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

dc.contributor.author Bunte, RM
dc.contributor.author Crowley, Steven Daniel
dc.contributor.author Griffiths, Robert
dc.contributor.author Madan, B
dc.contributor.author Patel, MB
dc.contributor.author Rudemiller, Nathan P
dc.contributor.author Virshup, DM
dc.contributor.author Zhang, J
dc.coverage.spatial United States
dc.date.accessioned 2016-05-02T20:37:59Z
dc.date.issued 2016-05
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/27083283
dc.identifier S0085-2538(16)00302-1
dc.identifier.uri https://hdl.handle.net/10161/11962
dc.description.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.
dc.language eng
dc.relation.ispartof Kidney Int
dc.relation.isversionof 10.1016/j.kint.2016.01.017
dc.subject chronic kidney disease
dc.subject cytokines
dc.subject fibrosis
dc.subject Acylation
dc.subject Animals
dc.subject Benzeneacetamides
dc.subject Cell Proliferation
dc.subject Cells, Cultured
dc.subject Collagen
dc.subject Disease Models, Animal
dc.subject Down-Regulation
dc.subject Enzyme Inhibitors
dc.subject Fibroblasts
dc.subject Fibrosis
dc.subject Inflammation Mediators
dc.subject Kidney
dc.subject Kidney Diseases
dc.subject Membrane Proteins
dc.subject Mice, Inbred C57BL
dc.subject Protein Processing, Post-Translational
dc.subject Pyridines
dc.subject Ureteral Obstruction
dc.subject Wnt Proteins
dc.subject Wnt Signaling Pathway
dc.subject beta Catenin
dc.title Experimental inhibition of porcupine-mediated Wnt O-acylation attenuates kidney fibrosis.
dc.type Journal article
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/27083283
pubs.begin-page 1062
pubs.end-page 1074
pubs.issue 5
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Medicine
pubs.organisational-group Medicine, Nephrology
pubs.organisational-group Pediatrics
pubs.organisational-group School of Medicine
pubs.publication-status Published
pubs.volume 89
dc.identifier.eissn 1523-1755


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