Glucocorticoid-mediated mineralocorticoid receptor activation and hypertension

Abstract

Purpose of review: Traditionally, the mineralocorticoid receptor was thought to be activated by the mineralocorticoid hormone aldosterone, and to exhibit its main action on epithelia by promoting renal sodium retention, potassium excretion and inducing hypertension upon excessive activation. Recently, evidence appeared that mineralocorticoid receptors are expressed in nonepithelial cells and activated by endogenous glucocorticoids including cortisol. Therefore, the prereceptor regulation of cortisol access to the mineralocorticoid receptors by 11beta-hydroxysteroid dehydrogenase enzymes (11beta-HSDs), a mechanism absent in most nonepithelial cells, appears to be relevant for disease states with cortisol-induced mineralocorticoid action. The present review focuses on direct and indirect effects attributable to mineralocorticoid receptor activation by glucocorticoids.

Recent findings: The determination of the intracellular topology of 11beta-HSD1, facing the endoplasmic reticulum lumen, and 11beta-HSD2, facing the cytoplasm, suggests that 11beta-HSD1 acts as a prereceptor mechanism in the local activation of glucocorticoid receptors, whereas 11beta-HSD2 controls mineralocorticoid receptors by interacting with the receptor in the absence of aldosterone. Downregulation of 11beta-HSD2 was observed with various stimuli including hypoxia, shear stress, angiotensin II and tumor necrosis factor alpha. The corresponding signal transcription pathways and some relevant transcription factors have been identified. Renal sodium retention in liver cirrhosis, nephrotic syndrome and hypoxia have been linked to 11beta-HSD2 reduced activity. Overexpression of 11beta-HSD1 specifically in adipose tissue in mice caused central obesity, a metabolic syndrome and hypertension due to increased intracellular cortisol concentrations. Peroxisome proliferator-activated receptor gamma agonists reduce 11beta-HSD1 activity and diminish the intracellular availability of cortisol, an effect accompanied by a decline in blood pressure. Three individuals with loss-of-function mutations of peroxisome proliferator-activated receptor gamma developed early hypertension. A potential mechanism might be glucocorticoid dependent mineralocorticoid receptor-mediated downregulation of endothelial nitric oxide synthase.

Summary: Recently, mineralocorticoid receptor antagonists have been used in the randomized aldactone evaluation study (RALES) with spironolactone, the eplerenone post-AMI heart failure efficacy and survival study (EPHESUS), and in severe and postmyocardial infarct heart failure, respectively. These investigations cannot be understood on the basis of the present physiological knowledge and underscore the relevance of focusing on mineralocorticoid receptor activation by ligands other than aldosterone.