MITF protects against oxidative damage-induced retinal degeneration by regulating the NRF2 pathway in the retinal pigment epithelium

作者：Shuxian Han, Jianjun Chen, Jiajia Hua, Xiaojuan Hu, Shuhui Jian, Guoxiao Zheng, Jing Wang, Huirong Li, Jinglei Yang, J. Fielding Hejtmancik, Jia Qu, Xiaoyin Ma, Ling Hou · 发表于：Redox Biology · 年份：2020 · DOI：10.1016/j.redox.2020.101537 · 被引用次数：49 · 研究领域：Genomics, phytochemicals, and oxidative stress、Antioxidant Activity and Oxidative Stress、Retinoids in leukemia and cellular processes

Oxidative damage is one of the major contributors to retinal degenerative diseases such as age-related macular degeneration (AMD), while RPE mediated antioxidant defense plays an important role in preventing retinopathies. However, the regulatory mechanisms of antioxidant signaling in RPE cells are poorly understood. Here we show that transcription factor MITF regulates the antioxidant response in RPE cells, protecting the neural retina from oxidative damage. In the oxidative stress-induced retinal degeneration mouse model, retinal degeneration in Mitf+/- mice is significantly aggravated compared to WT mice. In contrast, overexpression of Mitf in Dct-Mitf transgenic mice and AAV mediated overexpression in RPE cells protect the neural retina against oxidative damage. Mechanistically, MITF both directly regulates the transcription of NRF2, a master regulator of antioxidant signaling, and promotes its nuclear translocation. Furthermore, specific overexpression of NRF2 in Mitf+/- RPE cells activates antioxidant signaling and partially protects the retina from oxidative damage. Taken together, our findings demonstrate the regulation of NRF2 by MITF in RPE cells and provide new insights into potential therapeutic approaches for prevention of oxidative damage diseases.