Targeted Inhibition of β-Catenin/CBP Signaling Ameliorates Renal Interstitial Fibrosis

Abstract

Because fibrotic kidneys exhibit aberrant activation of ␤-catenin signaling, this pathway may be a potential target for antifibrotic therapy. In this study, we examined the effects of ␤-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 ␤-catenin-mediated gene transcription, in obstructive nephropathy. In vitro, ectopic expression of stabilized ␤-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 ␤-catenin-driven gene transcription in a dose-dependent manner and abolished TGF-␤1-induced expression of Snail1, PAI-1, collagen I, fibronectin, and ␣-smooth muscle actin (␣-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, ␣-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 ␤-catenin signaling may be an effective approach to the treatment of fibrotic kidney diseases.

Antagonism of Canonical Wnt/β-Catenin Signaling

“…2 Of high clinical relevance, both transient and late treatment with ICG-001 restored podocyte function and repressed proteinuria, renal inflammation, and fibrosis. The latter is consistent with the findings of many studies that documented potent antifibrotic effects of canonical Wnt signaling blockade in the kidney, 4 lung, 5 skin, 6 and other organs. It also provides an exciting link between the RAS, TGF-b, and the Wnt/b-catenin pathway.…”

“…Unfortunately, Zhou et al did not report BP, either early or late after initiation of ICG-001; nor did a prior study of the same group in which ICG-001 reduced renal fibrosis in mice with ureteral obstruction. 4 In particular, given the clinical problems of dual RAS blockade, such data will be essential in the future. Fourth, the potential for extrarenal adverse effects of Wnt/b-catenin antagonism is high, given the plethora of Wnt actions.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Boosting survival and regeneration of TECs might be renoprotective and antifibrotic as, for example, suggested for CSF-1 (143). Other TECs factors driving fibrosis include Notch (144), lipocalin-2 (NGAL) (28), kidney injury molecule-1 (KIM-1) (145), b-catenin signaling (146), and the EGFR (147,148). Paracrine signaling from damaged TECs is probably one of a major mechanisms driving renal fibrosis ( Figure 3).…”

Mutual Antagonism of Wilms’ Tumor 1 and β-Catenin Dictates Podocyte Health and Disease

“…In addition, incubation of podocytes with ICG-001, a small molecule that specifically disrupts b-catenin/CBP interaction, 35,36 was able to enhance WT1/CBP interaction ( Figure 6F). These results suggest that WT1 and b-catenin could mutually antagonize each other through competing for binding to CBP.…”