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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 8

IHC for DE genes from transcriptional profiling.

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IHC for DE genes from transcriptional profiling.
(A) RPE flat mounts sho...
(A) RPE flat mounts showing staining for antibodies against GCLC, TXNRD1, or MRP4. Each row shows flat mounts from pairs of left and right eyes from a P40 rd1 mouse (1 pair per antibody). In the left eyes, only a control AAV-hRedO-GFP was injected. In the right eyes, the eye was also injected with AAV-Best1-Nrf2. Staining was absent in the eyes on the left-hand side, which did not have overexpression of Nrf2. In the pair of eyes stained with MRP4, only the right half of the eye was infected with Nrf2. Scale bars: 200 μm. (B) Sections from pairs of left and right eyes from P40 rd1 mice. In the left eyes, only a control virus, AAV-Best1-GFP was injected. In the right eye, the eye was also injected with AAV-Best1-Nrf2. Selective expression of GFP showing the RPE layer was seen in both eyes (n = 2 per antibody). Scale bars: 50 μm.

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