Abstract
Mutations within the glucocorticoid receptor (GR) gene locus lead to glucocorticoid resistance which is characterized by several clinical symptoms such as adrenal gland hyperplasia and salt-sensitive hypertension, although the underlying mechanisms are still unknown. We studied GR haploinsufficient (GR+/−) Sprague Dawley rats which, on a standard diet, showed significantly increased plasma aldosterone and corticosterone levels and an adrenocortex hyperplasia accompanied by a normal systolic blood pressure. Following a high salt diet, these rats developed salt-sensitive hypertension and maintained elevated enzyme-soluble epoxide hydrolase (sEH) in adrenal glands, while sEH was significantly decreased in wild-type rats. Furthermore, GR+/− rats showed dysregulation of the equilibrated linoleic and arachidonic acid pathways, with a significant increase of less active metabolites such as 8,9-DiHETrE. In Sprague Dawley rats, GR haploinsufficiency induced steroid disturbances, which provoked hypertension only in combination with high salt intake, which was accompanied by disturbances in sEH and fatty acid metabolism. Our results suggest that sEH inhibition could be a potential target to treat hypertension in patients with GR haploinsufficiency.
Highlights
A systematic analysis of population-based studies from 90 countries showed that one-third of the human adult population is hypertensive [1]
glucocorticoid receptor (GR) transcript analysis for exons 2–3 (Figures S1D and S2), exons 2–4 (Figures S1E and S2) or exon 8 (Figures S1F and S2) did not reveal any fragment in homozygous mutant rats, demonstrating that the rat em2 mutant allele is a null allele. This was confirmed in protein lysates isolated from rat embryonic fibroblasts (REF) using in homozygous mutant rats, demonstrating that the rat em2 mutant allele is a null allele
We demonstrated that GR haploinsufficiency in Sprague Dawley rats induced primary generalized glucocorticoid resistance (PGGR) syndrome, leading to an adrenocortex hyperplasia, disturbances of the steroids profile and salt-sensitive hypertension that is associated with changes in fatty acids metabolites
Summary
A systematic analysis of population-based studies from 90 countries showed that one-third of the human adult population is hypertensive [1]. It is well established that hypertension and the associated cardiovascular symptoms are one of the leading causes of death worldwide [2]. Glucocorticoids are important for various pathophysiological and physiological processes such as metabolic homeostasis and regulation of blood pressure [3], energy intake, glucose and lipid homeostasis [4]. Glucocorticoid excess can cause hypertension, obesity, insulin resistance/diabetes and Cushing’s syndrome [5]. Previous studies [6,7] have reported excess glucocorticoid secretion in patients with primary aldosteronism that may contribute to associated metabolic risk and diastolic blood pressure [8]. It was proposed that treatment with mineralocorticoid receptor antagonists alone may not be sufficient to counteract adverse metabolic risk in patients with primary aldosteronism [8,9]
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