Endocrine Abstracts (2017) 50 S11.3 | DOI: 10.1530/endoabs.50.S11.3

Mechanisms of salt-sensitive hypertension

Matthew Bailey


The University of Edinburgh, Edinburgh, UK.


25–30% of normotensive people have salt-sensitive blood pressure, which is an independent risk factor for cardiovascular mortality. The underlying mechanisms are not clear but impaired renal salt excretion and vascular (endothelial) dysfunction are currently viewed as important processes for salt-sensitivity.

To add complexity, non-modulation of the hierarchical control systems that regulate renal and vascular function are critical to the development of salt-sensitivity. We have used the syndrome of Apparent Mineralocorticoid Excess (AME) as an exemplar system to interrogate mechanisms of salt-sensitivity. This syndrome is caused by loss of function of 11βHSD2, an enzyme which metabolizes cortisol in cells and thereby preventing glucocorticoids from activating the mineralocorticoid receptor. AME is characterised by sodium retention and severe salt-sensitive hypertension. Global knockout of the gene in mice or rats recapitulates human AME, inducing salt-sensitive hypertension, impaired sodium renal excretion and a rapid decline in renal function. Heterozygous knockout mice have normal BP but retain sodium and become hypertensive when fed a high salt diet, analogous to the mild type 2 variant of AME in humans. In each of these studies, aldosterone modulated appropriately with dietary salt but circulating corticosterone increased and the sympathetic nervous system was hyperactive.

We have used a cre-lox strategy to resolve components of salt-sensitivity. Deleting 11βHSD2 throughout the CNS does not change blood pressure per se but induces a phenotypic switch from salt-resistance to salt-sensitivity. This transition was amplified by an abnormal salt-appetite: such that ad lib salt-intake was ~3 times higher than in controls. We are currently examining renal and vascular function in CNS-knockout mice under basal salt intake and after high salt feeding. Our research highlights the physiological complexity of salt-sensitivity, providing evidence for brain-kidney cross talk influenced by the sympathetic nervous system and hypothalamic-pituitary–adrenal axis.

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