Induction of necrotic cell death by oxidative stress in retinal pigment epithelial cells.
Induction of necrotic cell death by oxidative stress in retinal pigment epithelial cells.
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DOI：
10.1038/cddis.2013.478
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发表时间：
2013-12-12
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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作者：
视网膜相关性黄斑变性（AMD）是视网膜的退行性疾病，是老年人失明的主要原因。视网膜色素上皮（RPE）细胞死亡和由此产生的光感受器凋亡是晚期干性AMD，特别是地图状萎缩（GA）的特征。虽然氧化应激和炎症与GA有关，但RPE细胞死亡的性质和潜在机制仍然存在争议，这阻碍了干性AMD靶向治疗的发展。本研究旨在系统地探讨氧化应激诱导RPE细胞死亡的机制。我们的研究结果表明，细胞凋亡的特征，包括DNA片段化，caspase 3激活，染色质凝聚和凋亡小体形成，没有观察到过氧化氢或叔丁基过氧化氢诱导的RPE细胞死亡。相反，RIP激酶抑制剂necrostatins可以阻止这种细胞死亡，但caspase抑制剂z-VAD不能，这表明RPE细胞死亡的坏死特征。此外，ATP耗竭，受体相互作用蛋白激酶3（RIPK 3）聚集，核膜和质膜渗漏和破裂，这是坏死的主要特征，在氧化应激后的RPE细胞中观察到。RIPK 3是坏死中的关键蛋白，沉默RIPK 3在很大程度上防止了氧化应激诱导的RPE死亡。RPE死亡的坏死性质与核蛋白高迁移率族蛋白B1释放到细胞质和细胞培养基中，诱导健康RPE和THP-1细胞中炎症基因TNFα的表达一致。有趣的是，在氧化应激处理的RPE细胞中没有观察到焦亡或自噬的特征。我们的研究结果明确表明，坏死，而不是凋亡，是一个主要类型的细胞死亡的RPE细胞在氧化应激反应。这表明预防氧化应激诱导的坏死性RPE死亡可能是治疗晚期干性AMD的可行方法。
Age-related macular degeneration (AMD) is a degenerative disease of the retina and the leading cause of blindness in the elderly. Retinal pigment epithelial (RPE) cell death and the resultant photoreceptor apoptosis are characteristic of late-stage dry AMD, especially geographic atrophy (GA). Although oxidative stress and inflammation have been associated with GA, the nature and underlying mechanism for RPE cell death remains controversial, which hinders the development of targeted therapy for dry AMD. The purpose of this study is to systematically dissect the mechanism of RPE cell death induced by oxidative stress. Our results show that characteristic features of apoptosis, including DNA fragmentation, caspase 3 activation, chromatin condensation and apoptotic body formation, were not observed during RPE cell death induced by either hydrogen peroxide or tert-Butyl hydroperoxide. Instead, this kind of cell death can be prevented by RIP kinase inhibitors necrostatins but not caspase inhibitor z-VAD, suggesting necrotic feature of RPE cell death. Moreover, ATP depletion, receptor interacting protein kinase 3 (RIPK3) aggregation, nuclear and plasma membrane leakage and breakdown, which are the cardinal features of necrosis, were observed in RPE cells upon oxidative stress. Silencing of RIPK3, a key protein in necrosis, largely prevented oxidative stress-induced RPE death. The necrotic nature of RPE death is consistent with the release of nuclear protein high mobility group protein B1 into the cytoplasm and cell medium, which induces the expression of inflammatory gene TNFα in healthy RPE and THP-1 cells. Interestingly, features of pyroptosis or autophagy were not observed in oxidative stress-treated RPE cells. Our results unequivocally show that necrosis, but not apoptosis, is a major type of cell death in RPE cells in response to oxidative stress. This suggests that preventing oxidative stress-induced necrotic RPE death may be a viable approach for late-stage dry AMD.
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影响因子：
2.9
作者：
Chang JY;Bora PS;Bora NS
通讯作者：
Bora NS
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
--
作者：
Kassoff, A;Kassoff, J;Chew, EY
通讯作者：
Chew, EY
DOI：
10.1196/annals.1420.023
发表时间：
2008-01-01
期刊：
CONTROL AND REGULATION OF TRANSPORT PHENOMENA IN THE CARDIAC SYSTEM
影响因子：
--
作者：
Juhaszova, Magdalena;Wang, Su;Sollott, Steven J.
通讯作者：
Sollott, Steven J.
影响因子：
64.5
作者：
Cho YS;Challa S;Moquin D;Genga R;Ray TD;Guildford M;Chan FK
通讯作者：
Chan FK