Abstract: SA-PO0134
Genetic Inhibition of Canonical Wnt Signaling Attenuates Cyst Expansion in HNF-1β Mutant Kidneys
Session Information
- ADPKD and Cystic Kidney Disease - 3
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)
Authors
- Diao, Ziteng, Stony Brook Medicine, Stony Brook, New York, United States
- Chatterton, Tyler, Stony Brook Medicine, Stony Brook, New York, United States
- Aboudehen, Karam S., Stony Brook Medicine, Stony Brook, New York, United States
- Igarashi, Peter, Stony Brook Medicine, Stony Brook, New York, United States
- Chan, Siu Chiu, Stony Brook Medicine, Stony Brook, New York, United States
Background
Hepatocyte nuclear factor-1β (HNF-1β) plays important roles in kidney development and tubular epithelial homeostasis. Human HNF1B mutations are associated with cystic kidney disease. Dysregulated canonical (β-catenin-dependent) Wnt signaling has been observed in HNF-1β mutant kidney cells. However, whether aberrant canonical Wnt activation directly contributes to cyst initiation and progression remains unclear.
Methods
RNA-seq, ChIP-seq, and Flow-CUT&Tag analyses were performed to identify HNF-1β–regulated genes and HNF-1β binding sites in wild-type and HNF-1β mutant mouse kidneys. To inhibit canonical Wnt signaling, kidney-specific HNF-1β mutant mice were crossed with mice carrying heterozygous or homozygous null alleles of Ctnnb1 and null alleles of Wnt11. Kidney size and cyst index were compared between HNF-1β single-mutant and double-mutant mice.
Results
RNA-seq analysis showed that the expression of Wnt pathway genes was upregulated in HNF-1β mutant kidneys. ChIP-seq analysis of chromatin from wild-type kidneys showed that many Wnt pathway genes contained nearby HNF-1β binding sites in vivo. Deletion of one allele of Ctnnb1 in HNF-1β mutant mice reduced kidney size and cyst index compared with HNF-1β mutant mice carrying two wild-type alleles of Ctnnb1. Deletion of both alleles of Ctnnb1 produced a more severe cystic phenotype. RNA-seq and RNAscope analysis identified Wnt11 as the most highly upregulated Wnt ligand in HNF-1β mutant kidneys at postnatal day 28. ChIP-seq analysis showed that HNF-1β binds to a site located 18.7 kb upstream from the Wnt11 transcription start site (TSS). Flow-CUT&Tag analysis showed enrichment of histone H3 K4 trimethylation at the upstream site, which was reduced in HNF-1β mutant cells. Deletion of Wnt11 in HNF-1β mutant mice reduced cyst index by 25% and decreased kidney weight/body weight ratio by 22% compared to HNF-1β single-mutant kidneys.
Conclusion
Canonical Wnt signaling is hyperactivated in HNF-1β mutant kidneys, and Wnt hyperactivity contributes to cyst progression. HNF-1β represses Wnt11 mRNA transcription through a distal enhancer located 18.7 kb upstream from the transcription start site. Genetic inhibition of Wnt11 attenuates cystic kidney disease in HNF-1β mutant mice. These findings support a model in which derepression of Wnt ligands sustains canonical Wnt signaling and promotes cyst expansion in HNF-1β-associated cystic kidney disease.
Funding
- NIDDK Support