title: Wnt5a induces renal AQP2 expression by activating calcineurin signalling pathway.
abstract: Heritable nephrogenic diabetes insipidus (NDI) is characterized by defective urine concentration mechanisms in the kidney, which are mainly caused by loss-of-function mutations in the vasopressin type 2 receptor. For the treatment of heritable NDI, novel strategies that bypass the defective vasopressin type 2 receptor are required to activate the aquaporin-2 (AQP2) water channel. Here we show that Wnt5a regulates AQP2 protein expression, phosphorylation and trafficking, suggesting that Wnt5a is an endogenous ligand that can regulate AQP2 without the activation of the classic vasopressin/cAMP signalling pathway. Wnt5a successfully increases the apical membrane localization of AQP2 and urine osmolality in an NDI mouse model. We also demonstrate that calcineurin is a key regulator of Wnt5a-induced AQP2 activation without affecting intracellular cAMP level and PKA activity. The importance of calcineurin is further confirmed with its activator, arachidonic acid, which shows vasopressin-like effects underlining that calcineurin activators may be potential therapeutic targets for heritable NDI.
authors.affiliation: Department of Nephrology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Ando
authors.affiliation: Department of Nephrology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Eisei
authors.initials: E
authors.lastname: Sohara
authors.affiliation: Division of Pediatrics, Tohoku Medical and Pharmaceutical University, Miyagi 983-8512, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Morimoto
authors.affiliation: Department of Nephrology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Yui
authors.affiliation: Department of Nephrology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Nomura
authors.affiliation: Department of Nephrology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Kikuchi
authors.affiliation: Department of Nephrology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Daiei
authors.initials: D
authors.lastname: Takahashi
authors.affiliation: Department of Nephrology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Takayasu
authors.initials: T
authors.lastname: Mori
authors.affiliation: Centre de Recherche sur l'Inflammation (CRI), UMRS 1149, Université Denis Diderot-Paris 7, 75018 Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Vandewalle
authors.affiliation: Department of Nephrology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Tatemitsu
authors.initials: T
authors.lastname: Rai
authors.affiliation: Department of Nephrology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Sei
authors.initials: S
authors.lastname: Sasaki
authors.affiliation: Department of Health Care Services Management, Nihon University School of Medicine, Tokyo 173-8610, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: Department of Nephrology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uchida
mesh_terms: D000818:Animals; D051399:Aquaporin 2 / Q000235:genetics* / Q000378:metabolism; D016718:Arachidonic Acid / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D018500:Diabetes Insipidus, Nephrogenic / Q000378:metabolism / Q000473:pathology / Q000652:urine; D004195:Disease Models, Animal; D000072261:Dishevelled Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009994:Osmolar Concentration; D010539:Permeability; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014867:Water; D000071818:Wnt-5a Protein / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051399:Aquaporin 2; D000072261:Dishevelled Proteins; D012333:RNA, Messenger; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D051176:beta Catenin; D014867:Water; D010768:Phosphoserine; D016718:Arachidonic Acid; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019703:Calcineurin; D002118:Calcium