Abstract
Purpose :
To analyze the intra-species and inter-species retinal gene expression profile variation in mouse and rat models of diabetic retinopathy (DR) and investigate the effectiveness of each model to have relevance to the study of human DR.
Methods :
Retinal microarray and RNA-seq datasets of mammalian DR models were extracted from public gene expression databases, and spatial and temporal gene expression patterns were explored. To analyze inter-species variance, datasets were merged and batch-normalized using an empirical Bayesian framework through the Combat and Combat-Seq tools to minimize non-biological variance. Differential gene expression (DGE) analysis was performed using limma and DESeq2, and the relative transcript expression levels were scaled using Bayesian shrinkage estimators. Results were validated using a PCA-based quality check and outlier test, and IPA analytics were performed to identify upstream regulators and their effects on cellular pathways.
Results :
Comparison of intra-species expression profiles (mice and rats) revealed an identical pattern of gene expression pathways that reflect common mechanisms of DR, including altered cytokine and endocytosis signaling. C57BL/6J streptozotocin-treated strain displayed inflammatory pathway activation characterized by activated macrophages. We identified significant downregulation of the CX3CR1 and PPARD genes in the Ins2Akita and C57BL/6J models. Interestingly, Long Evans and Sprague Dawley rats displayed activation of inflammatory response pathways mediated by IL6 and FOXO3 regulators. Inter-species analysis reveals that rat and human samples collectively upregulate angiogenesis and cytokine signaling pathways through the STAT3 gene. Overall the degree of preservation of transcript levels between the species showed a considerable overlap of gene networks associated with inflammatory signaling pathways.
Conclusions :
Our results suggest considerable similarities and minor differences in the mammalian diabetic retina. We found that the genes overexpressed are linked to the inflammatory response that distinguished the effect of diabetes in the rodent models of DR.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.