Identification and Validation of Autophagy-Related Genes in Diabetic Retinopathy

Abstract

BackgroundDiabetic retinopathy (DR) is one of the most common microvascular complications of diabetes, which is associated with damage of blood-retinal barrier and ischemia of retinal vasculature. It devastates visual acuity due to leakage of retinal vessels and aberrant pathological angiogenesis in diabetic patients. The etiology of DR is complex, accumulated studies have shown that autophagy plays an important role in the pathogenesis of DR, but its specific mechanism needs to be further studied.MethodsThis study chose the online Gene Expression Omnibus (GEO) microarray expression profiling dataset GSE146615 to carry on the research. Autophagy-related genes that were potentially differentially expressed in DR were screened by R software. Then, the differentially expressed autophagy-related genes were analyzed by correlation analysis, tissue-specific gene expression, gene-ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and protein-protein interaction (PPI) network analysis. Finally, retinal pigment epithelial cell line (ARPE-19) incubated with high glucose (HG) was used to mimic the DR model, and the mRNA level of key genes was verified by quantitative real-time polymerase chain reaction (qRT-PCR) in vitro.ResultsA total of 23 differentially expressed autophagy-related genes (9 up-regulated genes and 14 down-regulated genes) were identified by differential expression analysis. The analysis of tissue-specific gene expression showed that these differentially expressed autophagy-related genes were enriched in the retina. GO and KEGG enrichment analysis showed that differentially expressed autophagy-related genes were significantly enriched in autophagy-related pathways such as regulation of autophagy and macroautophagy. Then 10 hub genes were identified by PPI network analysis and construction of key modules. Finally, qRT-PCR confirmed that the expression of MAPK3 in the DR model was consistent with the results of bioinformatics analysis of mRNA chip.ConclusionThrough 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. It provides a novel insight into the pathogenesis of DR.

Autophagy and senescence of rat retinal precursor cells under high glucose

“…Like the studies by Wang et al. ( 17 , 48 ), we extrapolated the conclusions of the initial results to provide a new perspective on the pathogenesis of DR. This study preliminarily confirmed that autophagy and aging of RGCs are involved in high glucose injury combined with sequencing results and gene expression verification.…”

“…By mining the differentially expressed genes in FVMs and normal retinas, we obtained genes potentially altered in retinal under a high glucose environment and inferred the damage targets of high glucose to RGCs. Like the studies by Wang et al (17,48), we extrapolated the conclusions of the initial results to provide a new perspective on the pathogenesis of DR. This study preliminarily confirmed that autophagy and aging of RGCs are involved in high glucose injury combined with sequencing results and gene expression verification.…”

“…The BRB breakdown and retinal vascular disorders in DR are widely studied. Notably, Wang et al (17) have primarily demonstrated the role of RPE autophagy in BRB damage in DR. DRN is now considered an initial event contributing to DRV and is detectable before the clinical appearance of DRV (38). In-depth exploration of DRN is more helpful to directly understand the mechanism and prevention methods of blindness caused by DR.…”

“…Previous studies mainly focused on pericytes and RPE cells' autophagy in DR. Wang et al (17) found that the high expression of the autophagy-related gene (ARG) MAPK3 in retinal pigment epithelial cells might be involved in outer bloodretina barrier destruction in DR. Lin et al (18) described in detail the effect of oxidative stress-activated autophagy on RGCs; however, it remains controversial whether the autophagy in RGCs is beneficial. It is worth noting that there is increasing evidence that autophagy is related to senescence, another common pathological change in endocrine and neurological diseases (19)(20)(21).…”

Exploring the protective effects of herbal monomers against diabetic retinopathy based on the regulation of autophagy and apoptosis: A review

“…In contrast to surgery alone or anti-VEGF therapy, herbal monomers for the treatment of DR have received extensive attention from academic researchers recently because of their mild side effects. [116,117] Overall, autophagy has clearly become a research hotspot for DR. [27,116] The majority of evidence indicates that autophagy plays a dual role in time and volume accumulation (Fig. 4).…”