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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 4

Visual acuity of rd1 mice with and without AAV-Best1-Nrf2.

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Visual acuity of rd1 mice with and without AAV-Best1-Nrf2.
(A) Visual ac...
(A) Visual acuity (measured by the optomotor assay) for rd10 mice that were injected in one eye with AAV-Best1-Nrf2 and AAV-Best1-GFP and the other eye with AAV-Best1-GFP only (n = 19 mice for all time points except p50 [where only 9 of the mice were tested] and P60 [where n = 16 because 2 of the mice died between P55 and P60 and 1 did not cooperate with the test]). Data shown as mean ± SEM. *P<0.05 and **P<0.005 by paired t test. (B). Optomotor visual acuity for rd10 mice that were injected in one eye with AAV-CMV-Nrf2 plus AAV-hRedO-GFP-H2b and in the other eye with AAV-hRedO-GFP-H2b or no injection. In rd10 mice, eyes injected with AAV-hRedO-GFP-H2b and uninjected eyes were shown to have no difference in visual acuity between P45 and P60 in previously published work; therefore, both were used as controls (81) (n = 14 mice; one eye injected with AAV-CMV-Nrf2 and the contralateral eye injected with AAV-hRedO-GFP h2b [n = 3] or uninjected [n = 11] for all time points except P60, where n = 13 mice because 1 mouse developed a cataract and was excluded). Data shown as mean ± SEM. *P<0.05 and **P<0.005 by 1-way ANOVA (green asterisk indicates AAV-CMV-Nrf2 versus AAV-hRedO-GFP-H2b comparison, and blue asterisk indicates AAV-CMV-Nrf2 versus uninjected comparison).

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