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

Abstract

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 datasets and found specificity of REDD1 expression that was consistent with markers of retinal Müller glia. Thus, we investigated the hypothesis that REDD1 expression specifically in Müller glia contributes to diabetes-induced retinal pathology. The retina of Müller 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 as compared to diabetic control mice. In both Müller glia within the retina of diabetic mice and human Müller 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 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 Müller glial REDD1 in the failed adaptive response of the retina to diabetes that includes gliosis, neurodegeneration, and impaired vision.

Stress response protein REDD1 promotes diabetes-induced retinal inflammation by sustaining canonical NF-κB signaling

“…Diabetes promotes retinal expression of the stress response protein regulated in development and DNA damage 1 (REDD1) ( 11 , 15 , 16 , 17 ). REDD1 expression is dominant in retinal Müller glia, where the protein contributes to a failed adaptive response of the retina to diabetes that includes gliosis, neurodegeneration, and the development of functional deficits in vision ( 15 , 17 ). Indeed, therapeutic administration of an siRNA for REDD1 knockdown has demonstrated promise for improving best-corrected visual acuity (BCVA) in diabetic patients ( 18 ).…”

Neurodegeneration of the cornea and retina in patients with type 1 diabetes without clinical evidence of diabetic retinopathy

“…Müller glia provide critical homeostatic and trophic support for the neuronal layers and vasculature of the retina and hyperglycemia may target these cells, thus inducing neuroinflammation and leading to ganglion cell loss. A recent study by Miller and colleagues ( 48 ) assessing diabetic mice, suggested that enhancement of the protein regulated in development and DNA damage responses 1 (REDD1) expression leads to a failure of Müller cells to properly respond to the diabetic metabolic environment.…”

Spleen Tyrosine Kinase Contributes to Müller Glial Expression of Proangiogenic Cytokines in Diabetes

“…Immunofluorescent microscopy was performed as previously described. 18 Whole eyes were extracted, placed in 4% paraformaldehyde for 30 minutes, and then washed with PBS. After 48 hours of incubation in 30% sucrose at 4°C, the eyes were placed in optimal cutting temperature compound, flash-frozen, and sectioned.…”