Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Ophthalmology

Nrf2 overexpression rescues the RPE in mouse models of retinitis pigmentosa

  • Text
  • PDF
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

×

Figure 1

Morphological analyses of the RPE from WT mice and rd1 mice with or without AAV-Best1-Nrf2.

Options: View larger image (or click on image) Download as PowerPoint
Morphological analyses of the RPE from WT mice and rd1 mice with or with...
(A) An RPE flat mount from a P42 WT (CD1) mouse is shown. Phalloidin (gray) stains the F-actin belt around the circumference of individual RPE cells and shows the regular hexagonal array of this epithelial monolayer. (B) An RPE flat mount from a P42 rd1 mouse that received an injection only of control virus (AAV-hRedO-H2b-GFP) at P0. (C) The RPE flat mount from the other eye of the same P42 rd1 mouse as shown in B, following injection with AAV-Best1-Nrf2 plus AAV-hRedO-H2b-GFP. (D) An RPE flat mount of a P42 rd1 mouse that received an injection of control virus (AAV-hRedO-H2b-GFP). (E) The RPE flat mount from the other eye of the same mouse from D, which received an injection of AAV-hRedO-Nrf2 plus AAV-hRedO-H2b-GFP at P0. Panels are representative of findings from n > 20 mice per group. Scale bar: 100 μm.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts