Fang Gengjing, Zhou Yuling, Zhou Xiaopeng, Zhou Hui, Ge Yuan-Yuan, Luo Shengtao, Chen Jiang-Fan, Zhang Liping
The Molecular Neuropharmacology Laboratory and the Eye-Brain Research Center, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Optometry and Ophthalmology, Wenzhou Medical University, Wenzhou, 325000, China.
The Molecular Neuropharmacology Laboratory and the Eye-Brain Research Center, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Optometry and Ophthalmology, Wenzhou Medical University, Wenzhou, 325000, China.
Neuropharmacology. 2022 May 1;208:108981. doi: 10.1016/j.neuropharm.2022.108981. Epub 2022 Feb 9.
Blockade of adenosine A receptors (ARs) 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 AR 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 AR 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 AR 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 AR antagonist may contribute to understanding the transcriptome mechanism for protection against CCCP-induced retinal injury by AR antagonists.
腺苷A受体（ARs）的阻断可保护神经元免受包括线粒体毒性在内的各种脑损伤所引起的损害，但其确切的神经保护机制尚不清楚。在此，我们研究了AR拮抗剂KW6002对线粒体氧化磷酸化解偶联剂间氯苯腙（CCCP）诱导的视网膜损伤以及竞争性内源性RNA（ceRNA）网络变化的影响。我们发现，KW6002处理通过增加线粒体含量和减少视网膜神经节细胞凋亡，部分逆转了CCCP诱导的视网膜厚度降低和视网膜神经节细胞数量减少。此外，我们采用全转录组测序来探索与CCCP诱导的视网膜损伤及其被KW6002逆转相关的ceRNA网络变化。该分析显示，AR阻断使CCCP诱导的微小RNA数量减少了约60%，但使CCCP诱导的环状RNA数量增加了约50%。在ceRNA网络变化中，CCCP诱导的视网膜损伤可能与肿瘤坏死因子信号通路及其相关的126个微小RNA、237个长链非编码RNA、58个竞争性环状RNA的可能富集有关。此外，AR拮抗剂介导的对CCCP诱导的视网膜损伤的保护作用可能与成熟脑源性神经营养因子及其相关的4个微小RNA的上调有关，这4个微小RNA由43个长链非编码RNA和9个竞争性环状RNA竞争。CCCP处理引起的这些ceRNA网络改变及其被AR拮抗剂逆转可能有助于理解AR拮抗剂对CCCP诱导的视网膜损伤的保护作用的转录组机制。
