Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC

Eduardo R. Argaiz, Maria Chavez-Canales, Mauricio Ostrosky-Frid, Alejandro Rodríguez-Gama, Norma Vázquez, Xochiquetzal Gonzalez-Rodriguez, Jesus Garcia-Valdes, Juliette Hadchouel, David Ellison, Gerardo Gamba

Research output: Contribution to journalArticle

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Abstract

Familial hyperkalemic hypertension (FHHt) can be mainly attributed to increased activity of the renal Na+:Cl- cotransporter (NCC), which is caused by altered expression and regulation of the with-no-lysine (K) 1 (WNK1) or WNK4 kinases. The WNK1 gene gives rise to a kidney-specific isoform that lacks the kinase domain (KS-WNK1), the expression of which occurs primarily in the distal convoluted tubule. The role played by KS-WNK1 in the modulation of the WNK/STE20-proline-alanine rich kinase (SPAK)/ NCC pathway remains elusive. In the present study, we assessed the effect of human KS-WNK1 on NCC activity and on the WNK4-SPAK pathway. Microinjection of oocytes with human KS-WNK1 cRNA induces remarkable activation and phosphorylation of SPAK and NCC. The effect of KS-WNK1 was abrogated by eliminating a WNK-WNK-interacting domain and by a specific WNK inhibitor, WNK463, indicating that the activation of SPAK/NCC by KS-WNK1 is due to interaction with another WNK kinase. Under control conditions in oocytes, the activating serine 335 of the WNK4 T loop is not phosphorylated. In contrast, this serine becomes phosphorylated when the intracellular chloride concentration ([Cl-]i) is reduced or when KS-WNK1 is coexpressed with WNK4. KS-WNK1-mediated activation of WNK4 is not due to a decrease of the [Cl-]i. Coimmunoprecipitation analysis revealed that KS-WNK1 and WNK4 interact with each other and that WNK4 becomes autophosphorylated at serine 335 when it is associated with KS-WNK1. Together, these observations suggest that WNK4 becomes active in the presence of KS-WNK1, despite a constant [Cl-]i.

Original languageEnglish (US)
Pages (from-to)F734-F745
JournalAmerican Journal of Physiology - Renal Physiology
Volume315
Issue number3
DOIs
StatePublished - Sep 6 2018

Fingerprint

Member 3 Solute Carrier Family 12
Lysine
Protein Isoforms
Kidney
Phosphotransferases
Proline
Alanine
Serine
Oocytes
Complementary RNA
Microinjections

Keywords

  • Distal convoluted tubule
  • Diuretics
  • Na:Cl cotransporter
  • Salt transport
  • STE20-proline-alanine rich kinase

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Argaiz, E. R., Chavez-Canales, M., Ostrosky-Frid, M., Rodríguez-Gama, A., Vázquez, N., Gonzalez-Rodriguez, X., ... Gamba, G. (2018). Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC. American Journal of Physiology - Renal Physiology, 315(3), F734-F745. https://doi.org/10.1152/ajprenal.00145.2018

Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC. / Argaiz, Eduardo R.; Chavez-Canales, Maria; Ostrosky-Frid, Mauricio; Rodríguez-Gama, Alejandro; Vázquez, Norma; Gonzalez-Rodriguez, Xochiquetzal; Garcia-Valdes, Jesus; Hadchouel, Juliette; Ellison, David; Gamba, Gerardo.

In: American Journal of Physiology - Renal Physiology, Vol. 315, No. 3, 06.09.2018, p. F734-F745.

Research output: Contribution to journalArticle

Argaiz, ER, Chavez-Canales, M, Ostrosky-Frid, M, Rodríguez-Gama, A, Vázquez, N, Gonzalez-Rodriguez, X, Garcia-Valdes, J, Hadchouel, J, Ellison, D & Gamba, G 2018, 'Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC', American Journal of Physiology - Renal Physiology, vol. 315, no. 3, pp. F734-F745. https://doi.org/10.1152/ajprenal.00145.2018
Argaiz ER, Chavez-Canales M, Ostrosky-Frid M, Rodríguez-Gama A, Vázquez N, Gonzalez-Rodriguez X et al. Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC. American Journal of Physiology - Renal Physiology. 2018 Sep 6;315(3):F734-F745. https://doi.org/10.1152/ajprenal.00145.2018
Argaiz, Eduardo R. ; Chavez-Canales, Maria ; Ostrosky-Frid, Mauricio ; Rodríguez-Gama, Alejandro ; Vázquez, Norma ; Gonzalez-Rodriguez, Xochiquetzal ; Garcia-Valdes, Jesus ; Hadchouel, Juliette ; Ellison, David ; Gamba, Gerardo. / Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC. In: American Journal of Physiology - Renal Physiology. 2018 ; Vol. 315, No. 3. pp. F734-F745.
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AU - Rodríguez-Gama, Alejandro

AU - Vázquez, Norma

AU - Gonzalez-Rodriguez, Xochiquetzal

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