Aquaporin‐1 retards renal cyst development in polycystic kidney disease by inhibition of Wnt signaling

Abstract

ObjectiveAutosomal dominant polycystic kidney disease (ADPKD) is one of the most common human monogenic diseases. Aquaporin‐1 (AQP1) is expressed mainly at epithelial cell plasma membranes in renal proximal tubules, as well as in epithelial cells lining the cysts in ADPKD kidneys, postulating that AQP1 may be involved in cytogenesis. Here we investigated the role of AQP1 on ADPKD development.Methods: We used Aqp1/Pkd1 double knockout mice, embryonic kidney organ cultures, and matrix‐grown MDCK cells in this study to investigate the role of AQP1 in ADPKD. Expression of Wnt signaling‐related proteins were detected in MDCK and AQP1‐MDCK cells. Co‐immunoprecipitation was used to determine the interaction between AQP1 and β‐catenin,GSK3β,LRP6 and Axin1.Results: Kidney size and cyst number were significantly greater in AQP1‐null PKD mice than in AQP1‐expressing PKD mice. In embryonic kidney cultures, AQP1 deletion increased cyst development. In matrix‐grown MDCK cells, AQP1 inhibited cystogenesis and promoted tubulogenesis. AQP1 decreased β‐catenin and cyclinD1 expression, suggesting down‐regulation of Wnt signaling. Co‐immunoprecipitation showed AQP1 interaction with β‐catenin, GSK3β, LRP6 and Axin1. Biochemical analysis revealed decreased p‐β‐catenin and increased β‐catenin expression in Aqp1/Pkd1 double knockout mice, suggesting enhanced Wnt signaling.ConclusionsThese results suggest that AQP1 may be involved in maintaining the stability of the “destruction complex” to promote β‐catenin phosphorylation and suppress the Wnt signaling. This study reveals a previously unrecognized role of AQP1 in ADPKD and hence may provide new therapeutic targets.