Oxidative stress-related degeneration in RPE (retinal pigmented epithelium) and retina: role of DJ-1 and ageing

Abstract

Purpose : Degeneration of the RPE and retina due to cumulative oxidative damage plays an important role in diseases like AMD (age-related macular degeneration) and subsequent blindness. DJ-1, Parkinson’s Disease (PD)-associated gene protects neurons from oxidative damages. DJ-1 is highly expressed in RPE and photoreceptors of adult mice retina. Loss of DJ-1 results in age-related mild structural and physiological changes in retinas of DJ-1 knockout (KO) mice. Here, we characterized degeneration using the oxidizing agent sodium iodate (NaIO₃), in young (3 month old) and older (15 month-old) mice.

Methods : Mice (C57BL/6J and DJ-1 KO) received a single tail vein injection of 10mg/kg body weight of NaIO₃; parallel groups of mice were injected with PBS. Histological analysis of the area of retinal degeneration was performed in toluidine blue sections. The retina and RPE were isolated, total RNA was extracted, and cDNA was generated for RT-PCR and assayed for antioxidant genes (Nrf2, Nqo1, Hmox1, Sod1, Sod2, Prdx1, Gstp1, Gpx1). Retina and RPE lysates were assayed for oxidative stress enzymes by western blot.

Results : Injection of 3 month-old mice with NaIO₃ resulted in morphological retinal and RPE degeneration only in the DJ-1 KO mice while injection of 15 month-old mice resulted in morphological retinal and RPE degeneration in both strains. The increased susceptibility of the DJ-1 KO mice to oxidative stress was confirmed by measurements of the area of RPE degeneration. The transcript levels of antioxidant genes were significantly upregulated in RPE of DJ-1 KO compared to control but downregulated in the retina in 3-month-old mice. In 15-month-old mice, transcript levels of these genes were significantly downregulated in RPE of DJ-1 KO compared to control but remained unchanged in the retina. Increased oxidative stress induced by injection of NaIO₃ lead to upregulation in transcripts of antioxidant genes in the retina but no significant changes in the majority of the genes tested in the RPE of young control mice.

Conclusions : Our data suggest that DJ-1 is a key player to rescue the RPE and retina from oxidative damage and therefore, loss of DJ-1 renders RPE and retina more susceptible to oxidative stress. The transcriptional levels of antioxidant genes in the young DJ-1 KO RPE are comparable to the aged control.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.