Salt-sensitive hypertension is a major risk factor for cardiovascular morbidity. Humans and mice with glucocorticoid receptor haploinsufficiency (GR+/−) are hypertensive, which in mice reflects activation of the renin-angiotensin-aldosterone system. Furthermore, glucocorticoid receptor (GR) gene polymorphisms associate with increased cardiovascular disease risk. Here we investigated the effect of dietary salt intake on blood pressure, heart and kidney in GR+/− mice. Adult male GR+/− mice and wild-type (WT) littermates were fed a sodium-enriched (3%Na+) or standard chow diet (0.3%Na+) for one week, after which mice were anaesthetised for measurement of blood pressure and sodium excretion. Separate cohorts were killed by decapitation and kidneys and hearts taken for histology and mRNA quantification. Cardiac atrial natriuretic peptide (ANP) mRNA levels were elevated in GR+/− mice and were markedly augmented following sodium-enriched diet [Chow:WT 100±7%, GR+/−146±8%; Sodium:WT 157±7%, GR+/−281±25%; P<0.05(genotype), P<0.05(Sodium)]. Despite this, renal function studies showed GR+/− mice had a blunted natriuretic response to sodium-enriched diet. Furthermore, the high blood pressure found in GR+/− mice was augmented by sodium-enriched diet, with no effect in WT [Chow: WT 84±3 mmHg, GR+/− 95±3 mmHg; Sodium: WT 85±4 mmHg, GR+/− 105±3 mmHg; P<0.001(Genotype)]. Sodium-enriched diet increased kidney weight in both genotypes [Chow:WT 0.49±0.01%, GR+/−0.49±0.01%; Sodium:WT 0.64±0.1%, GR+/− 0.60±0.02%; P<0.001(Sodium)] but adrenal gland and heart weights were unaltered. Haematoxylin and eosin staining did not reveal any gross histological differences in sections of the kidneys or hearts. Interestingly, cardiac mineralocorticoid receptor mRNA levels were increased in GR+/− mice vs WT [Chow:WT 100±12%, GR+/−136±5%; Sodium:WT 97±16%, GR+/−146±24%; P<0.05 (Genotype)] possibly in response to reduced GR levels. These results suggest that altered cardio-renal interactions cause salt-sensitivity of blood pressure in GR+/− mice: the kidney develops insensitivity to ANP and the renal salt retention increases blood pressure in these animals. It will be important to investigate whether GR polymorphisms influence salt-sensitive hypertension in humans.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.