Kowluru Renu A, Mishra Manish
Kresge Eye Institute, Wayne State University, Detroit, MI, United States.
Kresge Eye Institute, Wayne State University, Detroit, MI, United States.
Free Radic Biol Med. 2017 Feb;103:155-164. doi: 10.1016/j.freeradbiomed.2016.12.030. Epub 2016 Dec 22.
Diabetic retinopathy is a major vision threatening disease among working age adults, and increased oxidative stress is one of the prime causative factors in its pathogenesis. Increased reactive oxygen species (ROS) in the cytosol damage mitochondria, and due to compromised antioxidant signaling system and dysfunctional mitochondria with damaged mitochondrial DNA, ROS continue to pile up, accelerating capillary cell loss. In addition to other cellular and enzymatic defense systems, the retina is also equipped with the nuclear erythroid-2-p45-related factor-2 (Nrf2) antioxidant response element signaling pathway, which controls the expression of genes important in detoxification and elimination of ROS. However, in diabetes, its transcriptional activity is impaired, further exacerbating and exposing the retina to elevated stress. Diabetic milieu also alters epigenetic factors responsible for chromatin modifications and gene regulation, and kelch-like ECH-associated protein 1 (Keap1), important in regulating Nrf2-antioxidant signaling axis, is epigenetically modified, impeding nuclear translocation of Nrf2, and this inhibits the transcription of genes with Antioxidant Response Element. This review discusses antioxidant signaling, especially the role of Nrf2, in diabetic retinopathy, and possible involvement of epigenetic modifications in antioxidant signaling and Nrf2 transcriptional activity. Therapies targeting Nrf2 activation, including epigenetic modifications, have potentional to prevent mitochondrial damage and inhibit the development, and progression of this sight-threatening disease which most of the patients get after 20-25 years of diabetes.
糖尿病视网膜病变是工作年龄成年人中一种主要的视力威胁性疾病，氧化应激增加是其发病机制中的主要致病因素之一。细胞质中活性氧（ROS）增加会损害线粒体，由于抗氧化信号系统受损以及线粒体DNA受损导致线粒体功能障碍，ROS持续堆积，加速毛细血管细胞丢失。除了其他细胞和酶防御系统外，视网膜还具备核红细胞2相关因子2（Nrf2）抗氧化反应元件信号通路，该通路控制着在解毒和清除ROS中起重要作用的基因的表达。然而，在糖尿病状态下，其转录活性受损，进一步加剧并使视网膜暴露于更高的应激状态。糖尿病环境还会改变负责染色质修饰和基因调控的表观遗传因子，而在调节Nrf2抗氧化信号轴中起重要作用的kelch样ECH相关蛋白1（Keap1）会发生表观遗传修饰，阻碍Nrf2的核转位，从而抑制具有抗氧化反应元件的基因的转录。本综述讨论了抗氧化信号，尤其是Nrf2在糖尿病视网膜病变中的作用，以及表观遗传修饰可能在抗氧化信号和Nrf2转录活性中的参与情况。针对Nrf2激活的疗法，包括表观遗传修饰，有可能预防线粒体损伤并抑制这种大多数患者在患糖尿病20 - 25年后出现的视力威胁性疾病的发生和发展。
