June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
REV-ERBα regulates retinal function and protects against retinal degeneration in experimental retinitis pigmentosa
Author Affiliations & Notes
  • Felix Yemanyi
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Chi-Hsiu Liu
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Shuo Huang
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Kiran Bora
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Meenakshi Maurya
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Alexandra K. Blomfield
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Zhongjie Fu
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • James Akula
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Jing Chen
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Felix Yemanyi None; Chi-Hsiu Liu None; Shuo Huang None; Kiran Bora None; Meenakshi Maurya None; Alexandra Blomfield None; Zhongjie Fu None; James Akula None; Jing Chen None
  • Footnotes
    Support  NIH/NEI R01s (EY024963, EY028100, and EY031765), BrightFocus Foundation, Mass Lions Eye Research Fund Inc., Research to Prevent Blindness (to JC).
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 864. doi:
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    • Get Citation

      Felix Yemanyi, Chi-Hsiu Liu, Shuo Huang, Kiran Bora, Meenakshi Maurya, Alexandra K. Blomfield, Zhongjie Fu, James Akula, Jing Chen; REV-ERBα regulates retinal function and protects against retinal degeneration in experimental retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2022;63(7):864.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : About 50% of retinitis pigmentosa (RP), an inherited retinal degenerative disease, results from mutations in >60 genes, yet gene therapy exists for only 1% of RP patients. Broad-spectrum therapies regardless of the RP-causing gene or other unknown factors are needed. REV-ERBα is a cytoprotective nuclear receptor that regulates development, metabolism, inflammation, and oxidative stress. We sought to determine whether REV-ERBα regulates retinal physiology in Rev-erbα-deficient (Rev-erbα-/-) mice, and whether REV-ERBα activation could ameliorate photoreceptor loss in the rd10 mouse model of RP.

Methods : Localization and relative abundance of Rev-erbα were determined in C57BL/6J mice retinas via immunohistochemistry and laser capture microdissection. The role of Rev-erbα in retinal function and metabolism was analyzed in wild-type (WT) vs. Rev-erbα-/- mice retinas via electroretinography (ERG), Seahorse assay, microarray analysis, and RT-qPCR. The role of Rev-erbα in 661W cell (photoreceptor) metabolism following its knockdown was determined in vitro. Rd10 mice were injected intraperitoneally with REV-ERB agonist (SR9009) or vehicle from postnatal day (P) 7 to P30; retinal structure, apoptosis, and visual function were evaluated via histology, TUNEL staining, Western blotting, and scotopic ERG. Effect of SR9009 on photoreceptor cell survival and metabolism was determined in vitro.

Results : Rev-erbα localizes throughout the mouse retina and its transcripts are more enriched in the photoreceptor layer than the inner retina. Rev-erbα-/- mice showed markedly dampened visual function in ERG relative to WT, associated with reduced mitochondrial respiration, and without retinal thinning. Microarray expression from the Rev-erbα-/- vs. WT retinas also demonstrated altered expression of genes involved in metabolism, signal transduction and molecular transport. Rev-erbα knockdown in 661W cells supported its role in photoreceptor metabolism, signal transduction and molecular transport. Activation of REV-ERBα in rd10 mice significantly protected against photoreceptor thinning, apoptosis, and loss of visual function. Modulation of REV-ERBα in 661W cells corroborated its role in improving photoreceptor cell survival and metabolism.

Conclusions : These data suggest REV-ERBα regulates retinal function and metabolism, and may be activated to slow RP progression by promoting photoreceptor survival.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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