title: Aquaporin-1 retards renal cyst development in polycystic kidney disease by inhibition of Wnt signaling.
abstract: Water channel aquaporin-1 (AQP1) is expressed at epithelial cell plasma membranes in renal proximal tubules and thin descending limb of Henle. Recently, AQP1 was reported to interact with β-catenin. Here we investigated the relationship between AQP1 and Wnt signaling in in vitro and in vivo models of autosomal dominant polycystic kidney disease (PKD). AQP1 overexpression decreased β-catenin and cyclinD1 expression, suggesting down-regulation of Wnt signaling, and coimmunoprecipitation showed AQP1 interaction with β-catenin, glycogen synthase kinase 3β, LRP6, and Axin1. AQP1 inhibited cyst development and promoted branching in matrix-grown MDCK cells. In embryonic kidney cultures, AQP1 deletion increased cyst development by up to ∼ 40%. Kidney size and cyst number were significantly greater in AQP1-null PKD mice than in AQP1-expressing PKD mice, with the difference mainly attributed to a greater number of proximal tubule cysts. Biochemical analysis revealed decreased β-catenin phosphorylation and increased β-catenin expression in AQP1-null PKD mice, suggesting enhanced Wnt signaling. These results implicate AQP1 as a novel determinant in renal cyst development that may involve inhibition of Wnt signaling by an AQP1-macromolecular signaling complex.
authors.affiliation: *Department of Pharmacology, School of Basic Medical Sciences, Peking University, and State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; and Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, California USA.
authors.forename: Weiling
authors.initials: W
authors.lastname: Wang
authors.affiliation: *Department of Pharmacology, School of Basic Medical Sciences, Peking University, and State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; and Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, California USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: *Department of Pharmacology, School of Basic Medical Sciences, Peking University, and State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; and Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, California USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.affiliation: *Department of Pharmacology, School of Basic Medical Sciences, Peking University, and State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; and Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, California USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Lei
authors.affiliation: *Department of Pharmacology, School of Basic Medical Sciences, Peking University, and State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; and Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, California USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.affiliation: *Department of Pharmacology, School of Basic Medical Sciences, Peking University, and State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; and Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, California USA.
authors.forename: Tianluo
authors.initials: T
authors.lastname: Lei
authors.affiliation: *Department of Pharmacology, School of Basic Medical Sciences, Peking University, and State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; and Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, California USA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Xia
authors.affiliation: *Department of Pharmacology, School of Basic Medical Sciences, Peking University, and State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; and Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, California USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
authors.affiliation: *Department of Pharmacology, School of Basic Medical Sciences, Peking University, and State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; and Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, California USA baoxue@bjmu.edu.cn.
authors.forename: Baoxue
authors.initials: B
authors.lastname: Yang
mesh_terms: D000818:Animals; D051398:Aquaporin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004285:Dogs; D007668:Kidney / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: C496021:Aqp1 protein, mouse; C495267:CTNNB1 protein, mouse; D046912:Multiprotein Complexes; D051176:beta Catenin; D051398:Aquaporin 1
keywords: ADPKD; MDCK; destruction complex; water channel