Abstract
Salt-sensitive hypertension is common in glucocorticoid excess. Glucocorticoid resistance also presents with hypercortisolemia and hypertension but the relationship between salt intake and blood pressure (BP) is not well defined. GRβgeo/+ mice have global glucocorticoid receptor (GR) haploinsufficiency and increased BP. Here we examined the effect of high salt diet on BP, salt excretion and renal blood flow in GRβgeo/+mice. Basal BP was ∼10 mmHg higher in male GRβgeo/+ mice than in GR+/+ littermates. This modest increase was amplified by ∼10 mmHg following a high-salt diet in GRβgeo/+ mice. High salt reduced urinary aldosterone excretion but increased renal mineralocorticoid receptor expression in both genotypes. Corticosterone, and to a lesser extent deoxycorticosterone, excretion was increased in GRβgeo/+ mice following a high-salt challenge, consistent with enhanced 24 h production. GR+/+ mice increased fractional sodium excretion and reduced renal vascular resistance during the high salt challenge, retaining neutral sodium balance. In contrast, sodium excretion and renal vascular resistance did not adapt to high salt in GRβgeo/+ mice, resulting in transient sodium retention and sustained hypertension. With high-salt diet, Slc12a3 and Scnn1a mRNAs were higher in GRβgeo/+ than controls, and this was reflected in an exaggerated natriuretic response to thiazide and benzamil, inhibitors of NCC and ENaC, respectively. Reduction in GR expression causes salt-sensitivity and an adaptive failure of the renal vasculature and tubule, most likely reflecting sustained mineralocorticoid receptor activation. This provides a mechanistic basis to understand the hypertension associated with loss-of-function polymorphisms in GR in the context of habitually high salt intake.
Highlights
Salt-sensitive blood pressure (BP) is an independent risk factor for both cardiovascular and renal disease and the salt-induced rise in BP reflects underlying renal (Hall, 2016) and vascular dysfunction (Morris et al, 2016)
We used GRβgeo/+ mice to model glucocorticoid resistance, assessing BP and renal sodium handling under basal and high salt conditions
Salt-sensitivity was associated with increased levels of deoxycorticosterone and corticosterone, an abnormal renal hemodynamic response and a failure of the distal nephron sodium to adapt to high salt intake
Summary
Salt-sensitive blood pressure (BP) is an independent risk factor for both cardiovascular and renal disease and the salt-induced rise in BP reflects underlying renal (Hall, 2016) and vascular (endothelial) dysfunction (Morris et al, 2016). The failure of neural and hormonal regulatory systems to adapt to high dietary salt intake is an important contributing factor to salt-sensitivity. In this context, sustained glucocorticoid excess, whether overt in Cushing’s or covert in Metabolic Syndrome, induces saltsensitive hypertension and increases cardiovascular risk (Bailey, 2017). Several groups, including ours, have used animal models to examine the relationship between abnormal glucocorticoid activity and BP Both modest glucocorticoid excess (Bailey et al, 2009; Mu et al, 2011) and impaired glucocorticoid metabolism (Bailey et al, 2011; Craigie et al, 2012; Mullins et al, 2015) cause salt-sensitive hypertension. Adrenalectomy induces non-dipping BP in mice (Sei et al, 2008) and in humans such circadian abnormalities have a detrimental impact on cardiovascular health (Henley and Lightman, 2014)
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