Protective effects of retinoid x receptors on retina pigment epithelium cells
Protective effects of retinoid x receptors on retina pigment epithelium cells
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DOI：
10.1016/j.bbamcr.2016.02.010
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发表时间：
2016-06-01
影响因子：
5.1
通讯作者：
Lorena German, Olga
中科院分区：
文献类型：
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作者：
Belen Ayala-Pena, Victoria;Pilotti, Fiorella;Lorena German, Olga
老年性黄斑变性(AMD)是导致成人失明的主要疾病之一，目前尚无治愈或有效的治疗方法。视网膜色素上皮(RPE)细胞的选择性凋亡导致光感受器神经元的进行性丧失，从而导致渐进性视力丧失。氧化应激在这一过程中起着重要作用。我们先前已经确定，RXRs的激活可以保护大鼠光感受器神经元免受氧化应激诱导的细胞凋亡。在这项研究中，我们研究了RXR配体是否能防止过氧化氢(H_2O_2)暴露下RPE细胞系D407细胞的凋亡。H_2O_2诱导D407细胞凋亡，促进p65NE-kappa B核转位，增加Bax mRNA表达，激活caspase-3，改变细胞形态。我们首次发现，RXR泛激动剂HX630可以保护D407细胞免受H_2O_2诱导的细胞凋亡，阻止p65NF-kappa B核转位，增加Bclx1和PPARγmRNA水平，同时降低Bax mRNA水平和caspase-3激活。RXR拮抗剂可阻断HX630的保护作用。LG100754与RXRs结合，但只激活异二聚体，是RXR同源二聚体的拮抗剂，也具有保护作用。此外，只有已知的与RXR/PPAR伽马结合的激动剂具有保护性。总体而言，我们的结果表明，RXR的激活保护RPE细胞免受氧化应激诱导的凋亡，这种保护可能涉及到通过异二聚体受体的信号传递，如RXR/PPAR Gamma。这些数据还表明，RXR激动剂可能为治疗视网膜退行性疾病提供潜在的药理学工具。(C)2016爱思唯尔B.V.保留所有权利。
Age-related macular degeneration (AMD) is among the main pathologies leading to blindness in adults and has currently no cure or effective treatment. Selective apoptosis of retina pigment epithelial (RPE) cells results in the progressive loss of photoreceptor neurons, with the consequent gradual vision loss. Oxidative stress plays an important role in this process. We have previously determined that activation of RXRs protects rat photoreceptor neurons from oxidative stress-induced apoptosis. In this study we investigated whether RXR ligands prevented apoptosis in an RPE cell line, D407 cells, exposed to hydrogen peroxide (H2O2). H2O2 induced apoptosis of D407 cells, promoting p65NE kappa B nuclear translocation, increasing Bax mRNA expression, activating caspase-3 and altering cell morphology. We show, for the first time, that HX630, a RXR pan-agonist, protected D407 cells from H2O2-induced apoptosis, preventing p65NF kappa B nuclear translocation, increasing Bclxl and PPAR gamma mRNA levels and simultaneously decreasing Bax mRNA levels and caspase-3 activation. Pretreatment with a RXR antagonist blocked HX630 protection. LG100754, which binds RXRs but only activates heterodimers and is an antagonist of RXR homodimers, also had a protective effect. In addition, only agonists known to bind to RXR/PPAR gamma were protective. As a whole, our results suggest that RXR activation protects RPE cells from oxidative stress-induced apoptosis and this protection might involve signaling through a heterodimeric receptor, such as RXR/PPAR gamma. These data also imply that RXR agonists might provide potential pharmacological tools for treating retina degenerative diseases. (C) 2016 Elsevier B.V. All rights reserved.