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

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...

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Bibliographic Details
Published in:The Journal of neuroscience 2012-06, Vol.32 (25), p.8560-8568
Main Authors: Ye, Zeng-You, Li, De-Pei, Byun, Hee Sun, Li, Li, Pan, Hui-Lin
Format: Article
Language:English
Subjects:
Animals
Blood Pressure - physiology
Blotting, Western
Cell Membrane - metabolism
Chlorides - metabolism
Electrophysiological Phenomena
gamma-Aminobutyric Acid - physiology
Ganglia, Sympathetic - physiology
Ganglionectomy
Glycosylation
Homeostasis - genetics
Hypertension - metabolism
Hypertension - physiopathology
Hypothalamus - metabolism
Male
Neurons - physiology
Paraventricular Hypothalamic Nucleus - metabolism
Paraventricular Hypothalamic Nucleus - physiopathology
Rats
Rats, Inbred SHR
Rats, Inbred WKY
Sodium-Potassium-Chloride Symporters - biosynthesis
Solute Carrier Family 12, Member 2
Sympathetic Nervous System - physiopathology
Synapses - physiology
Up-Regulation
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Summary: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 E(GABA) 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.
ISSN:0270-6474
1529-2401
1529-2401
DOI:10.1523/jneurosci.1346-12.2012