Noncanonical function of Pannexin1 promotes cellular senescence and renal fibrosis post-acute kidney injury

作者：Liuwei Huang, Yanting Shen, Xiaoling Pan, Jiaqi Li, Caizhen Li, Lixin Ruan, Shuai He, Lanlan Huang, Kangyi Liu, Xin Zhao, Jian Geng, Jie Guo, Fan Fan Hou, Jun Wang · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-63152-4 · 被引用次数：10 · 研究领域：Connexins and lens biology、Biomarkers in Disease Mechanisms、Heme Oxygenase-1 and Carbon Monoxide

Acute kidney injury (AKI) can lead to chronic kidney disease (CKD), a transition driven by cellular senescence, a state of irreversible cell-cycle arrest. However, the molecular mechanisms promoting this pathological process remain unclear. Here we show that the channel protein Pannexin1 (Panx1) promotes this detrimental senescence and subsequent kidney fibrosis. We found that Panx1 functions in a noncanonical role as a calcium (Ca2+) leak channel within the endoplasmic reticulum (ER), a key intracellular calcium store. This Panx1-mediated leak occurs at contact sites between the ER and mitochondria, leading to mitochondrial calcium overload, dysfunction, and the generation of pro-senescence signals. Genetically deleting Panx1 in male mouse models of AKI attenuates renal senescence and fibrosis. These findings, validated in human kidney tissue, identify ER-resident Panx1 as a critical driver of kidney disease progression and a potential therapeutic target. In a model of acute kidney injury the authors show that Pannexin1 can mediate a leak of Calcium from the endoplasmic reticulum leading to mitochondrial calcium overload and pro-senescence signals, and ultimately driving fibrosis and kidney disease progression