Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-28096-z
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Funding
- National Natural Science Foundation of China [81521003, 81920108007]
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory grants [2018GZR110104001, 2018GZR110102004, 2018GZR0201003]
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Loss of Klotho protein is involved in the development of chronic kidney diseases. Researchers have discovered a peptide called KP1 derived from Klotho protein that protects the kidneys by targeting the TGF-beta signaling pathway. KP1 inhibits TGF-beta signaling, prevents fibrosis, and improves kidney function.
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.
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