Noncanonical function of Pannexin1 promotes cellular senescence and renal fibrosis post-acute kidney injury
Abstract 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 (P...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-63152-4 |
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| author | Liuwei Huang Yanting Shen Xiaoling Pan Jiaqi Li Caizhen Li Lixin Ruan Sitan He Lanlan Huang Kangyi Liu Xin Zhao Jian Geng Jie Guo Fan Fan Hou Jun Wang |
| author_facet | Liuwei Huang Yanting Shen Xiaoling Pan Jiaqi Li Caizhen Li Lixin Ruan Sitan He Lanlan Huang Kangyi Liu Xin Zhao Jian Geng Jie Guo Fan Fan Hou Jun Wang |
| author_sort | Liuwei Huang |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-ab7eb527030a4d3c86cd84b05f753539 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ab7eb527030a4d3c86cd84b05f7535392025-08-24T11:38:07ZengNature PortfolioNature Communications2041-17232025-08-0116112110.1038/s41467-025-63152-4Noncanonical function of Pannexin1 promotes cellular senescence and renal fibrosis post-acute kidney injuryLiuwei Huang0Yanting Shen1Xiaoling Pan2Jiaqi Li3Caizhen Li4Lixin Ruan5Sitan He6Lanlan Huang7Kangyi Liu8Xin Zhao9Jian Geng10Jie Guo11Fan Fan Hou12Jun Wang13Division of Nephrology, National Key Laboratory for Prevention and Treatment of Multi-organ Injury, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, National Key Laboratory for Prevention and Treatment of Multi-organ Injury, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, National Key Laboratory for Prevention and Treatment of Multi-organ Injury, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, National Key Laboratory for Prevention and Treatment of Multi-organ Injury, Nanfang Hospital, Southern Medical UniversityThe First School of Clinical Medicine, Southern Medical UniversityDivision of Nephrology, National Key Laboratory for Prevention and Treatment of Multi-organ Injury, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, National Key Laboratory for Prevention and Treatment of Multi-organ Injury, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, National Key Laboratory for Prevention and Treatment of Multi-organ Injury, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, National Key Laboratory for Prevention and Treatment of Multi-organ Injury, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, National Key Laboratory for Prevention and Treatment of Multi-organ Injury, Nanfang Hospital, Southern Medical UniversityDepartment of Pathology, School of Basic Medical Sciences, Southern Medical UniversityDivision of Nephrology, Kashi Prefecture Second People’s HospitalDivision of Nephrology, National Key Laboratory for Prevention and Treatment of Multi-organ Injury, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, National Key Laboratory for Prevention and Treatment of Multi-organ Injury, Nanfang Hospital, Southern Medical UniversityAbstract 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.https://doi.org/10.1038/s41467-025-63152-4 |
| spellingShingle | Liuwei Huang Yanting Shen Xiaoling Pan Jiaqi Li Caizhen Li Lixin Ruan Sitan He Lanlan Huang Kangyi Liu Xin Zhao Jian Geng Jie Guo Fan Fan Hou Jun Wang Noncanonical function of Pannexin1 promotes cellular senescence and renal fibrosis post-acute kidney injury Nature Communications |
| title | Noncanonical function of Pannexin1 promotes cellular senescence and renal fibrosis post-acute kidney injury |
| title_full | Noncanonical function of Pannexin1 promotes cellular senescence and renal fibrosis post-acute kidney injury |
| title_fullStr | Noncanonical function of Pannexin1 promotes cellular senescence and renal fibrosis post-acute kidney injury |
| title_full_unstemmed | Noncanonical function of Pannexin1 promotes cellular senescence and renal fibrosis post-acute kidney injury |
| title_short | Noncanonical function of Pannexin1 promotes cellular senescence and renal fibrosis post-acute kidney injury |
| title_sort | noncanonical function of pannexin1 promotes cellular senescence and renal fibrosis post acute kidney injury |
| url | https://doi.org/10.1038/s41467-025-63152-4 |
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