The mineralocorticoid receptor: insights into its molecular and (patho)physiological biology

The last decade has witnessed tremendous progress in the understanding of the mineralocorticoid receptor (MR), its molecular mechanism of action, and its implications for physiology and pathophysiology. After the initial cloning of MR, and identification of its gene structure and promoters, it now appears as a major actor in protein-protein interaction networks. The role of transcriptional coregulators and the determinants of mineralocorticoid selectivity have been elucidated. Targeted oncogenesis and transgenic mouse models have identified unexpected sites of MR expression and novel roles for MR in non-epithelial tissues. These experimental approaches have contributed to the generation of new cell lines for the characterization of aldosterone signaling pathways, and have also facilitated a better understanding of MR physiology in the heart, vasculature, brain and adipose tissues. This review describes the structure, molecular mechanism of action and transcriptional regulation mediated by MR, emphasizing the most recent developments at the cellular and molecular level. Finally, through insights obtained from mouse models and human disease, its role in physiology and pathophysiology will be reviewed. Future investigations of MR biology should lead to new therapeutic strategies, modulating cell-specific actions in the management of cardiovascular disease, neuroprotection, mineralocorticoid resistance, and metabolic disorders

Mechanism of the antimineralocorticoid effects of spirolactones

Spirolactones are antimineralocorticoid compounds, which were introduced into therapeutics in 1960. They are useful in the treatment of hyperaldosteronism and essential hypertension, although their side effects (gynecomastia, impotence, menstrual cycle abnormalities) limit their use. They are known to antagonize the effect of aldosterone at the level of the target cells, and until recently this mechanism was the only one generally implicated. In 1972, Erbler showed that spironolactone inhibits aldosterone biosynthesis in vitro [1]. Since then, several authors have confirmed this effect, both in animals and man, and have therefore challenged the relative importance of peripheral aldosterone antagonism in favor of an inhibitory effect of these drugs on aldosterone biosynthesis.This editorial review attempts to clarify the findings and to determine whether antialdosterones act mainly at the target cell, or through inhibition of aldosterone production, or alternatively by a combination of each effect