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Pacheco Álvarez, Diana
WNK-SPAK-NCC cascade revisited: WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4
2014
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Chávez-Canales, María
,
Zhang, Chong
,
Soukaseum, Christelle
,
Moreno, Erika
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Pacheco Álvarez, Diana
,
Vidal-Petiot, Emmanuelle
,
Castañeda-Bueno, María
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Vázquez, Norma
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Rojas-Vega, Lorena
,
Meermeier, Nicholas P.
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Rogers, ,Shaunessy
,
Jeunemaitre, Xavier
,
Yang, Chao-Ling
,
Ellison, David H.
,
Gamba, Gerardo
,
Hadchouel, Juliette
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.