NKCC1 upregulation disrupts chloride homeostasis in the hypothalamus and increases neuronal activity-sympathetic drive in hypertension

Zengyou Ye, De Pei Li, Hee Sun Byun, Li Li, Hui Lin Pan

Research output: Contribution to journalArticle

Abstract

Hypertension is a major risk factor for coronary artery disease, stroke, and kidney failure. However, the etiology of hypertension in most patients is poorly understood. Increased sympathetic drive emanating from the hypothalamic paraventricular nucleus (PVN) plays a major role in the development of hypertension. Na +-K +-2Cl - cotransporter-1 (NKCC1) in the brain is critically involved in maintaining chloride homeostasis and in neuronal responses mediated by GABA A receptors. Here we present novel evidence that the GABA reversal potential (E GABA) of PVN presympathetic neurons undergoes a depolarizing shift that diminishes GABA inhibition in spontaneously hypertensive rats (SHRs). Inhibition of NKCC1, but not KCC2, normalizes E GABA and restores GABA inhibition of PVN neurons in SHRs. The mRNA and protein levels of NKCC1, but not KCC2, in the PVN are significantly increased in SHRs, and the NKCC1 proteins on the plasma membrane are highly glycosylated. Inhibiting NKCC1 N-glycosylation restores EGABA and GABAergic inhibition of PVN presympathetic neurons in SHRs. Furthermore, NKCC1 inhibition significantly reduces the sympathetic vasomotor tone and augments the sympathoinhibitory responses to GABA A receptor activation in the PVN in SHRs. These findings suggest that increased NKCC1 activity and glycosylation disrupt chloride homeostasis and impair synaptic inhibition in the PVN to augment the sympathetic drive in hypertension. This information greatly improves our understanding of the pathogenesis of hypertension and helps to design better treatment strategies for neurogenic hypertension.

Original languageEnglish (US)
Pages (from-to)8560-8568
Number of pages9
JournalJournal of Neuroscience
Volume32
Issue number25
DOIs
StatePublished - Jun 20 2012
Externally publishedYes

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Paraventricular Hypothalamic Nucleus
Hypothalamus
Chlorides
Homeostasis
Up-Regulation
Inbred SHR Rats
Hypertension
gamma-Aminobutyric Acid
GABA-A Receptors
Glycosylation
Neurons
Renal Insufficiency
Coronary Artery Disease
Proteins
Stroke
Cell Membrane
Messenger RNA
Brain

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

NKCC1 upregulation disrupts chloride homeostasis in the hypothalamus and increases neuronal activity-sympathetic drive in hypertension. / Ye, Zengyou; Li, De Pei; Byun, Hee Sun; Li, Li; Pan, Hui Lin.

In: Journal of Neuroscience, Vol. 32, No. 25, 20.06.2012, p. 8560-8568.

Research output: Contribution to journalArticle

Ye, Zengyou ; Li, De Pei ; Byun, Hee Sun ; Li, Li ; Pan, Hui Lin. / NKCC1 upregulation disrupts chloride homeostasis in the hypothalamus and increases neuronal activity-sympathetic drive in hypertension. In: Journal of Neuroscience. 2012 ; Vol. 32, No. 25. pp. 8560-8568.
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