The severe form of hypertension caused by the activating S810L mutation in the mineralocorticoid receptor is cortisone related

A gain of function mutation resulting in the substitution of leucine for serine at codon 810 (S810L) in the human mineralocorticoid receptor (MR) is responsible for early-onset hypertension that is exacerbated in pregnancy. All steroids, including progesterone, that display antagonist properties when bound to the wild-type MR are able to activate the mutant receptor (MRL810). These findings suggest that progesterone may contribute to the dramatic aggravation of hypertension in MRL810 carriers during pregnancy. However, the steroid(s) responsible for hypertension in MRL810 carriers (men and nonpregnant women) has not yet been identified. Here we show that cortisone and 11-dehydrocorticosterone, the main cortisol and corticosterone metabolites produced in the distal nephron, where sodium reabsorption stimulated by aldosterone takes place, bind with high affinity to MRL810. The potency with which cortisone and 11-dehydrocorticosterone bind to the mutant MR contrasts sharply with their low wildtype MR-binding capacity. In addition, cotransfection assays demonstrate that cortisone and 11-dehydrocorticosterone are potent activators of the MRL810 trans-activation function. Because the plasma concentration of cortisol in humans is about 30-fold higher than that of corticosterone, these findings strongly suggest that cortisone is one of the endogenous steroids responsible for early-onset hypertension in men and nonpregnant women carrying the MRL810 mutation.