Deletion of the stress response protein REDD1 prevents sodium iodate-induced RPE damage and photoreceptor loss.

Abstract

Age-related macular degeneration (AMD) is a leading cause of blindness in elderly populations, yet the molecular events that initiate the early retinal defects that lead to visual function deficits remain poorly understood. The studies here explored a role for the stress response protein Regulated in Development and DNA damage response 1 (REDD1) in the development of retinal pathology by using the oxidant stressor sodium iodate (NaIO) to model dry AMD in mice. REDD1 protein abundance was increased in the retinal pigmented epithelium (RPE) and retina of mice administered NaIO. In wild-type REDD1mice, reactive oxygen species (ROS) levels were robustly increased in the outer retinal layers 1 day after NaIOadministration, with focal areas of increased ROS seen throughout the outer retina after 7 days. In contrast with REDD1mice, ROS levels were blunted in REDD1mice after NaIOadministration. REDD1 was also required for upregulated expression of pro-inflammatory factors in the RPE/retina and immune cell activation in the outer retina following NaIOadministration. In REDD1mice, NaIOreduced RPE65 and rhodopsin levels in the RPE and photoreceptor layers, respectively. Unlike REDD1mice, REDD1mice did not exhibit disrupted RPE integrity, retinal degeneration, or photoreceptor thinning. Overall, REDD1 deletion was sufficient to prevent retinal oxidative stress, RPE damage, immune cell activation, and photoreceptor loss in response to NaIO. The findings support a potential role for REDD1 in the development of retinal complications in the context of dry AMD.