Sympathetic stimulation of thiazide-sensitive sodium chloride cotransport in the generation of salt-sensitive hypertension

Andrew S. Terker, Chao-Ling Yang, James (Jim) McCormick, Nicholas P. Meermeier, Shaunessy L. Rogers, Solveig Grossmann, Katja Trompf, Eric Delpire, Johannes Loffing, David Ellison

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Excessive renal efferent sympathetic nerve activity contributes to hypertension in many circumstances. Although both hemodynamic and tubular effects likely participate, most evidence supports a major role for α-adrenergic receptors in mediating the direct epithelial stimulation of sodium retention. Recently, it was reported, however, that norepinephrine activates the thiazide-sensitive NaCl cotransporter (NCC) by stimulating β-adrenergic receptors. Here, we confirmed this effect and developed an acute adrenergic stimulation model to study the signaling cascade. The results show that norepinephrine increases the abundance of phosphorylated NCC rapidly (161% increase), an effect largely dependent on β-adrenergic receptors. This effect is not mediated by the activation of angiotensin II receptors. We used immunodissected mouse distal convoluted tubule to show that distal convoluted tubule cells are especially enriched for β1- adrenergic receptors, and that the effects of adrenergic stimulation can occur ex vivo (79% increase), suggesting they are direct. Because the 2 protein kinases, STE20p-related proline- and alanine-rich kinase (encoded by STK39) and oxidative stress-response kinase 1, phosphorylate and activate NCC, we examined their roles in norepinephrine effects. Surprisingly, norepinephrine did not affect STE20p-related proline- and alanine-rich kinase abundance or its localization in the distal convoluted tubule; instead, we observed a striking activation of oxidative stress-response kinase 1. We confirmed that STE20p-related proline- and alanine-rich kinase is not required for NCC activation, using STK39 knockout mice. Together, the data provide strong support for a signaling system involving β1-receptors in the distal convoluted tubule that activates NCC, at least in part via oxidative stress-response kinase 1. The results have implications about device- and drug-based treatment of hypertension.

Original languageEnglish (US)
Pages (from-to)178-184
Number of pages7
JournalHypertension
Volume64
Issue number1
DOIs
StatePublished - 2014

Fingerprint

Thiazides
Sodium Chloride
Phosphotransferases
Salts
Hypertension
Adrenergic Receptors
Norepinephrine
Proline
Alanine
Adrenergic Agents
Oxidative Stress
Angiotensin Receptors
Knockout Mice
Protein Kinases
Hemodynamics
Sodium
Kidney
Equipment and Supplies
Pharmaceutical Preparations

Keywords

  • diuretics
  • hypertension
  • ion transport
  • sodium-potassium-chloride symporters
  • sympathetic nervous system

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Sympathetic stimulation of thiazide-sensitive sodium chloride cotransport in the generation of salt-sensitive hypertension. / Terker, Andrew S.; Yang, Chao-Ling; McCormick, James (Jim); Meermeier, Nicholas P.; Rogers, Shaunessy L.; Grossmann, Solveig; Trompf, Katja; Delpire, Eric; Loffing, Johannes; Ellison, David.

In: Hypertension, Vol. 64, No. 1, 2014, p. 178-184.

Research output: Contribution to journalArticle

Terker, Andrew S. ; Yang, Chao-Ling ; McCormick, James (Jim) ; Meermeier, Nicholas P. ; Rogers, Shaunessy L. ; Grossmann, Solveig ; Trompf, Katja ; Delpire, Eric ; Loffing, Johannes ; Ellison, David. / Sympathetic stimulation of thiazide-sensitive sodium chloride cotransport in the generation of salt-sensitive hypertension. In: Hypertension. 2014 ; Vol. 64, No. 1. pp. 178-184.
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