Mineralocorticoid receptor activation and mineralocorticoid receptor antagonist treatment in cardiac and renal diseases.

C ardiac and renal diseases remain major challenges for healthcare systems in developed countries and commonly coexist, with a disorder in the heart or kidney often leading to secondary dysfunction or injury in the other organ. Indeed, the term cardiorenal syndrome has been introduced to describe the broad spectrum of disease involving both the heart and kidneys. 1 Aldosterone is a steroid hormone with mineralocorticoid activity, produced primarily in the glomerular zone of the adrenal cortex. 2 Aldosterone fulfills its major physiological function of maintaining sodium and potassium balance and blood pressure control by binding to the mineralocorticoid receptor (MR) in the connecting tubule and cortical collecting duct in the kidneys, thereby increasing sodium reabsorption and potassium secretion. There is a growing body of evidence for a broader role of aldosterone and MR activation in the pathophysiology of cardiovascular and renal disease. 3,4 This article focuses on our knowledge and understanding of the direct roles of aldosterone and MR activation in the heart and kidneys, including common pathophysiological mechanisms in both organs and implications for clinical use of MR antagonists (MRAs) in the treatment of cardiac and renal diseases. MR expression has been demonstrated in vivo in vascular endo-thelial cells and vascular smooth muscle cells of interlobar arteries in mouse kidneys and ex vivo in cultured podocytes, mesangial cells, and renal fibroblasts. 3 The MR is also expressed in multiple cell types in the heart, including cardiomyocytes, coronary endothelial and vascular smooth muscle cells, fibro-blasts, and inflammatory cells, such as macrophages. 5 Aldosterone and the glucocorticoid cortisol bind to the MR with similar affinities. Plasma concentrations of glucocorti-coids are 100-to 1000-fold higher than those of aldosterone. Overstimulation of the MR is prevented by the coexpression of 11β-hydroxysteroid dehydrogenase type 2 (11-BHSD2). This enzyme converts cortisol into cortisone, which has a lower affinity for the MR. 11-BHSD2 activity has been demonstrated in both the kidneys and heart; 6,7 however, expression of 11-BHSD2 varies in different cell types, with some cells, such as cardio-myocytes, having very low levels of 11-BHSD2. There is not yet consensus on whether aldosterone or cortisol activates the MR in these cells, but direct effects of aldosterone have still been observed, suggesting mechanisms yet to be determined fully may operate to allow the binding of aldosterone to the MR. Once aldosterone binds to the MR, the hormone–receptor complex dimerizes, migrates into the nucleus, and binds to a specific …