Kidney Week

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

Yun Joon Jung,

• Kreidberg, Jordan A., Boston Children's Hospital, Boston, Massachusetts, United States

Jordan A. Kreidberg,

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-CreER^T2;Pkd1^flox/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;Pkd1^flox/flox mice and Ksp-CreER^T2;Pkd1^flox/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-CreER^T2;Pkd1^flox/flox mice. Reduced progression of cyst enlargement was observed in Ksp-CreER^T2;Pkd1^flox/flox;Ctnnb1^flox/+ mice. Furthermore, treatment of Ksp-CreER^T2;Pkd1^flox/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