A Common Polymorphism in the Mineralocorticoid Receptor Modulates Stress Responsiveness

TLDR

Mineralocorticoid receptors mediate aldosterone‑driven sodium reabsorption in the kidney but bind cortisol in the brain to regulate stress and cognition. The study aimed to determine how the MR I180V polymorphism influences neuroendocrine responses to psychosocial stress and electrolyte regulation. Researchers examined associations in healthy and mildly hypertensive participants using the Trier Social Stress Test and Weinberger's salt‑loading test, and performed in‑vitro transactivation assays comparing cortisol and aldosterone effects on the MR180V allele. Carriers of the MR180V allele exhibited heightened cortisol, salivary, and heart‑rate responses to stress, a mild loss of cortisol‑induced transactivation requiring higher ligand doses, but no differences in aldosterone responses or salt‑diet–related urinary sodium, aldosterone, or renin levels.

Abstract

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.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.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.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.The findings reveal that cortisol and heart rate responses to a psychosocial stressor are enhanced in carriers of the MR180V variant.