Abstract: PO1560
Pharmacological Inhibition of β-Catenin-Activated Transcription Slows Cystogenesis in a Postnatal Mouse Model of ADPKD
Session Information
- Cystic Kidney Diseases: Emerging Concepts, Biomarkers, and Clinical Trials
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1001 Genetic Diseases of the Kidneys: Cystic
Authors
- Schumacher, Valerie A., Boston Children's Hospital, Department of Urology, Boston, Massachusetts, United States
- Jung, Yun Joon, Boston Children's Hospital, Department of Urology, Boston, Massachusetts, United States
- Kreidberg, Jordan A., Boston Children's Hospital, Department of Urology, Boston, Massachusetts, United States
Background
The Wnt signaling pathway has an important role in nephron development and elevated expression of β-catenin, master regulator of the Wnt signaling pathway, has been shown to correlate with cystogenesis in autosomal dominant polycystic kidney disease (ADPKD). Here we provide evidence that pharmacological inhibition of β-catenin-activated transcription slows cystogenesis in a postnatal model of ADPKD.
Methods
To understand the pathological contribution of Wnt signaling to ADPKD, we measured expression of Wnt genes and β-catenin in vivo using a postnatal murine model of ADPKD. We also tested the effect of a selective β-catenin-CBP inhibitor on cyst formation.
Results
We observed both increased expression of Wnt 7a and higher levels of β-catenin in cystic kidneys of CAGG-CreERT2;Pkd1flox/flox mice. In addition, fibronectin, a known transcriptional target of β-catenin was significantly overexpressed in murine cystic kidneys and also in kidneys from humans with ADPKD. To test whether increased β-catenin transcriptional activity was required for cystogenesis, we treated CAGG-CreERT2;Pkd1flox/flox mice with a small molecule, ICG-001, that blocks the interaction of β-catenin with CBP. We detected significant reduced cyst formation as measured by the kidney/body weight ratio (0.047g ±0.004 vs 0.022g ±0.001) and the cyst area per kidney area (37.8% ±3.1 vs 13.7% ±3.1) and also observed a significant reduction in fibronectin after ICG-001 treatment. Interestingly, cysts that may have formed prior to the start of the treatment remained large suggesting that ICG-001 may primarily act on inhibiting cyst initiation, rather than inhibiting the enlargement of pre-existing cysts. Importantly, ICG-001 treatment did not affect the growth of the mice.
Conclusion
Our study demonstrates that increased β-catenin transcriptional activity has an important role in cystogenesis and inhibition of the β-catenin-CBP complex by ICG-001 may serve as a new therapeutic modality to decrease cyst formation.
Funding
- NIDDK Support