Noncanonical function of Pannexin1 promotes cellular senescence and renal fibrosis post-acute kidney injury
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<sup>2+</sup>) 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.
Authors
- Kangyi Liu (ORCID: https://orcid.org/0009-0003-0577-2958)
- Caizhen Li (ORCID: https://orcid.org/0000-0001-6854-116X)
- Fan Fan Hou (ORCID: https://orcid.org/0000-0003-3117-7418)
- Xin Zhao (ORCID: https://orcid.org/0000-0001-9798-7865)
- Xiaoling Pan (ORCID: https://orcid.org/0000-0002-4726-5095)
- Lixin Ruan
- Jiaqi Li (ORCID: https://orcid.org/0009-0005-4613-5116)
- Jun Wang (ORCID: https://orcid.org/0000-0001-6822-2863)
- Lanlan Huang (ORCID: https://orcid.org/0000-0001-8256-726X)
- Jian Geng (ORCID: https://orcid.org/0009-0005-8057-3929)
- Shuai He (ORCID: https://orcid.org/0009-0008-2380-2627)
- Jie Guo (ORCID: https://orcid.org/0000-0002-7772-9612)
- Yanting Shen (ORCID: https://orcid.org/0000-0001-8129-0844)
- Liuwei Huang
Institutions
- Nanfang Hospital (CN)
- The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture (CN)
- Guangdong Provincial Center for Disease Control and Prevention (CN)
- Guangdong Provincial People's Hospital (CN)
- Southern Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-19
- DOI
- https://doi.org/10.1038/s41467-025-63152-4
- Citations
- 5
- Primary Topic
- Connexins and lens biology
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- National Natural Science Foundation of China
- Nanfang Hospital
- Project 211
- Basic and Applied Basic Research Foundation of Guangdong Province