Huang Liuwei, Shen Yanting, Pan Xiaoling, Li Jiaqi, Li Caizhen, Ruan Lixin, He Sitan, Huang Lanlan, Liu Kangyi, Zhao Xin, Geng Jian, Guo Jie, Hou Fan Fan, Wang Jun
Division of Nephrology, National Key Laboratory for Prevention and Treatment of Multi-organ Injury, Nanfang Hospital, Southern Medical University, Guangzhou, China.
National Clinical Research Center of Kidney Disease, Nanfang Hospital, Guangzhou, China.
Nat Commun. 2025 Aug 19;16(1):7699. doi: 10.1038/s41467-025-63152-4.
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 (Ca) 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.
急性肾损伤（AKI）可导致慢性肾脏病（CKD），这种转变由细胞衰老驱动，细胞衰老即一种不可逆的细胞周期停滞状态。然而，促进这一病理过程的分子机制仍不清楚。在此，我们表明通道蛋白泛连接蛋白1（Panx1）促进了这种有害的衰老及随后的肾纤维化。我们发现，Panx1在内质网（ER）（一种关键的细胞内钙库）中作为钙（Ca）泄漏通道发挥非典型作用。这种由Panx1介导的泄漏发生在内质网与线粒体的接触部位，导致线粒体钙超载、功能障碍以及促衰老信号的产生。在雄性急性肾损伤小鼠模型中基因敲除Panx1可减轻肾脏衰老和纤维化。这些在人类肾脏组织中得到验证的发现表明，内质网驻留的Panx1是肾脏疾病进展的关键驱动因素及潜在治疗靶点。
