Abstract: TH-PO680
Inhibition of Wnt/β-Catenin Signaling Slowed Cystogenesis in Postnatal Mouse Model of ADPKD
Session Information
- ADPKD: Genetic and Model Studies
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidney
- 1001 Genetic Diseases of the Kidney: Cystic
Authors
- Jung, Yun Joon, Boston Children's Hospital, Boston, Massachusetts, United States
- Kreidberg, Jordan A., Boston Children's Hospital, Boston, Massachusetts, United States
Background
The Wnt signaling pathway has an important role for nephron development and elevated expression of β-catenin, master regulator of the Wnt signaling pathway, is shown to correlate with cystogenesis in autosomal dominant polycystic kidney disease (ADPKD). Here we provide further evidence that inhibition of Wnt/β-catenin pathway slowed cystogenesis in a postnatal model of ADPKD using Ksp-CreERT2;Pkd1flox/flox mice.
Methods
To understand the pathological contribution of Wnt signaling in ADPKD, we measured expression of Wnt gene and β-catenin expression in vivo using two murine models of ADPKD where postnatal cystogenesis could be observed. We also tested the effect on cyst formation of small molecule inhibitors of β-catenin interaction with either CBP or p300.
Results
We observed increased expression of Wnt genes in and higher levels of β-catenin in cystic kidneys of both Hoxb7-Cre-IRES-eGFP;Pkd1flox/flox mice and Ksp-CreERT2;Pkd1flox/flox mice. Although the overall pattern differed between these models, Wnt7a was consistently over-expressed in both models of ADPKD. To test whether canonical Wnt signaling was required for cystogensis, we inactivated one copy of the Ctnnb1 gene, encoding β-catenin, in Ksp-CreERT2;Pkd1flox/flox mice. Reduced progression of cyst enlargement was observed in Ksp-CreERT2;Pkd1flox/flox;Ctnnb1flox/+ mice. Furthermore, treatment of Ksp-CreERT2;Pkd1flox/flox mice with a small molecule, ICG-001, that blocks the interaction of β-catenin with CBP slowed the progression of cyst formation and mice showed reduced kidney:weight to body weight ratio. In contrast, a small molecule, IQ-1, which blocked the interaction of β-catenin with p300 had no effect in cyst progression.
Conclusion
Our study demonstrates that the canonical Wnt signaling pathway has an important role in cystogenesis and inhibition of the β-catenin-CBP complex by ICG-001 may serve as a new therapeutic target to decrease cyst formation.
Funding
- NIDDK Support