The effect of WNK4 on the Na+-Cl- cotransporter is modulated by intracellular chloride

Silvana Bazúa-Valenti, María Chávez-Canales, Lorena Rojas-Vega, Xochiquetzal González-Rodríguez, Norma Vázquez, Alejandro Rodríguez-Gama, Eduardo R. Argaiz, Zesergio Melo, Consuelo Plata, David Ellison, Jesús García-Valdés, Juliette Hadchouel, Gerardo Gamba

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Abstract

It is widely recognized that the phenotype of familial hyperkalemic hypertension is mainly a consequence of increased activity of the renal Na+-Cl- cotransporter (NCC) because of altered regulation by with no-lysinekinase 1 (WNK1) or WNK4. The effect ofWNK4 on NCC, however, has been controversial because both inhibition and activation have been reported. It has been recently shown that the long isoform of WNK1 (L-WNK1) is a chloride-sensitive kinase activated by a low Clconcentration. Therefore, we hypothesized that WNK4 effects on NCC could be modulated by intracellular chloride concentration ([Cl-]i), and we tested this hypothesis in oocytes injected with NCC cRNA with or without WNK4 cRNA. At baseline in oocytes, [Cl-]i was near 50 mM, autophosphorylation of WNK4 was undetectable, andNCC activity was either decreased or unaffected byWNK4. A reduction of [Cl-]i, either by low chloride hypotonic stress or coinjection of oocytes with the solute carrier family 26 (anion exchanger)-member 9 (SLC26A9) cRNA, promoted WNK4 autophosphorylation and increased NCC-dependent Na+ transport in a WNK4-dependent manner. Substitution of the leucine with phenylalanine at residue 322 ofWNK4, homologous to the chloride-binding pocket in L-WNK1, convertedWNK4 into a constitutively autophosphorylated kinase that activated NCC, even without chloride depletion. Elimination of the catalytic activity (D321A or D321K-K186D) or the autophosphorylation site (S335A) in mutant WNK4-L322F abrogated the positive effect on NCC. These observations suggest that WNK4 can exert differential effects on NCC, depending on the intracellular chloride concentration.

Original languageEnglish (US)
Pages (from-to)1781-1786
Number of pages6
JournalJournal of the American Society of Nephrology
Volume26
Issue number8
DOIs
StatePublished - Aug 1 2015

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Member 3 Solute Carrier Family 12
Chlorides
Complementary RNA
Oocytes
Protein Isoforms
Phosphotransferases
Osmotic Pressure
Phenylalanine
Leucine
Anions
Hypertension
Phenotype
Kidney

ASJC Scopus subject areas

  • Nephrology

Cite this

Bazúa-Valenti, S., Chávez-Canales, M., Rojas-Vega, L., González-Rodríguez, X., Vázquez, N., Rodríguez-Gama, A., ... Gamba, G. (2015). The effect of WNK4 on the Na+-Cl- cotransporter is modulated by intracellular chloride. Journal of the American Society of Nephrology, 26(8), 1781-1786. https://doi.org/10.1681/ASN.2014050470

The effect of WNK4 on the Na+-Cl- cotransporter is modulated by intracellular chloride. / Bazúa-Valenti, Silvana; Chávez-Canales, María; Rojas-Vega, Lorena; González-Rodríguez, Xochiquetzal; Vázquez, Norma; Rodríguez-Gama, Alejandro; Argaiz, Eduardo R.; Melo, Zesergio; Plata, Consuelo; Ellison, David; García-Valdés, Jesús; Hadchouel, Juliette; Gamba, Gerardo.

In: Journal of the American Society of Nephrology, Vol. 26, No. 8, 01.08.2015, p. 1781-1786.

Research output: Contribution to journalArticle

Bazúa-Valenti, S, Chávez-Canales, M, Rojas-Vega, L, González-Rodríguez, X, Vázquez, N, Rodríguez-Gama, A, Argaiz, ER, Melo, Z, Plata, C, Ellison, D, García-Valdés, J, Hadchouel, J & Gamba, G 2015, 'The effect of WNK4 on the Na+-Cl- cotransporter is modulated by intracellular chloride', Journal of the American Society of Nephrology, vol. 26, no. 8, pp. 1781-1786. https://doi.org/10.1681/ASN.2014050470
Bazúa-Valenti S, Chávez-Canales M, Rojas-Vega L, González-Rodríguez X, Vázquez N, Rodríguez-Gama A et al. The effect of WNK4 on the Na+-Cl- cotransporter is modulated by intracellular chloride. Journal of the American Society of Nephrology. 2015 Aug 1;26(8):1781-1786. https://doi.org/10.1681/ASN.2014050470
Bazúa-Valenti, Silvana ; Chávez-Canales, María ; Rojas-Vega, Lorena ; González-Rodríguez, Xochiquetzal ; Vázquez, Norma ; Rodríguez-Gama, Alejandro ; Argaiz, Eduardo R. ; Melo, Zesergio ; Plata, Consuelo ; Ellison, David ; García-Valdés, Jesús ; Hadchouel, Juliette ; Gamba, Gerardo. / The effect of WNK4 on the Na+-Cl- cotransporter is modulated by intracellular chloride. In: Journal of the American Society of Nephrology. 2015 ; Vol. 26, No. 8. pp. 1781-1786.
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AU - Argaiz, Eduardo R.

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