Muller Glial Expression of REDD1 Is Required for Retinal Neurodegeneration and Visual Dysfunction in Diabetic Mice

Clinical studies support a role for the protein regulated in development and DNA damage response 1 (REDD1) in ischemic retinal complications. To better understand how REDD1 contributes to retinal pathology, we examined human single-cell sequencing data sets and found specificity of REDD1 expression that was consistent with markers of retinal Muller glia. Thus, we investigated the hypothesis that REDD1 expression specifically in Muller glia contributes to diabetes-induced retinal pathology. The retina of Muller glia-specific REDD1 knockout (REDD1-mgKO) mice exhibited dramatic attenuation of REDD1 transcript and protein expression. In the retina of streptozotocin-induced diabetic control mice, REDD1 protein expression was enhanced coincident with an increase in oxidative stress. In the retina of diabetic REDD1-mgKO mice, there was no increase in REDD1 protein expression, and oxidative stress was reduced compared with diabetic control mice. In both Muller glia within the retina of diabetic mice and human Muller cell cultures exposed to hyperglycemic conditions, REDD1 was necessary for increased expression of the gliosis marker glial fibrillary acidic protein. The effect of REDD1 deletion in preventing gliosis was associated with suppression of oxidative stress and required the antioxidant transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2). In contrast to diabetic control mice, diabetic REDD1-mgKO mice did not exhibit retinal thinning, increased markers of neurodegeneration within the retinal ganglion cell layer, or deficits in visual function. Overall, the findings support a key role for Muller glial REDD1 in the failed adaptive response of the retina to diabetes that includes gliosis, neurodegeneration, and impaired vision.

Automated summary

Clinical studies support the role of REDD1 protein in ischemic retinal complications caused by diabetes. The study found that REDD1 expression specifically in Muller glia contributes to diabetes-induced retinal pathology, including gliosis, neurodegeneration, and impaired vision.