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

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.
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Highlights • MITF haploinsufficiency exacerbates oxidative stress-induced retinal degeneration. • Specific overexpression of MITF in RPE cells protects retinas from oxidative damage in vivo. • MITF directly regulates the transcription and nuclear translocation of NRF2. • Partial rescue of retinal oxidative damage in Mitf ±mice by gene transfer mediated RPE cell specific expression of NRF2.