WNK-SPAK-NCC cascade revisited: WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4
Journal
Hypertension
ISSN
0194-911X
1524-4563
Date Issued
2014
Author(s)
Chávez-Canales, María
Zhang, Chong
Soukaseum, Christelle
Moreno, Erika
Vidal-Petiot, Emmanuelle
Castañeda-Bueno, María
Vázquez, Norma
Rojas-Vega, Lorena
Meermeier, Nicholas P.
Rogers, ,Shaunessy
Jeunemaitre, Xavier
Yang, Chao-Ling
Ellison, David H.
Gamba, Gerardo
Hadchouel, Juliette
Type
text::journal::journal article
Abstract
The with-no-lysine (K) kinases, WNK1 and WNK4, are key regulators of blood pressure. Their mutations lead to familial hyperkalemic hypertension (FHHt), associated with an activation of the Na-Cl cotransporter (NCC). Although it is clear that WNK4 mutants activate NCC via Ste20 proline-alanine-rich kinase, the mechanisms responsible for WNK1-related FHHt and alterations in NCC activity are not as clear. We tested whether WNK1 modulates NCC through WNK4, as predicted by some models, by crossing our recently developed WNK1-FHHt mice (WNK1(+/FHHt)) with WNK4(-/-) mice. Surprisingly, the activated NCC, hypertension, and hyperkalemia of WNK1(+/FHHt) mice remain in the absence of WNK4. We demonstrate that WNK1 powerfully stimulates NCC in a WNK4-independent and Ste20 proline-alanine-rich kinase-dependent manner. Moreover, WNK4 decreases the WNK1 and WNK3-mediated activation of NCC. Finally, the formation of oligomers of WNK kinases through their C-terminal coiled-coil domain is essential for their activity toward NCC. In conclusion, WNK kinases form a network in which WNK4 associates with WNK1 and WNK3 to regulate NCC. © 2014 American Heart Association, Inc.