The adenosine A2A receptor antagonist protects against retinal mitochondrial injury in association with an altered network of competing endogenous RNAs

Abstract

Blockade of adenosine A2A receptors (A2ARs) protects against neuronal damage caused by various brain insults including mitochondrial toxicity, but the precise neuroprotective mechanisms are unclear. Here, we studied the effects of the A2AR antagonist KW6002 on retinal injury induced by the mitochondrial oxidative phosphorylation uncoupler, carbonylcyanide m-chlorophenyl hydrazine (CCCP) and alterations in competing endogenous RNA (ceRNA) network. We found that KW6002 treatment partially reversed CCCP-induced reduction in retinal thickness and retinal ganglia cell number by increasing mitochondrial content and reducing retinal ganglia cells apoptosis. Furthermore, we employed whole-transcriptome sequencing to explore ceRNA network changes associated with CCCP-induced retinal injury and its reversal by KW6002. This analysis revealed that A2AR blockade reduced the number of CCCP-induced microRNAs by ∼60%, but increased the number of CCCP-induced circular RNAs by ∼50%. Among CeRNA network changes, CCCP-induced retinal injury was associated with a possible enrichment of the tumor necrosis factor signaling pathway and its related 126 microRNAs, 237 long non-coding RNAs, 58 circular RNAs competing. Moreover, the A2AR antagonist-mediated protection against CCCP-induced retinal injury was possibly associated with the up-regulation of mature brain-derived neurotrophic factor and its related 4 microRNAs competed by 43 long non-coding RNAs and 9 circular RNAs competing. These ceRNA network alterations by CCCP treatment and its reversal by A2AR antagonist may contribute to understanding the transcriptome mechanism for protection against CCCP-induced retinal injury by A2AR antagonists.