2. Academic Validation
  3. A Klotho-derived peptide protects against kidney fibrosis by targeting TGF-β signaling

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

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. jinli730@smu.edu.cn.
  • 6 Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China. jinli730@smu.edu.cn.
  • 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. yhliu@pitt.edu.
  • 8 Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China. yhliu@pitt.edu.
  • 9 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. yhliu@pitt.edu.
  • # 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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