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

• Published in: Nature communications Vol. 13; no. 1; pp. 438 - 14
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.01.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/95; 14; 14/19; 14/34; 38; 59; 59/5; 631/154; 631/61/2298; 64; 692/4022/1585; Aging; Amino Acid Sequence; Animal models; Animals; Cell Line; Disease Models, Animal; Fibrosis; Humanities and Social Sciences; Humans; Inflammation - pathology; Intravenous administration; Kidney - injuries; Kidney - metabolism; Kidney - pathology; Kidney - physiopathology; Kidney diseases; Kidney Diseases - complications; Kidney Diseases - pathology; Kidneys; Kinases; Klotho protein; Klotho Proteins - chemistry; Male; Mice; Mice, Inbred BALB C; multidisciplinary; Pathogenesis; Peptides; Peptides - chemistry; Peptides - pharmacology; Phosphorylation - drug effects; Protective Agents - pharmacology; Protein Binding; Protein kinase; Proteins; Rats; Receptors, Transforming Growth Factor beta - metabolism; Reperfusion Injury - complications; Reperfusion Injury - pathology; Reperfusion Injury - physiopathology; Science; Science (multidisciplinary); Signal Transduction; Signaling; Smad Proteins - metabolism; Smad2 protein; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Ureteral Obstruction - complications; Ureteral Obstruction - pathology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-28096-z

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. 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-β signalling.