WNK-SPAK-NCC cascade revisited

WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4

María Chávez-Canales, Chong Zhang, Christelle Soukaseum, Erika Moreno, Diana Pacheco-Alvarez, Emmanuelle Vidal-Petiot, María Castañeda-Bueno, Norma Vázquez, Lorena Rojas-Vega, Nicholas P. Meermeier, Shaunessy Rogers, Xavier Jeunemaitre, Chao-Ling Yang, David Ellison, Gerardo Gamba, Juliette Hadchouel

Research output: Contribution to journalArticle

46 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)1047-1053
Number of pages7
JournalHypertension
Volume64
Issue number5
DOIs
StatePublished - Nov 1 2014

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Member 3 Solute Carrier Family 12
Hypertension
Phosphotransferases
Proline
Alanine
Hyperkalemia
Lysine

Keywords

  • Distal
  • Familial hypertensive hyperkalemia
  • Hypertension, renal
  • Kidney tubules
  • Knockout
  • Mice
  • Pseudohypoaldosteronism/
  • Type II
  • Water-electrolyte balance
  • Xenopus laevis

ASJC Scopus subject areas

  • Internal Medicine
  • Medicine(all)

Cite this

Chávez-Canales, M., Zhang, C., Soukaseum, C., Moreno, E., Pacheco-Alvarez, D., Vidal-Petiot, E., ... Hadchouel, J. (2014). WNK-SPAK-NCC cascade revisited: WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4. Hypertension, 64(5), 1047-1053. https://doi.org/10.1161/HYPERTENSIONAHA.114.04036

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

In: Hypertension, Vol. 64, No. 5, 01.11.2014, p. 1047-1053.

Research output: Contribution to journalArticle

Chávez-Canales, M, Zhang, C, Soukaseum, C, Moreno, E, Pacheco-Alvarez, D, Vidal-Petiot, E, Castañeda-Bueno, M, Vázquez, N, Rojas-Vega, L, Meermeier, NP, Rogers, S, Jeunemaitre, X, Yang, C-L, Ellison, D, Gamba, G & Hadchouel, J 2014, 'WNK-SPAK-NCC cascade revisited: WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4', Hypertension, vol. 64, no. 5, pp. 1047-1053. https://doi.org/10.1161/HYPERTENSIONAHA.114.04036
Chávez-Canales, María ; Zhang, Chong ; Soukaseum, Christelle ; Moreno, Erika ; Pacheco-Alvarez, Diana ; Vidal-Petiot, Emmanuelle ; Castañeda-Bueno, María ; Vázquez, Norma ; Rojas-Vega, Lorena ; Meermeier, Nicholas P. ; Rogers, Shaunessy ; Jeunemaitre, Xavier ; Yang, Chao-Ling ; Ellison, David ; Gamba, Gerardo ; Hadchouel, Juliette. / WNK-SPAK-NCC cascade revisited : WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4. In: Hypertension. 2014 ; Vol. 64, No. 5. pp. 1047-1053.
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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

AU - Gamba, Gerardo

AU - Hadchouel, Juliette

PY - 2014/11/1

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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.

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