ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO1560

Pharmacological Inhibition of β-Catenin-Activated Transcription Slows Cystogenesis in a Postnatal Mouse Model of ADPKD

Session Information

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