MOLECULAR-BIOLOGY OF MINERALOCORTICOID METABOLISM

Mineralocorticoids are adrenal steroid hormones that regulate the rete ntion of sodium by the kidney and, hence, are crucial in the regulatio n of sodium balance, intravascular volume, and blood pressure. The mol ecular biology of mineralocorticoid biosynthesis and action has only r ecently been elucidated. The genes encoding the various enzymes that c onvert cholesterol to mineralocorticoids have now been cloned. This ha s revealed the molecular basis of several inherited forms of mineraloc orticoid excess, which cause hypertension, and several forms of minera locorticoid deficiency, which cause salt loss. The cloning of the mine ralocorticoid receptor revealed a paradox. Both the mineralocorticoid and the glucocorticoid receptor are activated equally by cortisol, eve n though cortisol has very modest mineralocorticoid activity. This is explained by the cloning of two genes for the enzyme 11 beta-hydroxyst eroid dehydrogenase (11 beta HSD). Type-II 11 beta HSD, found primaril y in the kidney, irreversibly converts cortisol to cortisone, which do es not activate the mineralocorticoid receptor. Type-II 11 beta HSD th us defends the mineralocorticoid receptor from being activated by the very high concentrations of cortisol in the blood. Recent studies in g enetically hypertensive rats suggest that other enzymes or factors tha t regulate salt balance may remain undiscovered. Thus the study of min eralocorticoid biosynthesis and action remains one of the most promisi ng approaches to understanding hypertension.