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Pannexin 1 通过靶向线粒体自噬来介导肾缺血/再灌注损伤。

Pannexin 1 targets mitophagy to mediate renal ischemia/reperfusion injury.

机构信息

Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China.

Clinical Research Center of Hubei Critical Care Medicine, Wuhan, China.

出版信息

Commun Biol. 2023 Aug 29;6(1):889. doi: 10.1038/s42003-023-05226-x.

DOI:10.1038/s42003-023-05226-x
PMID:37644178
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10465551/
Abstract

Renal ischemia/reperfusion (I/R) injury contributes to the development of acute kidney injury (AKI). Kidney is the second organ rich in mitochondrial content next to the heart. Mitochondrial damage substantially contributes for AKI development. Mitophagy eliminates damaged mitochondria from the cells to maintain a healthy mitochondrial population, which plays an important role in AKI. Pannexin 1 (PANX1) channel transmembrane proteins are known to drive inflammation and release of adenosine triphosphate (ATP) during I/R injury. However, the specific role of PANX1 on mitophagy regulation in renal I/R injury remains elusive. In this study, we find that serum level of PANX1 is elevated in patients who developed AKI after cardiac surgery, and the level of PANX1 is positively correlated with serum creatinine and urea nitrogen levels. Using the mouse model of renal I/R injury in vivo and cell-based hypoxia/reoxygenation (H/R) model in vitro, we prove that genetic deletion of PANX1 mitigate the kidney tubular cell death, oxidative stress and mitochondrial damage after I/R injury through enhanced mitophagy. Mechanistically, PANX1 disrupts mitophagy by influencing ATP-P2Y-mTOR signal pathway. These observations provide evidence that PANX1 could be a potential biomarker for AKI and a therapeutic target to alleviate AKI caused by I/R injury.

摘要

肾缺血/再灌注 (I/R) 损伤导致急性肾损伤 (AKI) 的发生。肾脏是仅次于心脏的第二大富含线粒体的器官。线粒体损伤是 AKI 发展的主要原因。自噬可消除细胞内受损的线粒体，维持健康的线粒体群体，在 AKI 中发挥重要作用。已知连接蛋白 1 (PANX1) 通道跨膜蛋白在 I/R 损伤期间可驱动炎症和三磷酸腺苷 (ATP) 的释放。然而，PANX1 在肾 I/R 损伤中对自噬调节的具体作用仍不清楚。在这项研究中，我们发现心脏手术后发生 AKI 的患者血清中 PANX1 水平升高，且 PANX1 水平与血清肌酐和尿素氮水平呈正相关。通过体内肾 I/R 损伤小鼠模型和体外细胞缺氧/复氧 (H/R) 模型，我们证明通过增强自噬，PANX1 的基因缺失可减轻 I/R 损伤后的肾小管细胞死亡、氧化应激和线粒体损伤。在机制上，PANX1 通过影响 ATP-P2Y-mTOR 信号通路来破坏自噬。这些观察结果为 PANX1 可能成为 AKI 的潜在生物标志物以及减轻 I/R 损伤引起的 AKI 的治疗靶点提供了证据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c730/10465551/7ca9d18af8b0/42003_2023_5226_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c730/10465551/7ca9d18af8b0/42003_2023_5226_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c730/10465551/1fdba4f21881/42003_2023_5226_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c730/10465551/6ad31cc098c9/42003_2023_5226_Fig2_HTML.jpg
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