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

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 REDD1 mice, reactive oxygen species (ROS) levels were robustly increased in the outer retinal layers 1 day after NaIO administration, with focal areas of increased ROS seen throughout the outer retina after 7 days. In contrast with REDD1 mice, ROS levels were blunted in REDD1 mice after NaIO administration. REDD1 was also required for upregulated expression of pro-inflammatory factors in the RPE/retina and immune cell activation in the outer retina following NaIO administration. In REDD1 mice, NaIO reduced RPE65 and rhodopsin levels in the RPE and photoreceptor layers, respectively. Unlike REDD1 mice, REDD1 mice 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.