REDD1 ablation in Müller glia inhibits diabetes-induced retinal pathology in mice

Abstract

Purpose : Müller glia provide critical homeostatic, trophic, and structural support for both the retinal vasculature and neuronal layers. In diabetes, Müller cell dysfunction contributes to retinal inflammation, microvascular defects, and neuronal damage. Our laboratory has recently demonstrated a critical role for the stress response protein Regulated in Development and DNA damage response 1 (REDD1) in the development of diabetes-induced oxidative stress and retinal defects. Herein, we investigated the hypothesis that diabetes-induced REDD1 protein expression specifically in Müller cells contributes to the development of retinal pathology.

Methods : Conditional Müller-specific REDD1 knockout (REDD1 cKO) mice were generated using a PDGFRa-cre/lox recombination system. REDD1 cKO and floxed REDD1 control mice were administered streptozotocin to induce diabetes or received a vehicle control. The impact of diabetes was evaluated by optical coherence tomography and fluorescence microscopy. Retinal homogenates and nuclear isolates were also analyzed by Western blotting and ELISA.

Results : Müller glia from REDD1 cKO mice lacked REDD1, but expressed Müller cell markers similar to that of floxed REDD1 controls. In the retina of diabetic control mice, REDD1 protein expression was enhanced concomitant with an increase in oxidative stress and reduced activity of the antioxidant defense transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2). These effects of diabetes were attenuated by conditional deletion of REDD1 in Müller glia. REDD1 cKO mice also exhibited a reduction in diabetes-induced retinal thinning and retinal ganglion cell death as compared to control mice

Conclusions : The findings support a key role for REDD1 in diabetes-induced retinal defects and provide new insight into the specific molecular events in retinal Müller glia that contribute to the pathology of diabetic retinopathy.

This is a 2021 ARVO Annual Meeting abstract.