损伤的有效治疗策略。
The disruption of the retinal pigment epithelium (RPE), for example, through oxidative damage, is a common factor underlying age-related macular degeneration (AMD). Aberrant autophagy also contributes to AMD pathology, as autophagy maintains RPE homeostasis to ensure blood-retinal barrier (BRB) integrity and protect photoreceptors. Thioredoxin-interacting protein (TXNIP) promotes cellular oxidative stress by inhibiting thioredoxin reducing capacity and is in turn inversely regulated by reactive oxygen species levels; however, its role in oxidative stress-induced RPE cell dysfunction and the mechanistic link between TXNIP and autophagy are largely unknown. Here, we observed that TXNIP expression was rapidly downregulated in RPE cells under oxidative stress and that RPE cell proliferation was decreased. TXNIP knockdown demonstrated that the suppression of proliferation resulted from TXNIP depletion-induced autophagic flux, causing increased p53 activation via nuclear localization, which in turn enhanced AMPK phosphorylation and activation. Moreover, TXNIP downregulation further negatively impacted BRB integrity by disrupting RPE cell tight junctions and enhancing cell motility by phosphorylating, and thereby activating, Src kinase. Finally, we also revealed that TXNIP knockdown upregulated HIF-1 alpha, leading to the enhanced secretion of VEGF from RPE cells and the stimulation of angiogenesis in cocultured human retinal microvascular endothelial cells. This suggests that the exposure of RPE cells to sustained oxidative stress may promote choroidal neovascularization, another AMD pathology. Together, these findings reveal three distinct mechanisms by which TXNIP downregulation disrupts RPE cell function and thereby exacerbates AMD pathogenesis. Accordingly, reinforcing or restoring BRB integrity by targeting TXNIP may serve as an effective therapeutic strategy for preventing or attenuating photoreceptor damage in AMD.