Targeted Inhibition of β-Catenin/CBP Signaling Ameliorates Renal Interstitial Fibrosis
- 1 September 2011
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 22 (9), 1642-1653
- https://doi.org/10.1681/asn.2010101079
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.Keywords
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