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Abstract: FR-PO988

A Novel Klotho-Derived Peptide KP1 Attenuates Renal Fibrosis by Blocking TGF-Beta Signaling

Session Information

Category: Pathology and Lab Medicine

  • 1601 Pathology and Lab Medicine: Basic

Authors

  • Yuan, Qian, Nanfang hospital, Guangzhou City, China
  • Zhou, Lili, Nanfang hospital, Guangzhou City, China
  • Liu, Youhua, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background

Renal fibrosis, characterized by excessive extracellular matrix (ECM) deposition, is a common feature of a variety of CKD. Klotho is an antiaging protein with remarkable reno-protective potential. Because Klotho is a large transmembrane protein, making it difficult to be used clinically, we hypothesized that a small Klotho-derived peptide may mimic the reno-protective action of Klotho.

Methods

A peptide mini-library was established, which encompassed the extracellular region of Klotho. The anti-fibrotic activity of the Klotho-derived peptide was screened in normal kidney fibroblast cells (NRK-49F) stimulated with TGF-β1. The effect of the identified peptide on renal fibrosis was tested in mouse models of fibrosis including unilateral ureteral obstruction (UUO) and unilateral ischemia reperfusion injury (UIRI).

Results

After screening the klotho peptide mini-library, one peptide with potent anti-fibrotic potential, designated as klotho-derived peptide 1 (KP-1), was identified. KP-1 was effective in blocking the upregulation of fibronectin and α-smooth muscle actin (α-SMA) in NRK-49F cells induced by TGF-β1. Mechanistically, we found that KP-1 bound to the TGF-β receptor type II (TβR-II), which competitively inhibited TGF-β1/TβR-II engagement. As such, KP1 was able to block Smad2/3 phosphorylation and activation induced by TGF-β1. KP-1 also inhibited TGF-β1-mediated mitogen-activated protein kinase (MAPK) activation in NRK-49F cells. In vivo, KP-1 blocked renal Smad2/3 and MAPK activation, inhibited myofibroblast activation and matrix production, ameliorated renal interstitial fibrosis and restored the expression of endogenous klotho protein in two models of renal fibrosis induced UUO and IRI.

Conclusion

We have identified KP-1 is a novel Klotho-derived peptide that specifically inhibits TGF-β signaling via binding to TβR-II. KP-1 could be used as a therapeutic agent for treating fibrotic kidney disease.