Salt-Sensitive Hypertension in GR+/− Rats Is Accompanied with Dysregulation in Adrenal Soluble Epoxide Hydrolase and Polyunsaturated Fatty Acid Pathways

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.

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“…45 Study on the major pathways of hypertension has shown that the haploidy insufficiency of glucocorticoid receptor in rats can cause the disorder of linoleic acid metabolism pathway. 57 Another study on the mechanism of melatonin-mediated hypotension, at 18 h, melatonin acted on the (cGMP-PKG) signaling pathway involved in NO synthesis, suggesting that the regulation of blood pressure could be achieved through the cGMP-PKG signaling pathway. 118 According to KEGG pathway analysis of diabetes, there are drug metabolism-cytochrome P450, linoleic acid metabolism and Neuroactive ligand-receptor interaction, et al Hogan et al used quantitative reverse transcription Quantitative Real-time polymerase chain reaction (QRT-PCR) to identify differentially regulated gene expression of islet amyloid, which is associated with islet physiology and pathology of type II diabetes mellitus, and found that it contains steroidogenic acute regulatory protein (STAR protein), which is part of the synthetic response group of steroid hormone metabolism.…”

Role of glucocorticoid receptor mutations in hypertension and adrenal gland hyperplasia

“…A high salt diet induced furthermore an increase of corticosterone excretion and the BP in these mice. Similarly, rats with GR haploinsufficiency (GR +/em2 , [ 68 ]) when kept on a standard diet showed significantly increased plasma aldosterone and corticosterone levels and an adrenocortex hyperplasia but a normal systolic blood pressure. Salt-sensitive hypertension was only provoked in combination with high salt intake in the transgenic rats [ 68 ].…”

“…Similarly, rats with GR haploinsufficiency (GR +/em2 , [ 68 ]) when kept on a standard diet showed significantly increased plasma aldosterone and corticosterone levels and an adrenocortex hyperplasia but a normal systolic blood pressure. Salt-sensitive hypertension was only provoked in combination with high salt intake in the transgenic rats [ 68 ]. During prolonged salt exposure, both transgenic and control rats progressively reduced their salt intake [ 68 ].…”

“…Salt-sensitive hypertension was only provoked in combination with high salt intake in the transgenic rats [ 68 ]. During prolonged salt exposure, both transgenic and control rats progressively reduced their salt intake [ 68 ]. While, in the mouse, an adaptive failure of the renal vasculature and tubule resulting in transient sodium retention was documented, a dysregulation of the soluble epoxide hydroxylase enzyme (sEH) that regulates omega 3 and omega 6 non-polysaturated fatty acid metabolism was reported in rat, with a significant increase in less active metabolites [ 68 ].…”

“…During prolonged salt exposure, both transgenic and control rats progressively reduced their salt intake [ 68 ]. While, in the mouse, an adaptive failure of the renal vasculature and tubule resulting in transient sodium retention was documented, a dysregulation of the soluble epoxide hydroxylase enzyme (sEH) that regulates omega 3 and omega 6 non-polysaturated fatty acid metabolism was reported in rat, with a significant increase in less active metabolites [ 68 ]. Further studies are needed to elucidate whether this is a cause or consequence of salt-sensitive hypertension and/or this may affect the endothelial function.…”