Epigenetic regulation of redox signaling in diabetic retinopathy: Role of Nrf2.
Epigenetic regulation of redox signaling in diabetic retinopathy: Role of Nrf2.
复制标题
氧化还原信号传导在糖尿病性视网膜病中的表观遗传调节：NRF2的作用。
DOI：
10.1016/j.freeradbiomed.2016.12.030
复制
发表时间：
2017-02
影响因子：
7.4
通讯作者：
Mishra M
中科院分区：
文献类型：
--
作者：
Kowluru RA;Mishra M
糖尿病视网膜病变是一种严重威胁视力的疾病，氧化应激是其发病的主要原因之一。细胞质中活性氧（ROS）的增加会损伤线粒体，并且由于抗氧化剂信号系统受损和线粒体DNA受损的线粒体功能障碍，ROS继续堆积，加速毛细血管细胞损失。除了其他细胞和酶防御系统，视网膜还配备了核红细胞-2-p45相关因子-2（Nrf 2）抗氧化反应元件信号通路，其控制在ROS解毒和消除中重要的基因的表达。然而，在糖尿病中，其转录活性受损，进一步加剧并使视网膜暴露于升高的压力。糖尿病环境也改变了负责染色质修饰和基因调控的表观遗传因子，并且在调节Nrf 2-抗氧化剂信号传导轴中重要的kelch样ECH相关蛋白1（Keap 1）被表观遗传修饰，阻碍Nrf 2的核转位，这抑制了具有抗氧化剂氧化还原元件的基因的转录。本文综述了抗氧化信号，特别是Nrf 2的作用，在糖尿病视网膜病变，和可能参与的表观遗传修饰的抗氧化信号和Nrf 2的转录活性。靶向Nrf 2激活的疗法，包括表观遗传修饰，可以预防线粒体损伤并抑制这种威胁视力的疾病的发展和进展，大多数患者在糖尿病20-25年后患上这种疾病。
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 system, 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 Redox 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, could 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.