Aldosterone and mineralocorticoid receptors: Clinical studies and basic biology

With the enormous advances in our understanding of cellular and molecular biology over the past 30 years, it is perhaps not surprising that the term 'Translational Research' is commonly thought of as unidirectional, from benchtop to bedside. Just as enzymes are bidirectional, however much one reaction may be predominant, so is translation. This review sets out to chart how three sets of clinical observations, in hypertension and heart failure, have triggered a radical re-evaluation (and expansion) of our previous concepts of the basic (patho)physiology of aldosterone and mineralocorticoid receptors (MR). The first of these is an example of levering off classical translational research from benchtop to bedside, to revisit the accepted sequence of evolution of the MR, GR, AR and PR subfamily nuclear transactivating factors from a common primordial ancestor. The second example is a meta-analysis of two studies using the selective MR antagonist eplerenone as monotherapy in essential hypertension, which clearly distinguishes the effects of MR blockade on blood pressure from these on urinary electrolyte excretion; this in turn clearly calls into question current teaching of a primarily renal role for aldosterone in raising blood pressure. The final example is the demonstrated efficacy of MR blockade in clinical trials in heart failure and hypertension, when plasma aldosterone levels are in low normal range and sodium status unremarkable. This poses the question of what is activating cardiac and vascular smooth muscle MR under such circumstances, which in turn leads to a radical reconsideration of the role of glucocorticoids in non-epithelial mineralocorticoid receptors.