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

作者：Yuan, Qian; Ren, Qian; Li, Li; Tan, Huishi; Lu, Meizhi; Tian, Yuan; Huang, Lu; Zhao, Boxin; Fu, Haiyan; Hou, Fan Fan; Zhou, Lili^*; Liu, Youhua^*

来源：Nature Communications, 2022, 13(1): 438.

DOI：10.1038/s41467-022-28096-z

• RENAL FIBROSIS
• ALPHA-KLOTHO
• TYPES I
• MECHANISMS
• INJURY
• MYOFIBROBLASTS
• ORIGIN
• THERAPEUTICS
• ACTIVATION
• EXPRESSION

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-beta signaling. By screening a series of peptides derived from human Klotho protein, we identified KP1 that repressed fibroblast activation by binding to TGF-beta receptor 2 (T beta R2) and disrupting the TGF-beta/T beta R2 engagement. As such, KP1 blocked TGF-beta-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-beta 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. @@@ Klotho is an anti-ageing protein whose expression is downregulated in chronic kidney disease, but the large size of the protein makes it challenging to deliver therapeutically. Here, the authors develop a Klotho-derived peptide, and show that it recapitulates the anti-fibrotic action of Klotho and prevents kidney fibrosis in mice by targeting TGF-beta signalling.

• 单位
  广东工业大学; test; 南方医科大学; TEST