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

Qian Yuan, Qian Ren, Li Li, Huishi Tan, Meizhi Lu, Yuan Tian, Lu Huang, Boxin Zhao, Haiyan Fu, Fan Fan Hou, Lili Zhou () and Youhua Liu ()
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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
Lili Zhou: Nanfang Hospital, Southern Medical University
Youhua Liu: Nanfang Hospital, Southern Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28096-z

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