Induction of a Müller Glial Cell–Specific Protective Pathway Safeguards the Retina From Diabetes-Induced Damage

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. Using single-cell transcriptomics, we profiled the transcriptional changes induced by diabetes in different retinal cell types in rat models as the disease progressed. Rod photoreceptors, a subtype of amacrine interneurons, and Müller glial cells (MGs) 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 although MG initially increased the expression of genes playing protective roles, they cannot sustain this beneficial effect. We explored one of the candidate protective genes, Zinc finger protein 36 homolog (Zfp36), and observed that depleting Zfp36 in rat MGs in vivo using adeno-associated virus–based tools exacerbated diabetes-induced phenotypes, including glial reactivation, neurodegeneration, and vascular defects. Overexpression of Zfp36 slowed the development of these phenotypes. This work unveiled retinal cell types that are sensitive to diabetes and demonstrated that MGs can mount protective responses through Zfp36.

• In this study, we sought to unveil the molecular mechanisms underlying the diabetes-induced, cell type–specific responses, with the hope of advancing our understanding of diabetic retinopathy and informing therapeutic strategies.

• Single-cell transcriptomics revealed that retinal rod photoreceptors, A17 amacrine cells, and Müller glia are sensitive to diabetes at the transcript levels.

• Retinal Müller glial cells upregulate potential protective genes in response to diabetes but failed to sustain this beneficial effect.

• Enhanced Zfp36 expression in retinal Müller glial cells alleviates diabetes-induced damage in the retina.