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

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  • Liuwei Huang

    (Southern Medical University
    Nanfang Hospital
    Guangdong Provincial Institute of Nephrology
    Guangdong Provincial Clinical Research Center for Kidney disease)

  • Yanting Shen

    (Southern Medical University
    Nanfang Hospital
    Guangdong Provincial Institute of Nephrology
    Guangdong Provincial Clinical Research Center for Kidney disease)

  • Xiaoling Pan

    (Southern Medical University
    Nanfang Hospital
    Guangdong Provincial Institute of Nephrology
    Guangdong Provincial Clinical Research Center for Kidney disease)

  • Jiaqi Li

    (Southern Medical University
    Nanfang Hospital
    Guangdong Provincial Institute of Nephrology
    Guangdong Provincial Clinical Research Center for Kidney disease)

  • Caizhen Li

    (Southern Medical University
    Southern Medical University)

  • Lixin Ruan

    (Southern Medical University
    Nanfang Hospital
    Guangdong Provincial Institute of Nephrology
    Guangdong Provincial Clinical Research Center for Kidney disease)

  • Sitan He

    (Southern Medical University
    Nanfang Hospital
    Guangdong Provincial Institute of Nephrology
    Guangdong Provincial Clinical Research Center for Kidney disease)

  • Lanlan Huang

    (Southern Medical University
    Nanfang Hospital
    Guangdong Provincial Institute of Nephrology
    Guangdong Provincial Clinical Research Center for Kidney disease)

  • Kangyi Liu

    (Southern Medical University
    Nanfang Hospital
    Guangdong Provincial Institute of Nephrology
    Guangdong Provincial Clinical Research Center for Kidney disease)

  • Xin Zhao

    (Southern Medical University
    Nanfang Hospital
    Guangdong Provincial Institute of Nephrology
    Guangdong Provincial Clinical Research Center for Kidney disease)

  • Jian Geng

    (Southern Medical University
    Southern Medical University)

  • Jie Guo

    (Kashi Prefecture Second People’s Hospital)

  • Fan Fan Hou

    (Southern Medical University
    Nanfang Hospital
    Guangdong Provincial Institute of Nephrology
    Guangdong Provincial Clinical Research Center for Kidney disease)

  • Jun Wang

    (Southern Medical University
    Nanfang Hospital
    Guangdong Provincial Institute of Nephrology
    Guangdong Provincial Clinical Research Center for Kidney disease)

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.

Suggested Citation

  • 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, 2025. "Noncanonical function of Pannexin1 promotes cellular senescence and renal fibrosis post-acute kidney injury," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63152-4
    DOI: 10.1038/s41467-025-63152-4
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    1. Dorian V. Ziegler & David Vindrieux & Delphine Goehrig & Sara Jaber & Guillaume Collin & Audrey Griveau & Clotilde Wiel & Nadia Bendridi & Sophia Djebali & Valerio Farfariello & Natacha Prevarskaya & , 2021. "Calcium channel ITPR2 and mitochondria–ER contacts promote cellular senescence and aging," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Clotilde Wiel & Hélène Lallet-Daher & Delphine Gitenay & Baptiste Gras & Benjamin Le Calvé & Arnaud Augert & Mylène Ferrand & Natalia Prevarskaya & Hélène Simonnet & David Vindrieux & David Bernard, 2014. "Endoplasmic reticulum calcium release through ITPR2 channels leads to mitochondrial calcium accumulation and senescence," Nature Communications, Nature, vol. 5(1), pages 1-10, September.
    3. Letizia Chiara & Carolina Conte & Roberto Semeraro & Paula Diaz-Bulnes & Maria Lucia Angelotti & Benedetta Mazzinghi & Alice Molli & Giulia Antonelli & Samuela Landini & Maria Elena Melica & Anna Juli, 2022. "Tubular cell polyploidy protects from lethal acute kidney injury but promotes consequent chronic kidney disease," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
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