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

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 ?-catenin signaling in mouse embryonic fibroblasts, kidney renal epithelia, and isolated renal collecting duct cells. However, it remains unclear whether ?-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 ?-catenin signaling caused by PC2 deficiency contributes significantly to disease phenotypes in a mouse ortholog of human ADPKD. Pharmacologically inhibiting ?-catenin stability or the production of mature Wnt protein, or genetically reducing the expression of Ctnnb1 (which encodes ?-catenin), suppressed the formation of renal cysts, improved renal function, and extended survival in ADPKD mice. Our study clearly demonstrates the importance of ?-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.

SUBMITTER: Li A 

PROVIDER: S-EPMC5922276 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature