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bioRxiv · 10.1101/2024.06.10.598362

Induction of a Muller glial-specific protective pathway safeguards the retina from diabetes induced damage

Lin, C.-h.·Wu, M.-R.·Tanasa, B.·Prakhar, P.·Davis, A.·Li, L.·Xia, A.·Shan, Y.·Fort, P.·Wang, S.
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Abstract

Diabetes can lead to cell-type-specific responses in the retina, including vascular lesions, glial dysfunction and neurodegeneration, all of which contribute to retinopathy. However, the molecular mechanisms underlying these cell type-specific responses, and the cell types that are sensitive to diabetes have not been fully elucidated. Employing single cell transcriptomic analyses, we profiled the transcriptional changes induced by diabetes in different retinal cell types in diabetic rat models as the disease progressed. Rod photoreceptors, a subtype of amacrine interneurons, and Muller glial cells exhibited rapid responses to diabetes at the transcript levels. Genes associated with ion regulation were upregulated in all three cell types, suggesting a common response to diabetes. Furthermore, focused studies revealed that while Muller glial cells initially increased the expression of genes playing protective roles, they cannot sustain this beneficial effect as the disease progressed. We explored one of the candidate protective genes, Zinc finger protein 36 homolog (Zfp36), and observed that depleting Zfp36 in rat Muller glial cells in vivo using AAV-based tools exacerbated early diabetes-induced phenotypes, including gliosis, neurodegeneration, and vascular defects. Notably, the over-expression of Zfp36 slowed the development of phenotypes associated with diabetic retinopathy. In summary, this work unveiled retinal cell types that are sensitive to diabetes and demonstrated that Muller glial cells can mount protective responses through Zfp36. The failure to maintain Zfp36 levels contributes to the development of diabetic retinopathy.

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Lin, C.-h., Wu, M.-R., Tanasa, B., Prakhar, P., Davis, A., Li, L., Xia, A., Shan, Y., Fort, P., Wang, S.. 2024-06-10. Induction of a Muller glial-specific protective pathway safeguards the retina from diabetes induced damage. https://doi.org/10.1101/2024.06.10.598362

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