Abstract
Purpose :
Diabetes can induce distinct responses in retinal cell types, such as vascular lesions, glial dysfunction, and neurodegeneration, collectively contributing to retinopathy. Despite this, the precise molecular mechanisms governing these cell type-specific reactions and the cell types susceptible to diabetes remain incompletely understood.
Methods :
Diabetes-induced retinal responses have been extensively investigated utilizing various diabetic rodent models that exhibit early-stage phenotypes resembling human diabetic retinopathy (NPDR). Notably, the Streptozotocin (STZ)-induced diabetic rat model, known for its ease of induction and thorough characterization in DR research, has played a pivotal role. Employing this model, we conducted single-cell transcriptomic analyses of the retina, profiling transcriptional changes induced by diabetes in distinct retinal cell types at 1, 2, or 3 months post-STZ injection. Analysis of the obtained data followed established bioinformatic pipelines. To validate the findings, mRNA in situ hybridization and AAV-based gene manipulation were employed.
Results :
Within the 53 retinal cell types identified through scRNA-seq, rod photoreceptors, a subtype of amacrine interneurons, and Müller glial cells displayed swift transcript-level responses to diabetes. Notably, genes linked to ion regulation exhibited upregulation across all three cell types, indicating a shared response to diabetes. Further investigations revealed that, while Müller glial cells initially elevated the expression of genes with protective roles, they were unable to sustain this positive effect as the disease advanced. Our exploration focused on one potential protective gene, Zinc finger protein 36 homolog (Zfp36). Depleting Zfp36 in rat Müller glial cells in vivo using AAV-based tools exacerbated early diabetes-induced phenotypes, including gliosis, neuronal degeneration, and vascular defects. Significantly, the overexpression of Zfp36 decelerated the progression of phenotypes associated with DR.
Conclusions :
Rod photoreceptors, a subtype of amacrine cells, and Müller glia exhibit sensitivity to diabetes at the transcript level. During the initial stages of DR, Müller glia can play protective and beneficial roles. However, the breakdown of this adaptive response may contribute to the onset and advancement of DR.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.