Aldosterone mediates activation of the thiazide-sensitive Na-Cl cotransporter through an SGK1 and WNK4 signaling pathway

David Rozansky, Tonya Cornwall, Arohan R. Subramanya, Shaunessy Rogers, Yong Feng Yang, Larry David, Xiaoman Zhu, Chao-Ling Yang, David Ellison

Research output: Contribution to journalArticle

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Abstract

Aldosterone regulates volume homeostasis and blood pressure by enhancing sodium reabsorption in the kidney's distal nephron (DN). On the apical surface of these renal epithelia, aldosterone increases expression and activity of the thiazide-sensitive Na-Cl cotransporter (NCC) and the epithelial sodium channel (ENaC). While the cellular mechanisms by which aldosterone regulates ENaC have been well characterized, the molecular mechanisms that link aldosterone to NCC-mediated Na+/Cl- reabsorption remain elusive. The serine/threonine kinase with-no-lysine 4 (WNK4) has previously been shown to reduce cell surface expression of NCC. Here we measured sodium uptake in a Xenopus oocyte expression system and found that serum and glucocorticoid-induced kinase 1 (SGK1), an aldosterone-responsive gene expressed in the DN, attenuated the inhibitory effect of WNK4 on NCC activity. In addition, we showed - both in vitro and in a human kidney cell line - that SGK1 bound and phosphorylated WNK4. We found one serine located within an established SGK1 consensus target sequence, and the other within a motif that was, to our knowledge, previously uncharacterized. Mutation of these target serines to aspartate, in order to mimic phosphorylation, attenuated the effect of WNK4 on NCC activity in the Xenopus oocyte system. These data thus delineate what we believe to be a novel mechanism for aldosterone activation of NCC through SGK1 signaling of WNK4 kinase.

Original languageEnglish (US)
Pages (from-to)2601-2612
Number of pages12
JournalJournal of Clinical Investigation
Volume119
Issue number9
DOIs
StatePublished - Sep 1 2009

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Member 3 Solute Carrier Family 12
Aldosterone
Glucocorticoids
Phosphotransferases
Serum
Nephrons
Xenopus
Kidney
Serine
Oocytes
Sodium
Epithelial Sodium Channels
Protein-Serine-Threonine Kinases
Consensus Sequence
Aspartic Acid
Lysine
thiazide receptor
Homeostasis
Epithelium
Phosphorylation

ASJC Scopus subject areas

  • Medicine(all)

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Aldosterone mediates activation of the thiazide-sensitive Na-Cl cotransporter through an SGK1 and WNK4 signaling pathway. / Rozansky, David; Cornwall, Tonya; Subramanya, Arohan R.; Rogers, Shaunessy; Yang, Yong Feng; David, Larry; Zhu, Xiaoman; Yang, Chao-Ling; Ellison, David.

In: Journal of Clinical Investigation, Vol. 119, No. 9, 01.09.2009, p. 2601-2612.

Research output: Contribution to journalArticle

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