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 (MR(L810)). These findings suggest that progesterone may contribute to the dramatic aggravation of hypertension in MR(L810) carriers during pregnancy. However, the steroid(s) responsible for hypertension in MR(L810) 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 MR(L810). The potency with which cortisone and 11-dehydrocorticosterone bind to the mutant MR contrasts sharply with their low wild-type MR-binding capacity. In addition, cotransfection assays demonstrate that cortisone and 11-dehydrocorticosterone are potent activators of the MR(L810) 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 MR(L810) mutation.

Aldosterone acts in mineralocorticoid-sensitive cells by binding to the mineralocorticoid receptor (MR). Because the MR displays similar affinity for aldosterone and glucocorticoid hormones and because these latter hormones are 100- to 1000-fold more abundant than aldosterone in the plasma, mechanisms are required to avoid permanent illicit occupancy of MR by glucocorticoid hormones. The main mechanism of mineralocorticoid selectivity is enzymatic: the 11beta hydroxysteroid dehydrogenase (HSD2) metabolizes glucocorticoid hormones into derivatives with a low affinity for MR. The cell biology and regulation of HSD2 are reviewed in this article, as well as its implications in human hypertension. Other factors play a role in mineralocorticoid selectivity: the MR itself, the possibility to form homodimers (MR-MR), or heterodimers (with the glucocorticoid receptor). All of these cellular events participate to successive dynamic equilibriums, which allow fine tuning of transcriptional regulation of target genes, depending on the target tissue and the hormonal status.

Cardiac failure is a common feature in the evolution of cardiac disease. Among the determinants of cardiac failure, the reninangiotensin-aldosterone system has a central role, and antagonism of the mineralocorticoid receptor (MR) has been proposed as a therapeutic strategy. In this study, we questioned the role of the MR, not of aldosterone, on heart function, using an inducible and cardiac-specific transgenic mouse model. We have generated a conditional knock-down model by expressing solely in the heart an antisense mRNA directed against the murine MR, a transcription factor with unknown targets in cardiomyocytes. Within 2-3 mo, mice developed severe heart failure and cardiac fibrosis in the absence of hypertension or chronic hyperaldosteronism. Moreover, cardiac failure and fibrosis were fully reversible when MR antisense mRNA expression was subsequently suppressed.C ardiac failure is a major health problem with increasing incidence with aging of the population. Cardiac fibrosis is a marker of cardiac failure and a crucial determinant of myocardial heterogeneity, increasing diastolic stiffness, systolic dysfunction, and the propensity for reentry arrhythmias (1). Animal models are necessary to investigate the mechanisms of appearance and regression of cardiac remodeling and to improve therapeutic strategies. In this paper, we report on a conditional mouse transgenic model in which cardiac fibrosis can be induced and reversed. This was achieved by regulating the expression of the mineralocorticoid receptor (MR) in cardiomyocytes.Studies in both experimental animals and humans have suggested that aldosterone excess may have deleterious effects on cardiac function (2). Recently, the Randomized Aldactone Evaluation Study (RALES) showed that treatment of patients experiencing severe heart failure with spironolactone, an antagonist of the aldosterone receptor (mineralocorticoid receptor) used in the treatment of hypertension, improved both morbidity and mortality (3). These findings have resulted in the recommendation of spironolactone use in the treatment of severe heart failure (4). In RALES, the mechanisms and cellular targets involved in the beneficial effect of spironolactone action are largely unknown. Because MR is expressed in both cardiomyocytes (5) and the kidney (6), it has been difficult to separate the direct effects of signaling through the cardiac MR and indirect effects resulting from actions of the drug on renal MR. MR is a ligand-dependent transcription factor of the steroid receptor superfamily (7). In the kidney, aldosterone binding to MR increases sodium reabsorption and potassium excretion (6). Inactivating mutations of MR result in chronic renal salt wasting, and activating mutation of MR causes hypertension, underscoring the essential role of this pathway in sodium balance and the control of blood pressure (8, 9). In the heart, however, the role of MR in physiologic and pathologic situations has not been defined. A MR knockout mouse model is available (10), but these animals die in the first ...