Genomic and Non-Genomic Effects of Aldosterone

132 Current Signal Transduction Therapy, 2012, 7, 132-141 Genomic and Non-genomic Effects of Aldosterone Andrea Verhovez*, Tracy A. Williams, Silvia Monticone, Valentina Crudo, Jacopo Burrello, Maddalena Galmozzi, Michele Covella, Franco Veglio and Paolo Mulatero Department of Medicine and Experimental Oncology, Division of Internal Medicine and Hypertension, University of Torino, 10126 Torino, Italy Abstract: The last two decades have witnessed a growing number of experimental observations regarding the mineralocorticoid physiopathology, leading to a new understanding of the molecular basis of the aldosterone-induced target organ damage. As a matter of fact, although it has long been known that the combined administration of mineralocorticoids and salt leads to extensive vascular lesions in the target organs, the recognition that aldosterone is able to induce direct toxic effects on the various cell types that make up the cardiovascular organ has built up recently. Moreover, non-genomic effects have been attributed to aldosterone, i.e. effects which do not depend on the activation of the cellular transcription machinery, whose physiopathologic relevance is still being investigated. These advances in our understanding of aldosterone physiopathology have shed light on the biological reasons which are at the base of the impressive results obtained in clinical trials of aldosterone antagonism. Keywords: Aldosterone, hyperaldosteronism, endothelium. INTRODUCTION permeability by means of the generation of high electrochemical gradients. This action is performed by The hormone aldosterone was named after the aldehyde modulation of gene expression. group located on the carbon 18 of the steroidal skeleton which takes the place of the methyl group which Aldosterone synthase, the product of the CYP11B2 gene characterizes all the other steroidal compounds. It was and the final and rate-limiting enzyme of its synthetic isolated for the first time by Simpson and Tait in 1953 metabolic pathway, is expressed exclusively in the zona [1,2] and has since been characterized as the main glomerulosa, the outermost layer of the adrenal cortex, mineralocorticoid hormone in humans on the basis of its where it converts deoxycorticosterone to aldosterone by robust effects on the transepithelial unidirectional transport means of a three-step oxidative biochemical reaction [4,5]. of sodium [3]. Aldosterone action was originally believed to Its activity is regulated by the three main secretagogues of be limited to just few classical target organs, mainly of aldosterone, the plasma potassium concentration [6], the epithelial origin, where the hormone induced the activity of the renin-angiotensin system [7] and ACTH [8,9], biochemical modifications required to maintain volume and although many other compounds have been attributed a electrolyte homeostasis by acting through genomic minor role [10]. pathways. Nevertheless, in the last two decades a growing The genomic actions of aldosterone are mediated by its number of experimental observations has broadly expanded binding to the mineralocorticoid receptor (MR), a member of the limits of this classical model. In particular the spectrum the superfamily of ligand-regulated transcription factors. of tissues and organs involved in aldosterone action has This superfamily, featuring 49 members in humans [11] and turned out to be wider than previously expected and these including the receptors for the thyroid hormones, the retinoic targets (heart, blood vessels, brain) are now described as acid, the glucocorticoids and the sexual steroids, is made up “nonepithelial”. Moreover, aldosterone has been attributed of molecules which, in resting conditions, are localized in non-genomic effects, i.e. effects which do not depend on the the cytosol and that, following ligand binding, translocate to activation of the cellular transcription machinery. the nucleus to regulate gene expression. Further, its members CLASSICAL MOLECULAR PHYSIOLOGY OF display structural similarities, being composed of functionally ALDOSTERONE related distinct domains [12,13]: - a carboxy-terminal ligand binding domain (LBD) that Aldosterone has classically been described as a also binds heat shock proteins (HSPs) required to attain a mineralocorticoid hormone produced exclusively in the high affinity ligand-binding capacity [14], and is further adrenals and acting on a small number of epithelial target involved in receptor dimerization, nuclear targeting and organs (kidney, colon, salivary and sweat glands) exhibiting hormone-dependent transactivation; high electrical resistance and capable of regulating water - an amino-terminal domain, the most variable region within the steroid receptor superfamily, that has a ligand- *Address correspondence to this author at the Division of Internal Medicine independent transactivation function; and Hypertension, AOU San Giovanni Battista, Via Genova 3, 10126, Torino, Italy; Tel: -39-011-6336959; Fax: -39-011-6602707; - a highly conserved central DNA binding domain (DBD), E-mail: [email protected] involved in DNA binding and receptor dimerization; 1574-3624/12 $58.00+.00 ©2012 Bentham Science Publishers Genomic and Non-genomic Effects of Aldosterone Current Signal Transduction Therapy, 2012, Vol. 7, No. 2 133 - a hydrophilic hinge region between the DBD and the proteins, which are characterized by a single transmembrane LBD. domain and regulate the activity of pumps and ion transporters; it displays a 50% homology with the subunit Upon aldosterone binding, the HSPs dissociate from the + + of the Na /K -ATPase, is selectively expressed in the distal MR permitting the LBD to mediate the nuclear translocation parts of the nephron and in the epithelial cells of the distal [15,16] and the ensuing binding to specific hormone colon, and acts by increasing its affinity for the intracellular response elements in the promoter regions of target genes sodium; corticosteroid hormones, sodium restriction, low- [17]; the recruitment of the relevant transcription initiation potassium diet and metabolic acidosis have been shown to complex and coactivators or corepressors permits either to significantly up-regulate CHIF mRNA expression [32,33]. activate or repress gene transcription [18]. K-Ras is a monomeric GTPase whose activity stabilizes Since the cloning of the MR, its high sequence homology ENaC in the opening state [34]; it directly stimulates with the glucocorticoid receptor became evident [19]. This phosphoinositide 3-OH kinase (PI3K) to produce inositol homology is not limited to the DBD but also to the LBD and triphosphate which in turn acts onto the ENaC [35]. These determines a ten-fold higher affinity of cortisol for the MR data have shed light on previous observations regarding the compared to its own receptor [20]. Since cortisol circulates crucial role of PI3K for aldosterone to induce early and late at much higher concentrations than aldosterone, it would be effects on its epithelial target cells [36]. expected to preferentially occupy the MR: however, in the NON-GENOMIC EFFECTS epithelial target tissues of aldosterone and in some other tissues, aldosterone specificity is maintained by the action of Non-genomic effects are characterized by their short time the enzyme 11-hydroxysteroid dehydrogenase type 2 (11- lag of action, occurring in a few minutes or even seconds, HSD2) which converts cortisol to its inactive metabolite and their insensitivity to transcription and translation cortisone [21]. In case of genetic or pharmacological inhibitors. The first rapid non-genomic actions of aldosterone inactivation of this enzyme, the syndrome of apparent to be described date back to the sixties, when enhanced mineralocorticoid excess ensues, where the MR is constantly sodium exchange was reported in canine erythrocytes [37]. activated by circulating glucocorticoids [22]. Nevertheless, Later on, aldosterone was reported to trigger non-genomic other mechanisms that confer receptor activation specificity effects on a large number of cells types, most notably must exist in those tissues where 11-HSD2 has not been mononuclear leucocytes, endothelial cells, vascular smooth detected, such as hypothalamus and cardiomyocytes [23]. muscle cells (VSMC) and cardiomyocytes [38]. The first studies focused on the rapid modulation of the trans- The regulation of gene transcription in the classical membrane electrolyte transport consisting of a rapid and epithelial target organs occurs in a two step modality; in the transient increase in intracellular Ca2+ followed by activation early phase, which takes place in the first three hours from of the NHE [39,40]; the final effect consists in an increase in aldosterone stimulation, regulatory proteins of pre-existing cell volume that can be monitored by atomic force ion channels and transporters are modulated; in the second microscopy and intracellular alkalinization [41]. The one, new pumps, transporters and ion channels are directly intracellular metabolic pathways mediating these events rely produced with an increase in their density at the membrane on the c-Src dependent activation of EGFR and the ensuing level. These last molecules are considered the final effectors MAPK activation [42], although other authors have proposed of the mineralocorticoid action in epithelia and have been a role also for protein kinase C [43,44] and PI3K [45]. identified as the epithelial sodium channel (ENaC), acting on the luminal side, and the Na+/K+-ATPase, acting on the Debate still persists

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