Kidney Week

Abstract: TH-OR048

Canonical Wnt Inhibitors Ameliorate Cystogenesis in a Mouse Orthologue of Human ADPKD

Session Information

• Cystic Kidney Diseases: Genes, Mechanisms, Interventions
  November 02, 2017 | Location: Room 390, Morial Convention Center
  Abstract Time: 05:54 PM - 06:06 PM

Category: Genetic Diseases of the Kidney

• 801 Cystic Kidney Diseases

Authors

• Li, Ao, Anhui Province PKD Center, Institute/Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China

Ao Li, PhD

• Xu, Yuchen, Anhui Province PKD Center, Institute/Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China

Yuchen Xu,

• Fan, Song, Anhui Province PKD Center, Institute/Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China

Song Fan,

• Meng, Jialin, Anhui Province PKD Center, Institute/Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China

Jialin Meng,

• Shen, Xufeng, Anhui Province PKD Center, Institute/Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China

Xufeng Shen,

• Ma, Dongyue, Anhui Province PKD Center, Institute/Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China

Dongyue Ma,

• Zhang, Li, Anhui Province PKD Center, Institute/Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China

Li Zhang,

• Zhang, Xiansheng, Anhui Province PKD Center, Institute/Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China

Xiansheng Zhang,

• Wu, Guanqing, Anhui Province PKD Center, Institute/Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China

Guanqing Wu,

• Liang, Chaozhao, Anhui Province PKD Center, Institute/Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China

Chaozhao Liang,

Background

ADPKD is a heterogeneous disease which is caused by mutations in the PKD1 or PKD2 genes. Our previous study indicated that lack of Pkd2 causes elevated β-catenin signaling in mouse tissues and cells (Kim et al. JASN 2009;20:2556). However, it remains unclear if β-catenin signaling plays a role in PKD phenotypes and if Wnt inhibitor halts the cyst formation in the disease models.

Methods

In this study, we crossed a newly generated standardized ADPKD mouse model for Pkd2 (Vil-Cre;Pkd2^f3/f3) (Li et al J. Cell Mol. Med. 2017) with Ctnnb1^+/- mice to generate the mouse model that haploinsufficiency of Ctnnb1 (Vil-Cre;Pkd2^f3/f3;Ctnnb1^+/-). In addition, we also explored the effects of canonical Wnt signaling inhibitors (XAV939 and LGK974) on amelioration of disease phenotypes. XAV939-treated group and its solvent DMSO control group (n≥5/group) were intraperitoneally treated by 50 mg/kg/d and the same amount of DMSO from postnatal days 10 (P10) to 60 (P60); while LGK974-treated group and its solvent control group were intragastrically treated by 3mg/kg/d from postnatal days 30 (P30) to 90 (P90). The XAV939 and LGK974 treated animals were sacrificed at P65 and P95, respectively.

Results

Vil-Cre;Pkd2^f3/f3 mice with Ctnnb1^+/- allele and the mice treated with XAV939 or LGK974 exhibit significantly prolonged lifespan, decreased cyst index, kidney/body ratio and improved renal function (BUN and Cr). All treated mice also showed significantly decreased proliferation, but no change for apoptosis, in renal cyst-lining epithelial cells. Canonical Wnt signaling targeted genes, including Axin2, Ccnd1 and c-Myc, were also significantly downregulated in the treated ADPKD mouse kidney.

Conclusion

Our study provides clear evidence for the importance of β-catenin signaling in Pkd2-associated ADPKD phenotypes and develops new Wnt inhibitors XAV939 and LGK974, which affects at different targets of Wnt signaling, as a potential therapeutic modality for ADPKD that currently lacks effective therapy.

Funding

• Government Support - Non-U.S.