Although diabetic retinopathy (DR) is among the retinal vascular diseases that may initially present with minor vision problems, it can also be asymptomatic at onset. And although minor cases of DR can be managed, the condition can lead to blindness. Despite a complex etiology, DR has been linked in prior research to autophagy.

 

Identifying the Genes that Contribute to Diabetic Retinopathy

To identify the autophagy-related genes that contribute to the development of DR, Nan Wang and colleagues extracted data from the Gene Expression Omnibus (GEO) database profiling GSE146615. Three groups of individuals were identified: individuals without diabetes, patients with type 1 diabetes without complications from DR, and patients with diagnosed DR. Lymphoblastoid cell lines were extracted from all participants and processed accordingly: the non-diabetic group sample was treated with standard glucose, and the DR group with high glucose.

Wang and colleagues analyzed the expression of 232 differentially expressed genes (DEGs) related to autophagy using the “limma” package in R software. Genes were considered DEG if they had a P-value of less than 0.05. The study team identified nine up-regulated genes (involved in decreasing cellular component) and 14 down-regulated genes (involved in the increase in cellular response resulting from an increase in the number of receptors on the cell’s surface).

In total, 23 differentially expressed autophagy-related genes were identified between the DR group and the non-diabetic group. “The analysis of tissue-specific gene expression showed that these differentially expressed autophagy-related genes were enriched in the retina,” wrote Wang and team.

 

Differential Gene Activities

The most prominent activities of these differential genes included regulation of autophagy, positive regulation of the catabolic process, macro-autophagy, positive regulation of autophagy; late endosome, mitochondrial outer membrane, organelle outer membrane; ubiquitin-like protein ligase binding, chaperone binding, and Bcl-2 homology domain binding. The 12 common genes in the three most prominent pathways were CDKN1B, BAX, DAPK1, FOXO3, BAG3, MAPK3, CHMP4B, DRAM1, NPC1, CAMKK2, ITPR1, and TSC1.

MAPK3 stood out as a potential candidate for affecting the occurrence and development of DR because of its role in regulating autophagy. The protein encoded by MAPK3 is a member of the MAP kinese family. “Through bioinformatics analysis, we identified 23 potential DR autophagy-related genes, among which the down-regulated expression of MAPK3 may affect the occurrence and development of DR by regulating autophagy,” concluded Wang and colleagues. “It provides a novel insight into the pathogenesis of DR. In the future, further experiments are needed to investigate the regulatory role of MAPK3 in DR models in order to clarify its value as potential clinical biomarkers or therapeutic targets.”