From mice to humans: Cross-species transcriptomics analysis to uncover distinct mechanisms of Diabetic Retinopathy (DR)

ABSTRACT Diabetic Retinopathy (DR) is the leading risk for vision loss in working adults worldwide, affecting more than 100 million people. While risk factors such as diabetes duration, hyperglycemia, and dyslipidemia are well-acknowledged, the unifying molecular mechanisms underlying the pathogenesis of DR remain incompletely understood across different species. To bridge this gap, we conducted a comprehensive RNA-sequencing (RNA-seq) meta-analysis on retinal tissue samples from mice, rats, and humans with diabetes. Our integrative bioinformatics analysis elucidated both conserved and species-specific transcriptional landscapes associated with DR. Notably, pro-inflammatory pathways were ubiquitously activated in the retinal tissues across all examined species. However, unique human-specific immune-metabolic signatures emerged, which were not observed in rodent models. In summary, our investigation unveils both universal and species-specific molecular underpinnings of DR, enhancing our understanding of its complex pathobiology. These findings validate the utility of animal models in DR research and underscore the importance of human-focused studies to uncover mechanisms uniquely relevant to human pathology.