Editors' ChoicePhysiology

A role for Cl in salt-sensitive hypertension

Sci. Signal.  10 Feb 2015:
Vol. 8, Issue 363, pp. ec30
DOI: 10.1126/scisignal.aaa8636

Increased sodium in the circulation stimulates neurons in the hypothalamus to release vasopressin, a hormone that causes vasoconstriction and increased blood pressure. Blood pressure is normalized through a negative feedback circuit between mechanosensing baroreceptors in arteries and GABAA receptors in the hypothalamic neurons. Choe et al. found that a chronic high-salt diet in rats impairs this negative feedback, leading to hypertension. Rats given a 2% NaCl drinking solution for one week had increased mean arterial blood pressure compared with rats that received normal drinking water. The basal firing rate of hypothalamic magnocellular neurosecretory cells (MNCs) that were isolated from rats that drank salt water was increased. GABAA receptors are part of ligand-gated Cl channel complexes that control neuronal activity: Chloride influx is hyperpolarizing and inhibitory, whereas chloride efflux is depolarizing and excitatory. The chloride exporter KCC2 (K+/Cl cotransporter 2) maintains a low intracellular chloride concentration that enables inhibitory GABAergic signaling. Antagonizing GABAA receptors with bicuculline showed that GABAergic signaling was inhibitory in MNCs from rats that drank normal water but stimulatory in MNCs from rats that drank salt water, indicating a shift in GABAergic output in high-salt conditions. Application of a KCC2 antagonist had no effect on MNCs from rats that drank salt water. Activation of the neurotrophin receptor TrkB, which is activated by BDNF (brain-derived neurotrophic factor) decreases KCC2 abundance in neurons. The abundance of KCC2 was decreased and the phosphorylation of TrkB was increased in hypothalamic tissue from rats that drank salt water. MNCs isolated from rats that drank salt water and received hypothalamic application of a soluble TrkB extracellular domain to scavenge endogenous TrkB agonists were hyperpolarized, which would reduce their activity. Injection of short-hairpin RNA against BDNF into the hypothalamus hyperpolarized MNCs in salt water-drinking rats after electrical stimulation of the region that relays arterial baroreceptor-activated GABAergic feedback. The findings suggest that chronic salt intake switches GABAergic output in MNCs, impairing the negative feedback circuitry that maintains normal blood pressure.

K. Y. Choe, S. Y. Han, P. Gaub, B. Shell, D. L. Voisin, B. A. Knapp, P. A. Barker, C. H. Brown, J. T. Cunningham, C. W. Bourque, High salt intake increases blood pressure via BDNF-mediated downregulation of KCC2 and impaired baroreflex inhibition of vasopressin neurons. Neuron 85, 549–560 (2015). [PubMed]