Salt-sensitive hypertension in GR mutant rats is associated with altered plasma polyunsaturated fatty acid levels and aortic vascular reactivity

In humans, glucocorticoid resistance is attributed to mutations in the glucocorticoid receptor (GR). Most of these mutations result in decreased ligand binding, transactivation, and/or translocation, albeit with normal protein abundances. However, there is no clear genotype‒phenotype relationship be...

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Bibliographic Details
Published in:	Pflügers Archiv
Main Authors:	Verouti, S, Aeschlimann, G, Wang, Q, Del Olmo, D Ancin, Peyter, A C, Menétrey, S, Winter, D V, Odermatt, A, Pearce, D, Hummler, E, Vanderriele, P E
Format:	Journal Article
Language:	English
Published:	Germany 10-09-2024
Subjects:	Hypertension Chrousos syndrome Adrenal gland hyperplasia Soluble epoxide hydrolase Glucocorticoid receptor
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Summary:	In humans, glucocorticoid resistance is attributed to mutations in the glucocorticoid receptor (GR). Most of these mutations result in decreased ligand binding, transactivation, and/or translocation, albeit with normal protein abundances. However, there is no clear genotype‒phenotype relationship between the severity or age at disease presentation and the degree of functional loss of the receptor. Previously, we documented that a GR rat line developed clinical features of glucocorticoid resistance, namely, hypercortisolemia, adrenal hyperplasia, and salt-sensitive hypertension. In this study, we analyzed the GR rat model heterozygously mutant for the deletion of exon 3, which encompasses the second zinc finger, including the domains of DNA binding, dimerization, and nuclear localization signals. On a standard diet, mutant rats exhibited a trend toward increased corticosterone levels and a normal systolic blood pressure and heart rate but presented with adrenal hyperplasia. They exhibited increased adrenal soluble epoxide hydroxylase (sEH), favoring an increase in less active polyunsaturated fatty acids. Indeed, a significant increase in nonactive omega-3 and omega-6 polyunsaturated fatty acids, such as 5(6)-DiHETrE or 9(10)-DiHOME, was observed with advanced age (10 versus 5 weeks old) and following a switch to a high-salt diet accompanied by salt-sensitive hypertension. In thoracic aortas, a reduced soluble epoxide hydrolase (sEH) protein abundance resulted in altered vascular reactivity upon a standard diet, which was blunted upon a high-salt diet. In conclusion, mutations in the GR affecting the ligand-binding domain as well as the dimerization domain resulted in deregulated GR signaling, favoring salt-sensitive hypertension in the absence of obvious mineralocorticoid excess.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0031-6768 1432-2013 1432-2013
DOI:	10.1007/s00424-024-03014-y