A SPAK isoform switch modulates renal salt transport and blood pressure

James A. McCormick, Kerim Mutig, Joshua H. Nelson, Turgay Saritas, Ewout J. Hoorn, Chao Ling Yang, Shaunessy Rogers, Joshua Curry, Eric Delpire, Sebastian Bachmann, David H. Ellison

Research output: Contribution to journalArticle

118 Scopus citations

Abstract

The renal thick ascending limb (TAL) and distal convoluted tubule (DCT) play central roles in salt homeostasis and blood pressure regulation. An emerging model suggests that bumetanide- and thiazide-sensitive NaCl transporters (NKCC2 and NCC) along these segments are phosphorylated and activated by WNK kinases, via SPAK and OSR1. Here, we show that a kidney-specific SPAK isoform, which lacks the kinase domain, inhibits phosphorylation of NCC and NKCC2 by full-length SPAK in vitro. Kidney-specific SPAK is highly expressed along the TAL, whereas full-length SPAK is more highly expressed along the DCT. As predicted from the differential expression, SPAK knockout in animals has divergent effects along TAL and DCT, with increased phosphorylated NKCC2 along TAL and decreased phosphorylated NCC along DCT. In mice, extracellular fluid volume depletion shifts SPAK isoform abundance to favor NaCl retention along both segments, indicating that a SPAK isoform switch modulates sodium avidity along the distal nephron.

Original languageEnglish (US)
Pages (from-to)352-364
Number of pages13
JournalCell Metabolism
Volume14
Issue number3
DOIs
StatePublished - Sep 7 2011

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ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

McCormick, J. A., Mutig, K., Nelson, J. H., Saritas, T., Hoorn, E. J., Yang, C. L., Rogers, S., Curry, J., Delpire, E., Bachmann, S., & Ellison, D. H. (2011). A SPAK isoform switch modulates renal salt transport and blood pressure. Cell Metabolism, 14(3), 352-364. https://doi.org/10.1016/j.cmet.2011.07.009