Open AccessWnt5a induces renal AQP2 expression by activating calcineurin signalling pathway
Author(s) -
Fumiaki Ando,
Eisei Sohara,
Takeshi Morimoto,
Naofumi Yui,
Naohiro Nomura,
Eriko Kikuchi,
Daichi Takahashi,
Takayasu Mori,
Alain Vandewalle,
Tatemitsu Rai,
Sei Sasaki,
Yoshiaki Kondo,
Shinichi Uchida
Publication year - 2016
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/ncomms13636
Subject(s) - aquaporin 2 , calcineurin , microbiology and biotechnology , nephrogenic diabetes insipidus , vasopressin , arginine vasopressin receptor 2 , activator (genetics) , reabsorption , endocrinology , medicine , biology , vasopressin receptor , apical membrane , chemistry , receptor , kidney , biochemistry , antagonist , membrane , mechanical engineering , water channel , transplantation , engineering , inlet
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.