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

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posted on 15.02.2022, 22:33 by William P. Miller, Allyson L. Toro, Siddharth Sunilkumar, Shaunaci A. Stevens, Ashley M. VanCleave, David L. Williamson, Alistair J. Barber, Michael D. Dennis
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.

Funding

This research was supported by the American Diabetes Association Pathway to Stop Diabetes grant 1-14-INI-04, National Institutes of Health grants R01 EY029702, R01 EY032879 (to MDD), and F31 EY031199 (to WPM).

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