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 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 glia 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 Müller glia 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 Müller glial cells in vivo using AAV-based tools exacerbated diabetes-induced phenotypes, including glial reactivation, neurodegeneration, and vascular defects. Over-expression of Zfp36 slowed the development of these phenotypes. This work unveiled retinal cell types that are sensitive to diabetes and demonstrated that Müller glial cells can mount protective responses through Zfp36.

中文翻译：

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Müller 神经胶质细胞特异性保护通路的诱导可保护视网膜免受糖尿病引起的损伤


糖尿病可导致视网膜中出现细胞类型特异性反应，包括血管病变、神经胶质功能障碍和神经退行性变，所有这些都会导致视网膜病变。然而，这些细胞类型特异性反应背后的分子机制以及对糖尿病敏感的细胞类型尚未完全阐明。采用单细胞转录组学，我们分析了糖尿病在大鼠模型中随着疾病进展在不同视网膜细胞类型中诱导的转录变化。棒状光感受器（无长突呤中间神经元的一种亚型）和 Müller 胶质细胞在转录水平上表现出对糖尿病的快速反应。与离子调节相关的基因在所有三种细胞类型中均上调，表明对糖尿病的共同反应。此外，重点研究表明，虽然 Müller 胶质细胞最初增加了发挥保护作用的基因的表达，但它们无法维持这种有益效果。我们探索了其中一个候选保护基因锌指蛋白 36 同源物 （Zfp36），并观察到使用基于 AAV 的工具在体内消耗大鼠 Müller 神经胶质细胞中的 Zfp36 加剧了糖尿病诱导的表型，包括神经胶质细胞再激活、神经退行性和血管缺陷。Zfp36 的过表达减缓了这些表型的发展。这项工作揭示了对糖尿病敏感的视网膜细胞类型，并证明 Müller 神经胶质细胞可以通过 Zfp36 产生保护性反应。