title: Targeted inhibition of β-catenin/CBP signaling ameliorates renal interstitial fibrosis.
abstract: Because fibrotic kidneys exhibit aberrant activation of β-catenin signaling, this pathway may be a potential target for antifibrotic therapy. In this study, we examined the effects of β-catenin activation on tubular epithelial-mesenchymal transition (EMT) in vitro and evaluated the therapeutic efficacy of the peptidomimetic small molecule ICG-001, which specifically disrupts β-catenin-mediated gene transcription, in obstructive nephropathy. In vitro, ectopic expression of stabilized β-catenin in tubular epithelial (HKC-8) cells suppressed E-cadherin and induced Snail1, fibronectin, and plasminogen activator inhibitor-1 (PAI-1) expression. ICG-001 suppressed β-catenin-driven gene transcription in a dose-dependent manner and abolished TGF-β1-induced expression of Snail1, PAI-1, collagen I, fibronectin, and α-smooth muscle actin (α-SMA). This antifibrotic effect of ICG-001 did not involve disruption of Smad signaling. In the unilateral ureteral obstruction model, ICG-001 ameliorated renal interstitial fibrosis and suppressed renal expression of fibronectin, collagen I, collagen III, α-SMA, PAI-1, fibroblast-specific protein-1, Snail1, and Snail2. Late administration of ICG-001 also effectively attenuated fibrotic lesions in obstructive nephropathy. In conclusion, inhibiting β-catenin signaling may be an effective approach to the treatment of fibrotic kidney diseases.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, S-405 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA.
authors.forename: Sha
authors.initials: S
authors.lastname: Hao
authors.forename: Weichun
authors.initials: W
authors.lastname: He
authors.forename: Yingjian
authors.initials: Y
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Ding
authors.forename: Yayi
authors.initials: Y
authors.lastname: Hou
authors.forename: Jing
authors.initials: J
authors.lastname: Nie
authors.forename: Fan Fan
authors.initials: FF
authors.lastname: Hou
authors.forename: Michael
authors.initials: M
authors.lastname: Kahn
authors.forename: Youhua
authors.initials: Y
authors.lastname: Liu
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D058750:Epithelial-Mesenchymal Transition; D005786:Gene Expression Regulation; D006801:Humans; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism; D011744:Pyrimidinones / Q000494:pharmacology / Q000627:therapeutic use*; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C492448:ICG 001; D011744:Pyrimidinones; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D050882:CREB-Binding Protein