A Common Polymorphism in the Mineralocorticoid Receptor Modulates Stress Responsiveness

Context: Mineralocorticoid receptors (MR) mediate the action of aldosterone on sodium resorption in kidney tubular cells, but in brain they respond to the glucocorticoid cortisol in stress regulation and cognitive processes. Objective: The objective of the study was to investigate the role of the MR...

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Published in:The journal of clinical endocrinology and metabolism 2006-12, Vol.91 (12), p.5083-5089
Main Authors: DeRijk, Roel H, Wüst, Stefan, Meijer, Onno C, Zennaro, Maria-Christina, Federenko, Ilona S, Hellhammer, Dirk H, Giacchetti, Gilberta, Vreugdenhil, Erno, Zitman, Frans G, de Kloet, E. Ronald
Format: Article
Language:English
Subjects:
Adaptation, Biological - genetics
Adolescent
Adrenocorticotropic Hormone - blood
Adult
Aldosterone - metabolism
Animals
Biological and medical sciences
Blood Pressure - drug effects
Cells, Cultured
Cricetinae
Endocrinopathies
Female
Fundamental and applied biological sciences. Psychology
Genetic Testing
Heart Rate
Humans
Hydrocortisone - analysis
Hydrocortisone - blood
Hydrocortisone - metabolism
Male
Medical sciences
Middle Aged
Mouse mammary tumor virus
Polymorphism, Genetic - physiology
Receptors, Mineralocorticoid - genetics
Receptors, Mineralocorticoid - metabolism
Saliva - chemistry
Stress, Psychological - genetics
Transfection
Vertebrates: endocrinology
Water-Electrolyte Balance - physiology
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Summary:Context: Mineralocorticoid receptors (MR) mediate the action of aldosterone on sodium resorption in kidney tubular cells, but in brain they respond to the glucocorticoid cortisol in stress regulation and cognitive processes. Objective: The objective of the study was to investigate the role of the MR gene variant I180V in the neuroendocrine response to a psychosocial stressor and in electrolyte regulation. Design: Associations between the MRI180V and outcome variables in a healthy cohort subjected to psychosocial challenge (Trier Social Stress Test) and in a mild hypertensive cohort exposed to acute salt loading (Weinberger’s test) were investigated. In vitro transactivational assays were applied to compare the effects of cortisol and aldosterone on the MRI180V. Results: Carriers of the MR180V allele showed higher saliva (P < 0.01), plasma cortisol (P < 0.01), and heart rate responses (P < 0.05) to the Trier Social Stress Test than noncarriers (MR180I). After 3 d of a normal salt diet and the Weinberger’s test, no association was found with urinary sodium excretion, plasma aldosterone, and plasma renin activity or with changes in blood pressure, aldosterone, and renin responses. In vitro testing of the MR180V allele revealed a mild loss of function using cortisol as a ligand, compared with the MR180I allele. Significantly higher doses of cortisol were needed for half-maximal induction on the TAT-1 (P < 0.002), TAT-3 (P < 0.03), or mouse mammary tumor virus (P < 0.02) promoters, whereas maximal induction was not different. These differences were not observed using aldosterone as a ligand. Conclusion: The findings reveal that cortisol and heart rate responses to a psychosocial stressor are enhanced in carriers of the MR180V variant.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.2006-0915