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A Klotho-derived peptide protects against kidney fibrosis by targeting TGF-β signaling

Author

Listed:
  • Qian Yuan

    (Nanfang Hospital, Southern Medical University)

  • Qian Ren

    (Nanfang Hospital, Southern Medical University)

  • Li Li

    (Nanfang Hospital, Southern Medical University)

  • Huishi Tan

    (Nanfang Hospital, Southern Medical University)

  • Meizhi Lu

    (Nanfang Hospital, Southern Medical University)

  • Yuan Tian

    (Nanfang Hospital, Southern Medical University)

  • Lu Huang

    (Guangdong University of Technology)

  • Boxin Zhao

    (Nanfang Hospital, Southern Medical University)

  • Haiyan Fu

    (Nanfang Hospital, Southern Medical University)

  • Fan Fan Hou

    (Nanfang Hospital, Southern Medical University
    Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory))

  • Lili Zhou

    (Nanfang Hospital, Southern Medical University
    Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory))

  • Youhua Liu

    (Nanfang Hospital, Southern Medical University
    Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)
    University of Pittsburgh School of Medicine)

Abstract

Loss of Klotho, an anti-aging protein, plays a critical role in the pathogenesis of chronic kidney diseases. As Klotho is a large transmembrane protein, it is challenging to harness it as a therapeutic remedy. Here we report the discovery of a Klotho-derived peptide 1 (KP1) protecting kidneys by targeting TGF-β signaling. By screening a series of peptides derived from human Klotho protein, we identified KP1 that repressed fibroblast activation by binding to TGF-β receptor 2 (TβR2) and disrupting the TGF-β/TβR2 engagement. As such, KP1 blocked TGF-β-induced activation of Smad2/3 and mitogen-activated protein kinases. In mouse models of renal fibrosis, intravenous injection of KP1 resulted in its preferential accumulation in injured kidneys. KP1 preserved kidney function, repressed TGF-β signaling, ameliorated renal fibrosis and restored endogenous Klotho expression. Together, our findings suggest that KP1 recapitulates the anti-fibrotic action of Klotho and offers a potential remedy in the fight against fibrotic kidney diseases.

Suggested Citation

  • Qian Yuan & Qian Ren & Li Li & Huishi Tan & Meizhi Lu & Yuan Tian & Lu Huang & Boxin Zhao & Haiyan Fu & Fan Fan Hou & Lili Zhou & Youhua Liu, 2022. "A Klotho-derived peptide protects against kidney fibrosis by targeting TGF-β signaling," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28096-z
    DOI: 10.1038/s41467-022-28096-z
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    Cited by:

    1. Hirotaka Iijima & Gabrielle Gilmer & Kai Wang & Allison C. Bean & Yuchen He & Hang Lin & Wan-Yee Tang & Daniel Lamont & Chia Tai & Akira Ito & Jeffrey J. Jones & Christopher Evans & Fabrisia Ambrosio, 2023. "Age-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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