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首页> 外文期刊>Neuroscience: An International Journal under the Editorial Direction of IBRO >17 beta-ESTRADIOL UP-REGULATES NRF2 VIA PI3K/AKT AND ESTROGEN RECEPTOR SIGNALING PATHWAYS TO SUPPRESS LIGHT-INDUCED DEGENERATION IN RAT RETINA
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17 beta-ESTRADIOL UP-REGULATES NRF2 VIA PI3K/AKT AND ESTROGEN RECEPTOR SIGNALING PATHWAYS TO SUPPRESS LIGHT-INDUCED DEGENERATION IN RAT RETINA

机译：17β-雌二醇通过PI3K / AKT和雌激素受体信号通路上调NRF2，以抑制大鼠视网膜中光诱导的变性

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Human age-related retinal diseases, such as agerelated macular degeneration (AMD), are intimately associated with decreased tissue oxygenation and hypoxia. Different antioxidants have been investigated to reverse AMD. In the present study, we describe the antioxidant 17 beta-estradiol (beta E2) and investigate its protective effects on retinal neurons. Fourteen days after ovariectomy, adult Sprague-Dawley rats were exposed to 8000-lux light for 12 h to induce retinal degeneration. Reactive oxygen species (ROS) levels were assessed by confocal fluorescence microscopy using 2,7-dichlorofluorescein diacetate. Nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant enzyme mRNA expression were detected by real-time PCR. Western blotting was used to evaluate NRF2 activation. NRF2 translocation was determined by immunohistochemistry, with morphological changes monitored by hematoxylin and eosin staining. Following light exposure, beta E2 significantly reduced ROS production. beta E2 also upregulated NRF2 mRNA and protein levels, with maximal expression at 4 and 12 h post-exposure, respectively. Interestingly, following beta E2 administration, NRF2 was translocated from the cytoplasm to the nucleus, primarily in the outer nuclear layer. beta E2 also up-regulated NRF2, which triggered phase-2 antioxidant enzyme expression (superoxide dismutases 1 and 2, catalase, glutaredoxins 1 and 2, and thioredoxins 1 and 2), reduced ROS production, and ameliorated retinal damage. However, the beneficial effects of beta E2 were markedly suppressed by pretreatment with LY294002 or ICI182780, specific inhibitors of the phosphatidylinositol 3-kinase-Akt (PI3K/AKT), and estrogen receptor (ER) signaling pathways, respectively. Taken together, these observations suggest that beta E2 exerts antioxidative effects following light-induced retinal degeneration potentially via NRF2 activation. This protective mechanism may depend on two pathways: a rapid, non-genomic-type PI3K/AKT response, and a genomic-type ER-dependent response. Our data provide evidence that beta E2 is a potentially effective in the treatment of retinal degeneration diseases. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
机译：人类年龄相关的视网膜疾病，例如年龄相关的黄斑变性（AMD），与组织氧合减少和缺氧密切相关。已经研究了不同的抗氧化剂来逆转AMD。在本研究中，我们描述了抗氧化剂17β-雌二醇（βE2），并研究了其对视网膜神经元的保护作用。卵巢切除术后第十四天，成年Sprague-Dawley大鼠在8000 lux的光照下暴露12 h，以诱导视网膜变性。通过使用2,7-二氯荧光素二乙酸酯的共聚焦荧光显微镜法评估活性氧（ROS）水平。实时荧光定量PCR检测核因子红系2相关因子2（Nrf2）和抗氧化酶mRNA的表达。蛋白质印迹用于评估NRF2激活。通过免疫组织化学确定NRF2易位，并通过苏木精和曙红染色监测形态变化。曝光后，βE2显着降低了ROS的产生。 βE2还上调了NRF2 mRNA和蛋白质水平，分别在暴露后4小时和12小时达到最大表达。有趣的是，在施用βE2之后，NRF2从细胞质转移到细胞核，主要在外核层。 βE2也上调NRF2，从而触发2期抗氧化酶表达（超氧化物歧化酶1和2，过氧化氢酶，戊二醛毒素1和2以及硫氧还蛋白1和2），减少ROS产生并减轻视网膜损伤。但是，分别用LY294002或ICI182780，磷脂酰肌醇3-激酶-Akt的特异性抑制剂（PI3K / AKT）和雌激素受体（ER）信号通路进行预处理，可显着抑制βE2的有益作用。综上所述，这些观察结果表明，βE2在光诱导的视网膜变性后可能通过NRF2激活发挥抗氧化作用。这种保护机制可能取决于两个途径：快速的非基因组型PI3K / AKT反应和基因组型ER依赖性反应。我们的数据提供了证据，证明βE2在治疗视网膜变性疾病方面可能是有效的。 （C）2015年IBRO。由Elsevier Ltd.出版。保留所有权利。

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