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

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

doi:10.1172/jci.insight.95874

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.

Highlights

Autosomal dominant polycystic kidney disease (ADPKD) is the most common of a group of inherited kidney disorders characterized by progressive cyst development and various extrarenal manifestations [1, 2]
We considered a spectrum of Wnt inhibitors with various molecular targets along the Wnt signaling pathway and identified XAV939 and LGK974 as agents that effectively reduced cystogenesis, improved renal function, and extended survival in our ADPKD animal model
These results indicated that elevated β-catenin levels, due to the loss-of-function Pkd2 mutation, contribute to the disease phenotype

Summary

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is the most common of a group of inherited kidney disorders characterized by progressive cyst development and various extrarenal manifestations [1, 2]. Cystogenesis in the human kidneys can progressively occupy the normal parenchyma of the kidney and lead to renal failure, which usually occurs in mid-to-late adulthood. This disease is the fourth most common single cause of end-stage renal failure worldwide [3, 4]. The most common extrarenal manifestation of ADPKD is the formation of bile duct–derived cysts in the liver [2, 7]. Other ADPKD phenotypes include pancreatic cysts [10, 11], aneurysms [12,13,14,15], and aortic root/thoracic aorta abnormalities [16,17,18]

Methods

Results

Conclusion