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Canonical Wnt inhibitors ameliorate cystogenesis in a mouse ortholog of human ADPKD
Ao Li, … , Chaozhao Liang, Dianqing Wu
Ao Li, … , Chaozhao Liang, Dianqing Wu
Published March 8, 2018
Citation Information: JCI Insight. 2018;3(5):e95874. https://doi.org/10.1172/jci.insight.95874.
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Research Article Genetics Nephrology

Canonical Wnt inhibitors ameliorate cystogenesis in a mouse ortholog of human ADPKD

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Abstract

Autosomal dominant polycystic kidney disease (ADPKD) can be caused by mutations in the PKD1 or PKD2 genes. The PKD1 gene product is a Wnt cell-surface receptor. We previously showed that a lack of the PKD2 gene product, PC2, increases β-catenin signaling in mouse embryonic fibroblasts, kidney renal epithelia, and isolated renal collecting duct cells. However, it remains unclear whether β-catenin signaling plays a role in polycystic kidney disease phenotypes or if a Wnt inhibitor can halt cyst formation in ADPKD disease models. Here, using genetic and pharmacologic approaches, we demonstrated that the elevated β-catenin signaling caused by PC2 deficiency contributes significantly to disease phenotypes in a mouse ortholog of human ADPKD. Pharmacologically inhibiting β-catenin stability or the production of mature Wnt protein, or genetically reducing the expression of Ctnnb1 (which encodes β-catenin), suppressed the formation of renal cysts, improved renal function, and extended survival in ADPKD mice. Our study clearly demonstrates the importance of β-catenin signaling in disease phenotypes associated with Pkd2 mutation. It also describes the effects of two Wnt inhibitors, XAV939 and LGK974, on various Wnt signaling targets as a potential therapeutic modality for ADPKD, for which there is currently no effective therapy.

Authors

Ao Li, Yuchen Xu, Song Fan, Jialin Meng, Xufeng Shen, Qian Xiao, Yuan Li, Li Zhang, Xiansheng Zhang, Guanqing Wu, Chaozhao Liang, Dianqing Wu

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Figure 1

Effects of allelic reduction of the Ctnnb1 gene.

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Effects of allelic reduction of the Ctnnb1 gene.
(A and B) Allelic reduc...
(A and B) Allelic reduction of the Ctnnb1 gene reduced the active, nuclear, and total β-catenin levels. (B) Representative Western blots of tissue lysates from the kidneys of Pkd2f/f, VilCrePkd2f/f, and VilCrePkd2f/fCtnnb1+/– mice are shown, along with (B) normalized quantitative analysis of the densitometry values of the tested tissues. (C and D) Allelic reduction of the Ctnnb1 gene suppressed β-catenin–mediated transcription (including Axin2, c-Myc, and cyclin D1) activated by PC2 deficiency. All data are presented as mean ± SEM (*P < 0.05, **P < 0.01, Student’s t test). Data are from 3 animals/group.

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