Targeting P2RX1 alleviates renal ischemia/reperfusion injury by preserving mitochondrial dynamics
Targeting P2RX1 alleviates renal ischemia/reperfusion injury by preserving mitochondrial dynamics
复制标题
靶向 P2RX1 通过保持线粒体动力学减轻肾缺血/再灌注损伤
DOI：
10.1016/j.phrs.2021.105712
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发表时间：
2021-06-10
影响因子：
9.3
通讯作者：
Wang, Xu
中科院分区：
文献类型：
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作者：
Zhuang, Shaoyong;Xia, Shengqiang;Wang, Xu
肾缺血/再灌注损伤（IRI）是急性肾损伤的主要原因。然而，肾功能突然丧失和组织损伤的机制仍有待充分阐明。在这里，我们进行RNA测序，系统地比较IR损伤的肾脏和假肾之间的转录组差异。我们观察到肾IRI时线粒体动力学受到破坏。线粒体融合相关基因的表达减少，而线粒体分裂相关基因的表达增加，在肾IRI，这些发现进一步证实了线粒体形态学观察。通过筛选19种嘌呤能受体，我们发现P2 RX 1在肾IRI中表达显著上调。RNA测序和线粒体形态学观察显示，线粒体动力学在P2 RX 1基因敲除（P2 rx 1（-/-））小鼠中得以保留。据报道，神经细胞外陷阱（NETs）在肾IRI的组织损伤中是必不可少的，但详细的机制仍不清楚。在本研究中，我们发现P2 RX 1有利于IRI中中性粒细胞胞外陷阱（NETs）的形成，而NETs对于线粒体动力学的损害是必不可少的。从机制上讲，P2 RX 1参与的血小板和中性粒细胞之间的代谢相互作用支持NET的形成。P2 RX 1的激活促进血小板ATP释放，从而促进中性粒细胞糖酵解代谢和NETs的产生。
Renal ischemia/reperfusion injury (IRI) is the major cause of acute kidney injury. However, mechanisms underlying the sudden loss in kidney function and tissue injury remain to be fully elucidated. Here, we performed RNA sequencing to systematically compare the transcriptome differences between IR injured kidneys and sham kidneys. We observed that mitochondrial dynamics was destructed in renal IRI. Expression of mitochondrial fusion-associated genes was reduced, whereas expression of mitochondrial fission-related genes was increased in renal IRI, and these findings were further confirmed by mitochondrial morphological observations. By screening 19 purinergic receptors, we noticed that P2RX1 expression was markedly upregulated in renal IRI. RNA sequencing and mitochondrial morphological observations revealed that mitochondrial dynamics was preserved in P2RX1 genetic knockout (P2rx1(-/-)) mice. Neutrophil extracellular traps (NETs) were reported to be essential for tissue injury in renal IRI, but the detailed mechanism remained unclear. In the present study, we found that P2RX1 favored the formation of neutrophil extracellular traps (NETs) in IRI, and NETs was essential for the impairment of mitochondrial dynamics. Mechanistically, P2RX1-involved metabolic interaction between platelets and neutrophils supported NETs formation. Activation of P2RX1 promoted platelets ATP release, which subsequently contributed to neutrophil glycolytic metabolism and NETs generation.