X-box binding protein 1 is essential for the anti-oxidant defense and cell survival in the retinal pigment epithelium.
X-box binding protein 1 is essential for the anti-oxidant defense and cell survival in the retinal pigment epithelium.
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DOI：
10.1371/journal.pone.0038616
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Zhang SX
中科院分区：
文献类型：
--
作者：
Zhong Y;Li J;Wang JJ;Chen C;Tran JT;Saadi A;Yu Q;Le YZ;Mandal MN;Anderson RE;Zhang SX
视网膜色素上皮（RPE）损伤是年龄相关性黄斑变性（AMD）发病机制中的早期事件。X-box结合蛋白1（X-box binding protein 1，XBP 1）是调节内质网（endoplasmic reticulum，ER）稳态和细胞存活的关键转录因子。本研究旨在阐明内源性XBP 1在RPE中的作用。我们的研究结果表明，在光诱导的视网膜变性的大鼠模型中，在RPE/脉络膜复合体中，XBP 1的激活被抑制，伴随着抗氧化基因的减少和氧化应激的增加。通过siRNA敲低XBP 1导致SOD 1、SOD 2、过氧化氢酶和谷胱甘肽合酶的表达减少，并使RPE细胞对氧化损伤敏感。使用Cre/LoxP系统，我们产生了仅在RPE细胞中缺乏XBP 1的小鼠系。与野生型同窝仔相比，RPE-XBP 1 KO小鼠在RPE中表达较少的SOD 1、SOD 2和过氧化氢酶，并且具有增加的氧化应激。在3个月或更大时，这些小鼠表现出RPE细胞凋亡、锥状光感受器数量减少、光感受器外段缩短、ONL厚度减少和视网膜功能缺陷。电子显微镜显示异常的超微结构，布鲁赫膜增厚，破坏基底膜内折叠在XBP 1缺陷的RPE。这些结果表明，XBP 1是参与调节RPE中抗氧化防御的重要基因，并且XBP 1的受损活化可能导致视网膜变性和AMD期间的RPE功能障碍和细胞死亡。
Damage to the retinal pigment epithelium (RPE) is an early event in the pathogenesis of age-related macular degeneration (AMD). X-box binding protein 1 (XBP1) is a key transcription factor that regulates endoplasmic reticulum (ER) homeostasis and cell survival. This study aimed to delineate the role of endogenous XBP1 in the RPE. Our results show that in a rat model of light-induced retinal degeneration, XBP1 activation was suppressed in the RPE/choroid complex, accompanied by decreased anti-oxidant genes and increased oxidative stress. Knockdown of XBP1 by siRNA resulted in reduced expression of SOD1, SOD2, catalase, and glutathione synthase and sensitized RPE cells to oxidative damage. Using Cre/LoxP system, we generated a mouse line that lacks XBP1 only in RPE cells. Compared to wildtype littermates, RPE-XBP1 KO mice expressed less SOD1, SOD2, and catalase in the RPE, and had increased oxidative stress. At age 3 months and older, these mice exhibited apoptosis of RPE cells, decreased number of cone photoreceptors, shortened photoreceptor outer segment, reduced ONL thickness, and deficit in retinal function. Electron microscopy showed abnormal ultrastructure, Bruch's membrane thickening, and disrupted basal membrane infolding in XBP1-deficient RPE. These results indicate that XBP1 is an important gene involved in regulation of the anti-oxidant defense in the RPE, and that impaired activation of XBP1 may contribute to RPE dysfunction and cell death during retinal degeneration and AMD.
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