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Published on: November 10, 2021
A Klotho-derived peptide protects against kidney fibrosis by targeting TGF-β signaling
1State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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.
Insights
A new peptide, KP1, derived from the anti-aging protein Klotho, protects kidneys from fibrosis. KP1 targets TGF-β signaling, offering a potential therapeutic for fibrotic kidney diseases.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Loss of Klotho, an anti-aging protein, is implicated in chronic kidney disease pathogenesis.
- Klotho's large size poses challenges for its therapeutic use.
- Targeting transforming growth factor-beta (TGF-β) signaling is crucial for treating kidney fibrosis.
Purpose of the Study:
- To discover a Klotho-derived therapeutic peptide for kidney protection.
- To investigate the mechanism of action of the identified peptide.
- To evaluate the efficacy of the peptide in preclinical models of renal fibrosis.
Main Methods:
- Screening of human Klotho-derived peptides to identify kidney-protective candidates.
- In vitro assays to assess peptide binding to TGF-β receptor 2 (TβR2) and inhibition of TGF-β signaling.
- In vivo studies using mouse models of renal fibrosis to evaluate peptide efficacy, biodistribution, and effects on kidney function and fibrosis.
Main Results:
- Identification of Klotho-derived peptide 1 (KP1) with anti-fibrotic properties.
- KP1 binds to TβR2, disrupting TGF-β/TβR2 engagement and inhibiting downstream signaling (Smad2/3, MAPKs).
- KP1 preferentially accumulates in injured kidneys, preserves function, reduces fibrosis, and restores Klotho expression in mouse models.
Conclusions:
- KP1 effectively recapitulates Klotho's anti-fibrotic effects.
- KP1 demonstrates therapeutic potential for treating fibrotic kidney diseases.
- KP1 represents a promising novel therapeutic strategy for kidney fibrosis.
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