Genetic deficiency of nuclear receptor REV-ERBα causes retinal pigment epithelial cell degeneration in mice

Abstract

Purpose : Oxidative damage-induced retinal pigment epithelium (RPE) dysfunction and atrophy contribute to the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. REV-ERBα is a redox (reduction/oxidation) -sensing nuclear receptor and transcription repressor that regulates circadian control and cell metabolism, yet its function in the eye is not clear. In this project we investigated the role of REV-ERBα in the regulation of RPE metabolism and degeneration in mice genetically deficient of REV-ERBα.

Methods : REV-ERBα deficient (Rev-erbα^-/-) mice and littermate wild type (WT) controls were analyzed at various time points during aging. Morphological features were analyzed with in vivo fundus imaging and in isolated RPE/choroid complex flat mounts and cross-sections from enucleated eyes. Visual function was evaluated with electroretinography. Expression levels of Rev-erbα and relevant metabolic and inflammatory genes were analyzed in RPE isolated from Rev-erbα^-/- and WT mice.

Results : REV-ERBα was expressed in RPE in WT eyes. Deficiency of REV-ERBα in aged mouse eyes caused abnormal subretinal lesions in fundus imaging, and patchy areas of RPE degeneration with disrupted cell junction in RPE/choroidal flat mounts and cross sections. ERG analysis of aging mice revealed substantial decrease in both a- and b-waves, indicating deficits in retinal visual function. In addition, Rev-erbα^-/- RPE showed decreased expression of tight junction genes (ZO-1, Ocln and Clnd5), consistent with junctional disruption. Substantial decrease in cell metabolic genes and increased expression of inflammatory genes were also found in Rev-erbα^-/- RPE.

Conclusions : Together these findings suggest that REV-ERBα is a novel transcriptional regulator of RPE function in AMD pathogenesis and a potential target for future therapeutics.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.