SPAK differentially mediates vasopressin effects on sodium cotransporters

Turgay Saritas, Aljona Borschewski, James A. McCormick, Alexander Paliege, Christin Dathe, Shinichi Uchida, Andrew Terker, Nina Himmerkus, Markus Bleich, Sylvie Demaretz, Kamel Laghmani, Eric Delpire, David H. Ellison, Sebastian Bachmann, Kerim Mutig

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63 Scopus citations

Abstract

Activation of the Na+-K+-2Cl-- cotransporter (NKCC2) and the Na+-Cl--cotransporter (NCC) by vasopressin includes their phosphorylation at defined, conservedN-terminal threonine and serine residues, but the kinase pathways thatmediate this action of vasopressin are not well understood. Two homologous Ste20- like kinases, SPS-related proline/alanine-rich kinase (SPAK) and oxidative stress responsive kinase (OSR1), can phosphorylate the cotransporters directly. In this process, a full-length SPAK variant and OSR1 interact with a truncated SPAK variant, which has inhibitory effects. Here, we tested whether SPAK is an essential component of the vasopressin stimulatory pathway. We administered desmopressin, a V2 receptor- specific agonist, to wild-type mice, SPAK-deficient mice, and vasopressin-deficient rats. Desmopressin induced regulatory changes in SPAK variants, but not in OSR1 to the same degree, and activated NKCC2 and NCC. Furthermore, desmopressin modulated both the full-length and truncated SPAK variants to interact with and phosphorylate NKCC2, whereas only full-length SPAK promoted the activation of NCC. In summary, these results suggest that SPAK mediates the effect of vasopressin on sodium reabsorption along the distal nephron.

Original languageEnglish (US)
Pages (from-to)407-418
Number of pages12
JournalJournal of the American Society of Nephrology
Volume24
Issue number3
DOIs
StatePublished - Feb 28 2013

ASJC Scopus subject areas

  • Nephrology

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    Saritas, T., Borschewski, A., McCormick, J. A., Paliege, A., Dathe, C., Uchida, S., Terker, A., Himmerkus, N., Bleich, M., Demaretz, S., Laghmani, K., Delpire, E., Ellison, D. H., Bachmann, S., & Mutig, K. (2013). SPAK differentially mediates vasopressin effects on sodium cotransporters. Journal of the American Society of Nephrology, 24(3), 407-418. https://doi.org/10.1681/ASN.2012040404