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

  • Nat Commun. 2022 Jan 21;13(1):438. doi: 10.1038/s41467-022-28096-z.
Qian Yuan  #  1 ,  Qian Ren  #  1 ,  Li Li  #  1 ,  Huishi Tan  1 ,  Meizhi Lu  1 ,  Yuan Tian  1 ,  Lu Huang  2 ,  Boxin Zhao  3 ,  Haiyan Fu  1 ,  Fan Fan Hou  1  4 ,  Lili Zhou  5  6 ,  Youhua Liu  7  8  9
Affiliations
  • 1. State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 2. Analysis and Test Center, Guangdong University of Technology, Guangzhou, China.
  • 3. Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 4. Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.
  • 5. State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China. [email protected].
  • 6. Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China. [email protected].
  • 7. State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China. [email protected].
  • 8. Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China. [email protected].
  • 9. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. [email protected].
  • # Contributed equally.
PMID: 35064106 DOI: 10.1038/s41467-022-28096-z
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.

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