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Kidney Int. 2016 May;89(5):1062-1074. doi: 10.1016/j.kint.2016.01.017. Epub 2016 Mar 25.

Experimental inhibition of porcupine-mediated Wnt O-acylation attenuates kidney fibrosis.

Author information

1
Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore. Electronic address: Babita.Madan@duke-nus.edu.sg.
2
Department of Medicine, Division of Nephrology, Duke University and Durham VA Medical Centers, Durham, North Carolina, USA.
3
Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
4
Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore; Department of Biochemistry, National University of Singapore, Singapore; Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.
5
Department of Medicine, Division of Nephrology, Duke University and Durham VA Medical Centers, Durham, North Carolina, USA. Electronic address: Steven.d.crowley@duke.edu.

Abstract

Activated Wnt signaling is critical in the pathogenesis of renal fibrosis, a final common pathway for most forms of chronic kidney disease. Therapeutic intervention by inhibition of individual Wnts or downstream Wnt/β-catenin signaling has been proposed, but these approaches do not interrupt the functions of all Wnts nor block non-canonical Wnt signaling pathways. Alternatively, an orally bioavailable small molecule, Wnt-C59, blocks the catalytic activity of the Wnt-acyl transferase porcupine, and thereby prevents secretion of all Wnt isoforms. We found that inhibiting porcupine dramatically attenuates kidney fibrosis in the murine unilateral ureteral obstruction model. Wnt-C59 treatment similarly blunts collagen mRNA expression in the obstructed kidney. Consistent with its actions to broadly arrest Wnt signaling, porcupine inhibition reduces expression of Wnt target genes and bolsters nuclear exclusion of β-catenin in the kidney following ureteral obstruction. Importantly, prevention of Wnt secretion by Wnt-C59 blunts expression of inflammatory cytokines in the obstructed kidney that otherwise provoke a positive feedback loop of Wnt expression in collagen-producing fibroblasts and epithelial cells. Thus, therapeutic targeting of porcupine abrogates kidney fibrosis not only by overcoming the redundancy of individual Wnt isoforms but also by preventing upstream cytokine-induced Wnt generation. These findings reveal a novel therapeutic maneuver to protect the kidney from fibrosis by interrupting a pathogenic crosstalk loop between locally generated inflammatory cytokines and the Wnt/β-catenin signaling pathway.

KEYWORDS:

chronic kidney disease; cytokines; fibrosis

PMID:
27083283
PMCID:
PMC4834146
DOI:
10.1016/j.kint.2016.01.017
[Indexed for MEDLINE]
Free PMC Article

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