TY - JOUR
T1 - WNK-SPAK-NCC cascade revisited
T2 - WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4
AU - Chávez-Canales, María
AU - Zhang, Chong
AU - Soukaseum, Christelle
AU - Moreno, Erika
AU - Pacheco-Alvarez, Diana
AU - Vidal-Petiot, Emmanuelle
AU - Castañeda-Bueno, María
AU - Vázquez, Norma
AU - Rojas-Vega, Lorena
AU - Meermeier, Nicholas P.
AU - Rogers, Shaunessy
AU - Jeunemaitre, Xavier
AU - Yang, Chao Ling
AU - Ellison, David H.
AU - Gamba, Gerardo
AU - Hadchouel, Juliette
N1 - Publisher Copyright:
© 2014 American Heart Association, Inc.
PY - 2014/11/1
Y1 - 2014/11/1
N2 - 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 WNK4CD25-/- 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.
AB - 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 WNK4CD25-/- 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.
KW - Distal
KW - Familial hypertensive hyperkalemia
KW - Hypertension, renal
KW - Kidney tubules
KW - Knockout
KW - Mice
KW - Pseudohypoaldosteronism/
KW - Type II
KW - Water-electrolyte balance
KW - Xenopus laevis
UR - http://www.scopus.com/inward/record.url?scp=84922392921&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84922392921&partnerID=8YFLogxK
U2 - 10.1161/HYPERTENSIONAHA.114.04036
DO - 10.1161/HYPERTENSIONAHA.114.04036
M3 - Article
C2 - 25113964
AN - SCOPUS:84922392921
SN - 0194-911X
VL - 64
SP - 1047
EP - 1053
JO - Hypertension
JF - Hypertension
IS - 5
ER -