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Loss of CLDN5 in podocytes deregulates WIF1 to activate WNT signaling and contributes to kidney disease

Author

Listed:
  • Hui Sun

    (Binzhou Medical University)

  • Hui Li

    (West China Hospital, Sichuan University)

  • Jie Yan

    (Binzhou Medical University)

  • Xiangdong Wang

    (Binzhou Medical University)

  • Mengyuan Xu

    (Binzhou Medical University)

  • Mingxia Wang

    (Binzhou Medical University)

  • Baozhen Fan

    (Binzhou Medical University)

  • Jieying Liu

    (Binzhou Medical University)

  • Ninghua Lin

    (Binzhou Medical University)

  • Xin Wang

    (Qingdao University)

  • Li Li

    (Binzhou Medical University)

  • Shengtian Zhao

    (Binzhou Medical University Hospital
    Shandong Provincial Engineering Laboratory of Urologic Tissue Reconstruction
    Shandong Provincial Hospital Affiliated to Shandong First Medical University)

  • Yongfeng Gong

    (Binzhou Medical University)

Abstract

Although mature podocytes lack tight junctions, tight junction integral membrane protein claudin-5 (CLDN5) is predominantly expressed on plasma membranes of podocytes under normal conditions. Using podocyte-specific Cldn5 knockout mice, we identify CLDN5 as a crucial regulator of podocyte function and reveal that Cldn5 deletion exacerbates podocyte injury and proteinuria in a diabetic nephropathy mouse model. Mechanistically, CLDN5 deletion reduces ZO1 expression and induces nuclear translocation of ZONAB, followed by transcriptional downregulation of WNT inhibitory factor-1 (WIF1) expression, which leads to activation of WNT signaling pathway. Podocyte-derived WIF1 also plays paracrine roles in tubular epithelial cells, as evidenced by the finding that animals with podocyte-specific deletion of Cldn5 or Wif1 have worse kidney fibrosis after unilateral ureteral obstruction than littermate controls. Systemic delivery of WIF1 suppresses the progression of diabetic nephropathy and ureteral obstruction-induced renal fibrosis. These findings establish a function for podocyte CLDN5 in restricting WNT signaling in kidney.

Suggested Citation

  • Hui Sun & Hui Li & Jie Yan & Xiangdong Wang & Mengyuan Xu & Mingxia Wang & Baozhen Fan & Jieying Liu & Ninghua Lin & Xin Wang & Li Li & Shengtian Zhao & Yongfeng Gong, 2022. "Loss of CLDN5 in podocytes deregulates WIF1 to activate WNT signaling and contributes to kidney disease," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29277-6
    DOI: 10.1038/s41467-022-29277-6
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    References listed on IDEAS

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    1. Jen-Chih Hsieh & Laurent Kodjabachian & Martha L. Rebbert & Amir Rattner & Philip M. Smallwood & Cynthia Harryman Samos & Roel Nusse & Igor B. Dawid & Jeremy Nathans, 1999. "A new secreted protein that binds to Wnt proteins and inhibits their activites," Nature, Nature, vol. 398(6726), pages 431-436, April.
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    Cited by:

    1. Ying Zhao & Shijie Fan & Hong Zhu & Qingqing Zhao & Zimin Fang & Diyun Xu & Wante Lin & Liming Lin & Xiang Hu & Gaojun Wu & Julian Min & Guang Liang, 2024. "Podocyte OTUD5 alleviates diabetic kidney disease through deubiquitinating TAK1 and reducing podocyte inflammation and injury," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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