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Nrf2 overexpression rescues the RPE in mouse models of retinitis pigmentosa
David M. Wu, … , Wenjun Xiong, Constance L. Cepko
David M. Wu, … , Wenjun Xiong, Constance L. Cepko
Published January 25, 2021
Citation Information: JCI Insight. 2021;6(2):e145029. https://doi.org/10.1172/jci.insight.145029.
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Research Article Ophthalmology

Nrf2 overexpression rescues the RPE in mouse models of retinitis pigmentosa

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Abstract

Nrf2, a transcription factor that regulates the response to oxidative stress, has been shown to rescue cone photoreceptors and slow vision loss in mouse models of retinal degeneration (rd). The retinal pigment epithelium (RPE) is damaged in these models, but whether it also could be rescued by Nrf2 has not been previously examined. We used an adeno-associated virus (AAV) with an RPE-specific (Best1) promoter to overexpress Nrf2 in the RPE of rd mice. Control rd mice showed disruption of the regular array of the RPE, as well as loss of RPE cells. Cones were lost in circumscribed regions within the cone photoreceptor layer. Overexpression of Nrf2 specifically in the RPE was sufficient to rescue the RPE, as well as the disruptions in the cone photoreceptor layer. Electron microscopy showed compromised apical microvilli in control rd mice but showed preserved microvilli in Best1-Nrf2–treated mice. The rd mice treated with Best1-Nrf2 had slightly better visual acuity. Transcriptome profiling showed that Nrf2 upregulates multiple oxidative defense pathways, reversing declines seen in the glutathione pathway in control rd mice. In summary, Nrf2 overexpression in the RPE preserves RPE morphology and survival in rd mice, and it is a potential therapeutic for diseases involving RPE degeneration, including age-related macular degeneration (AMD).

Authors

David M. Wu, Xuke Ji, Maryna V. Ivanchenko, Michelle Chung, Mary Piper, Parimal Rana, Sean K. Wang, Yunlu Xue, Emma West, Sophia R. Zhao, Hongbin Xu, Marcelo Cicconet, Wenjun Xiong, Constance L. Cepko

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Figure 2

Changes in retinal structure in rd1 mice and the effect of overexpression of Nrf2 in the RPE.

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Changes in retinal structure in rd1 mice and the effect of overexpressio...
(A) Confocal images of pairs of retina flat mounts from the right and left eyes of a P41 rd1 mice that received a coinjection of AAV-Best1-Nrf2 and AAV-hRedO-H2b-GFP in the left eye (left panel) and control AAV-hRedO-H2b-GFP in the right eye (right panel) (n = 13 mice). Each point of fluorescence is the nucleus of a cone. Note the disruptions, which appear as “holes” or “craters” in the cone mosaic, particularly in the right eyes. (B) Confocal images of a pair of retinas from the right and left eyes of P48 rd1 mouse, with anti-GFAP labeling, demonstrating fairly uniform GFAP distribution in the left retina from the eye that received AAV-Best1-Nrf2 but significant upregulation and distortion of the radial Muller glial fibers in areas of cone loss in the right retina from the eye that received AAV-hRedO-H2b-GFP only (n = 2 mice). Insets show higher magnification of these areas with GFP (C) and GFAP (D). Scale bars: 500 μm for A and B, 200 μm for C and D.

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ISSN 2379-3708

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