Wnt5a induces renal AQP2 expression by activating calcineurin signalling pathway

Fumiaki Ando, Eisei Sohara, Tetsuji Morimoto, Naofumi Yui, Naohiro Nomura, Eriko Kikuchi, Daiei Takahashi, Takayasu Mori, Alain Vandewalle, Tatemitsu Rai, Sei Sasaki, Yoshiaki Kondo and Shinichi Uchida ()
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Fumiaki Ando: Tokyo Medical and Dental University
Eisei Sohara: Tokyo Medical and Dental University
Tetsuji Morimoto: Tohoku Medical and Pharmaceutical University
Naofumi Yui: Tokyo Medical and Dental University
Naohiro Nomura: Tokyo Medical and Dental University
Eriko Kikuchi: Tokyo Medical and Dental University
Daiei Takahashi: Tokyo Medical and Dental University
Takayasu Mori: Tokyo Medical and Dental University
Alain Vandewalle: Centre de Recherche sur l’Inflammation (CRI), UMRS 1149
Tatemitsu Rai: Tokyo Medical and Dental University
Sei Sasaki: Tokyo Medical and Dental University
Yoshiaki Kondo: Nihon University School of Medicine
Shinichi Uchida: Tokyo Medical and Dental University

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13636

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