title: Experimental inhibition of porcupine-mediated Wnt O-acylation attenuates kidney fibrosis.
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.
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore. Electronic address: Babita.Madan@duke-nus.edu.sg.
authors.forename: Babita
authors.initials: B
authors.lastname: Madan
authors.affiliation: Department of Medicine, Division of Nephrology, Duke University and Durham VA Medical Centers, Durham, North Carolina, USA.
authors.forename: Mehul B
authors.initials: MB
authors.lastname: Patel
authors.affiliation: Department of Medicine, Division of Nephrology, Duke University and Durham VA Medical Centers, Durham, North Carolina, USA.
authors.forename: Jiandong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Bunte
authors.affiliation: Department of Medicine, Division of Nephrology, Duke University and Durham VA Medical Centers, Durham, North Carolina, USA.
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Rudemiller
authors.affiliation: Department of Medicine, Division of Nephrology, Duke University and Durham VA Medical Centers, Durham, North Carolina, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Griffiths
authors.affiliation: 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.
authors.forename: David M
authors.initials: DM
authors.lastname: Virshup
authors.affiliation: Department of Medicine, Division of Nephrology, Duke University and Durham VA Medical Centers, Durham, North Carolina, USA. Electronic address: Steven.d.crowley@duke.edu.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Crowley
mesh_terms: D000215:Acylation; D000217:Acyltransferases; D000818:Animals; D044482:Benzeneacetamides / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005355:Fibrosis; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D011499:Protein Processing, Post-Translational; D011725:Pyridines / Q000494:pharmacology*; D014517:Ureteral Obstruction / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C579131:2-(4-(2-methylpyridin-4-yl)phenyl)-N-(4-(pyridin-3-yl)phenyl)acetamide; D044482:Benzeneacetamides; C495267:CTNNB1 protein, mouse; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D008565:Membrane Proteins; D011725:Pyridines; D051153:Wnt Proteins; D051176:beta Catenin; D003094:Collagen; D000217:Acyltransferases; C491187:Porcn protein, mouse
keywords: chronic kidney disease; cytokines; fibrosis