International Journal of Molecular Sciences Conference Report Aldosterone and Mineralocorticoid Receptors—Physiology and Pathophysiology John W. Funder Hudson Institute of Medical Research, Monash University, 27–31 Wright St., Clayton 3168, Australia; [email protected] Academic Editors: Anastasia Susie Mihailidou, Jan Danser, Sadayoshi Ito, Fumitoshi Satoh and Akira Nishiyama Received: 8 March 2017; Accepted: 4 May 2017; Published: 11 May 2017 Abstract: Aldosterone is a uniquely terrestrial hormone, first appearing in lungfish, which have both gills and lungs. Mineralocorticoid receptors (MRs), on the other hand, evolved much earlier, and are found in cartilaginous and bony fish, presumptive ligand cortisol. MRs have equivalent high affinity for aldosterone, progesterone, and cortisol; in epithelia, despite much higher cortisol circulating levels, aldosterone selectively activates MRs by co-expression of the enzyme 11β-hydroxysteroid dehydrogenase, Type 11. In tissues in which the enzyme is not expressed, MRs are overwhelmingly occupied but not activated by cortisol, which normally thus acts as an MR antagonist; in tissue damage, however, cortisol mimics aldosterone and acts as an MR agonist. The risk profile for primary aldosteronism (PA) is much higher than that in age-, sex-, and blood pressure-matched essential hypertensives. High levels of aldosterone per se are not the problem: in chronic sodium deficiency, as seen in the monsoon season in the highlands of New Guinea, plasma aldosterone levels are extraordinarily high, but cause neither hypertension nor cardiovascular damage. Such damage occurs when aldosterone levels are out of the normal feedback control, and are inappropriately elevated for the salt status of the individual (or experimental animal). The question thus remains of how excess salt can synergize with elevated aldosterone levels to produce deleterious cardiovascular effects. One possible mechanism is through the agency of the elusive ouabain-like factors (OLFs). Such factors are secreted from the adrenal in response to ACTH (adrenalocortical tropic hormone), to angiotensin via AT2R, and—the polar opposite of aldosterone—to sodium loading. They act on blood vessels to cause vasoconstriction and thus elevate blood pressure to dump excess sodium through pressure natriuresis. Their levels are chronically elevated in PA in response to the continually elevated sodium status, and they thus act to constrict coronary and systemic arteries. In the context of the elevated blood volume and total body sodium in a PA patient, this raises blood pressure and acts as the proximate cause of cardiovascular damage. If this is the case, it would appear to offer new insights into therapy for PA. One would be the use of digibindin, or its more recent successors as antagonists of OLFs acting on Na/K ATPase at the vessel wall. A second would be to routinely combine a low dose MR antagonist, an ENaC inhibitor, and sodium restriction as first-line therapy for bilateral aldosterone overproduction. Finally, for unilateral cases post-surgery, there is good reason to include low-dose MRs in drug therapy if required, given the ability of cortisol in damaged blood vessels to mimic aldosterone vasoconstrictor action. Keywords: endogenous ouabain; cortisol; sodium and primary aldosteronism 1. Physiology Commonly, the physiology of aldosterone and mineralocorticoid receptors (MRs) begins (and sometimes, unfortunately ends) with the action of aldosterone via renal MRs to retain sodium (as well as water) and to excrete potassium. This is not surprising, given that aldosterone is characterized Int. J. Mol. Sci. 2017, 18, 1032; doi:10.3390/ijms18051032 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2017, 18, 1032 2 of 9 Int. J. Mol. Sci. 2017, 18, 1032 2 of 9 by the demonstration of its effects on transepithelial electrolyte transport and what was initially termed by the demonstration of its effects on transepithelial electrolyte transport and what was initially “electrocortin” [1]. Similarly, the first identification of high affinity receptors for aldosterone occurred termed “electrocortin” [1]. Similarly, the first identification of high affinity receptors for aldosterone in vitro studies on rat kidney slices [2]. Again, these were initially termed “Type 1 corticosteroid occurred in vitro studies on rat kidney slices [2]. Again, these were initially termed “Type 1 receptors”,corticosteroid in contrast receptors”, with the in contrast dexamethasone-binding with the dexamethasone-binding Type 2 receptors; Type now Type2 receptors; 1 and Type now 2Type are 1 knownand Type as MRs 2 are and known glucocorticoid as MRs and receptors glucocorticoid (GRs). Accordingly,receptors (GRs). for aAccordingly, considerably for nephrological a considerably audience,nephrological the focus audience, of the currentthe focus section of the will current be on section lesser-known will be aspects on lesser-known of aldosterone aspects and of MRaldosterone physiology. and MR physiology. In allIn all ligand–receptor ligand–receptor systems, systems, an an obvious obvious question question is which is which came came first, first, signal signal or receptor—chickenor receptor—chicken or egg.or egg. For For aldosterone aldosterone and MRs,and theMRs, answer the answer is unequivocal: is unequivocal: the MRs precededthe MRs aldosteronepreceded aldosterone by millions by of years.millions Figure of years.1 shows Figure a 1 dendrogram shows a dendrogram of the evolution of the evolution of the tight-knitof the tight-knit MRs/GRs/progesterone MRs/GRs/progesterone receptorsreceptors (PRs)/androgen (PRs)/androgen receptors receptors (ARs) (ARs) subsequently subsequently from from a common a common ancestor. ancestor. The The first first of theof the four four to branchto branch off off is the is the primordial primordial MRs, MRs, as shown as shown in Figure in Figure1; the 1; inset the inset details details its presence its presence in a number in a number of species,of species, including including bony bony fish and fish cartilaginous and cartilaginous species species such assuch sharks as sharks and rays and [ 3rays]. [3]. Figure 1. Dendrogram of evolution of mineralocorticoid receptors (MRs). Glucocorticoid receptors Figure 1. Dendrogram of evolution of mineralocorticoid receptors (MRs). Glucocorticoid receptors (GRs), progesterone receptors (PRs), and androgen receptors (ARs) from common ancestral protein. (GRs), progesterone receptors (PRs), and androgen receptors (ARs) from common ancestral protein. Inset: MRs across different species expanded. Redrawn from Kassahn et al., 2011 [3]. Inset: MRs across different species expanded. Redrawn from Kassahn et al., 2011 [3]. In contrast, Figure 2 shows the first creature in which aldosterone appears, the lungfish. These animals,In contrast, as their Figure name2 implies,shows thehave first both creature gills and in lungs, which marking aldosterone the transition appears, from the lungfish. an obligate Theseaquatic animals, to a as terrestrial their name milieu. implies, The have first both thing gills andthatlungs, one needs marking to theknow transition about frommineralocorticoid an obligate aquaticreceptors to a terrestrial is that they milieu. evolved The firstmillions thing of that years one be needsfore aldosterone to know about did, mineralocorticoid that their early receptorsphysiologic is thatroles they are evolvednot yet well-defined, millions of years that beforetheir probable aldosterone but not did, certain that their ligand early was physiologic cortisol, and roles that are we notavoid yet well-defined, these insights that on theirevolution probable at our but peril. not certain ligand was cortisol, and that we avoid these insights on evolution at our peril. Int. J. Mol. Sci. 2017, 18, 1032 3 of 9 Int. J. Mol. Sci. 2017, 18, 1032 3 of 9 FigureFigure 2. 2.The The lungfish, lungfish, firstfirst creaturecreature to to make make aldosterone. aldosterone. The second thing one needs to know is that MRs are truly promiscuous. We all know that they Thebind secondaldosterone thing with one high needs affinity: to in know fact, they is that have MRs equivalent are truly high promiscuous.affinity for a range We of steroids— all know that theyaldosterone, bind aldosterone cortisol, with corticosterone, high affinity: deoxycor in fact,ticosterone they have (DOC), equivalent and progesterone. high affinity Given for athe range of steroids—aldosterone,emergence of aldosterone cortisol, as the corticosterone,physiologic mine deoxycorticosteroneralocorticoid, our terrestrial (DOC), MRs and might progesterone. have Givenundergone the emergence mutation of aldosteroneso that they no as longer the physiologic recognized mineralocorticoid,cortisol. This did not ourhappen terrestrial over the MRs eons, might haveand undergone we must mutation thus face sowhy that contemporary they no longer MRs recognized remain promiscuous cortisol. This and didwhat not this happen means overfor the eons,physiology and we must and thuspathophysiology. face why contemporary MRs remain promiscuous and what this means for For some years before characterization of aldosterone DOC was the ‘gold standard’ physiology and pathophysiology. mineralocorticoid; in terms of physiology, it appears to be of no real importance in this role. Under For some years before characterization of aldosterone DOC was the ‘gold standard’ normal circumstances its plasma levels are low, about the same as those of aldosterone, but the secretion mineralocorticoid;of DOC, unlike that in termsof