Abstract
Purpose :
Age-related macular degeneration (AMD) is a leading cause of blindness in elderly populations. The pathogenesis of AMD is multifactorial; however, it is well accepted that oxidative stress and inflammation play major role in the development and progression of complications that lead to visual impairment. Prior studies support a critical role for the stress response protein Regulated in Development and DNA damage response 1 (REDD1) in diabetes-induced retinal pathophysiology by promoting both oxidative stress and inflammation. Therefore, we explored a potential role for REDD1 in the development of AMD-like pathology.
Methods :
A single intraperitoneal injection of sodium iodate (NaIO3, 20 mg/kg) was used to model dry AMD in REDD1+/+ and REDD1-/- mice. Retinal pigmented epithelium (RPE) isolates and retina were collected after 1 or 7 days for examination by RT-PCR and western blotting. Whole eye sections were examined by immunofluorescence and H&E staining. TUNEL assay was used to detect apoptotic cells. Complementary analyses were performed in ARPE-19 cells after exposure to hydrogen peroxide.
Results :
NaIO3 decreased RPE and photoreceptor-specific gene expression, disrupted RPE integrity, and led to photoreceptor thinning and immune cell activation in the outer retina. REDD1 protein abundance was increased in RPE and retina after NaIO3 administration in coordination with an increase in oxidative stress and pro-inflammatory gene expression. The toxic effects of NaIO3 were reduced or absent in REDD1-/- mice as compared to REDD1+/+ mice. REDD1 deletion prevented RPE damage, immune cell activation, and retinal degeneration in response to NaIO3. In ARPE-19 cells, exposure to hydrogen peroxide increased REDD1 protein abundance accompanied by increased mitochondrial superoxide formation and cell death. REDD1 deletion prevented oxidative stress-induced cell death in ARPE-19 cells in coordination with upregulation of the Nrf2 antioxidant response.
Conclusions :
The findings support a potential role for REDD1 in development of retinal degeneration in the context of dry AMD.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.