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A Common Polymorphism in the Mineralocorticoid Receptor Modulates Stress Responsiveness

Division of Medical Pharmacology (R.H.D., O.C.M., E.V., E.R.d.K.), Leiden/Amsterdam Center for Drug Research, Department of Psychiatry (R.H.D., F.G.Z.), Leiden University Medical Center, Leiden University, 2300 RA Leiden, The Netherlands; Department of Psychobiology (S.W., D.H.H.), University of Trier, 54290 Trier, Germany; Institut National de la Santé et de la Recherche Médicale (M.-C.Z.), U772, Collège de France, 75231 Paris, France; Department of Psychology and Social Behavior (I.S.F.), University of California, Irvine, Irvine, CA 92697-7085; and Clinica di Endocrinologia (G.G.), Università Politecnica delle Marche, 60131 Ancona, Italy

Address all correspondence and requests for reprints to: Roel H. DeRijk, Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research/Leiden University Medical Center, Gorlaeus Laboratories, P.O. Box 9502, 2300 RA Leiden, The Netherlands. E-mail: r.h.de.rijk{at}lacdr.leidenuniv.nl.

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.

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