Aldosterone’s Mechanism of Action

C H A P T E R

10 Aldosterone’s Mechanism of Action: Genomic and Nongenomic Signaling Rene Baudrand1, Luminita Pojoga2, Jose R. Romero2 1Pontificia

Universidad Catolica de Chile, Santiago, Chile; 2Harvard Medical School, Boston, MA, United States

O U T L I N E 1. Introduction

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2. The Mineralocorticoid Receptor 174 2.1 Nuclear Mineralocorticoid Receptor and Cytosolic Mineralocorticoid Receptor 174 2.2 Cell Membrane Mineralocorticoid Receptor 175 2.3 Coregulators of Aldosterone Signaling 175 2.4 Mineralocorticoid Receptor Interaction With the Estrogen Receptor 176 2.5 Mineralocorticoid Receptor Ligands and Their Selectivity176 3. Genomic Actions of Aldosterone 3.1 Classical Target Tissues 3.2 Nonclassical Target Tissues

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3.2.1 Cardiac Tissue 3.2.2 Endothelium 3.2.3 Vascular Smooth Muscle Cells 3.2.4 Adipose Tissue

4. Nongenomic Actions of Aldosterone 4.1 Rapid Signaling Cascades 4.2 Striatin 4.3 G Protein-Coupled Estrogen Receptor

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5. Epigenetic Effects

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6. Mineralocorticoid Receptor Modulators 6.1 Sodium 6.2 Caveolin-1 6.3 Rac1

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7. Novel Mineralocorticoid Receptor Antagonists183 8. Conclusions

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References

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1. INTRODUCTION Adrenal hormones from the cortex, such as cortisol and aldosterone, are essential for human life and evolved with a complex regulatory system to play a crucial role in metabolism homeostasis, stress response, and blood pressure (BP) regulation. Despite their importance in human physiology for millions of years, the history of the renin–angiotensin– aldosterone system (RAAS) only starts by the end of the 19th century with the discovery of renin by analyzing the effect of renal extracts on arterial pressure.1 Then followed the enzymatic activity of renin and the production of angiotensin (formerly hypertensin/angiotonin) in the 1940s and the isolation of aldosterone by the Taits (formerly electrocortin) in the 1950s.2 Two decades after, it was described that aldosterone acted through a specific steroid receptor that was named the mineralocorticoid receptor (MR).3

Textbook of Nephro-Endocrinology, Second Edition http://dx.doi.org/10.1016/B978-0-12-803247-3.00010-6

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© 2018 Elsevier Inc. All rights reserved.

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Over the last decades, our conventional understanding of aldosterone biosynthesis and signaling has been dramatically challenged. Novel evidence has shown that aldosterone and the RAAS can also be locally synthesized by adipose tissue.4 We also learned that a local regulatory system modifies tissue levels of cortisol to improve aldosterone selectivity5 and that steroid receptor signaling includes rapid nongenomic effects.6 Moreover, the MR has been identified in a wide variety of tissues beyond epithelial cells, which includes endothelial cells (ECs), vascular smooth muscle cells (VSMCs), fibroblasts, adipocytes, and myocytes.7 Intriguingly, the function of aldosterone in these cells is different from the classic renal actions and could be explained by different signaling mechanisms and/or tissue-specific modulators. Likewise, aldosterone not only works through a classic nuclear receptor but also through a cell-surface receptor that regulate diverse intracellular events. Also, besides the well-known effects of sodium (Na+) and potassium (K+) on aldosterone regulation, new mechanisms include inadequate aldosterone feedback of adipocyte releasing factors, such as leptin and alternative MR modulators.8,9 Finally, by improving our understanding of MR signaling we have reshaped our vision of aldosterone beyond its classic role in electrolyte regulation to include newly discovered roles of MR in extrarenal tissues and a potential pathogenic role in cardiometabolic disorders.

2.  THE MINERALOCORTICOID RECEPTOR 2.1 Nuclear Mineralocorticoid Receptor and Cytosolic Mineralocorticoid Receptor The MR (encoded by the NR3C2 gene) belongs to the steroid receptor superfamily that include the progesterone, estrogen, androgen, and the glucocorticoid receptors (GRs). The MR is the longest member of the superfamily of ligand-regulated transcription factors that includes steroid and thyroid hormone receptors, and also the retinoic acid, vitamin D, peroxisome proliferator-activated, and retinoid X receptors.7,10 The structure of MR consists of an N-terminal A/B domain (NTD), responsible for cofactor, the C-domain where DNA binding takes places, with a high homology to the GR, and after a short hinge region comes the C-terminal ligand-binding domain (LBD).11 The NTD regulates transactivation (mainly by region activation function 1, AF-1) but also interacts with the LBD in an N–C interaction that stabilizes the receptor conformation. The DNA-binding domain (DBD) binds to the hormone response element (HRE) of MR-regulated genes to mediate transcription.12 The MR LBD is very conserved between species and has multiple functions, that includes, besides ligand binding, also nuclear localization, dimerization, interaction with chaperones, and modulation of transcriptional coactivators and ligand-dependent transactivation.10 Interestingly, while aldosterone is known to be the primary physiological MR ligand in humans, in some tissues with scarce 11β-hydroxysteroid dehydrogenase (11β-HSD2) it is believed that cortisol may act as the primary ligand for MR, whereas progesterone behaves as a predominant antagonist.10 Classically, all steroid hormone receptors are ligand-activated nuclear transcription factors. In the case of MR (but also for GR and the androgen receptor), in the absence of ligand most MR is located primarily in the cytoplasm. If activated by the proper ligand, MR is shuttled to the nucleus and then back to the cytoplasm after unbound or when transcriptionally inactive.7 In its unliganded state in the cytosol, MR is associated with a large heterocomplex of chaperone molecules such as HSP90, HSP70, and p23 that are key players in trafficking but also facilitate the posttranslational modification of the receptors, such as phosphorylation.11 Recent evidence has shown that the existence of this chaperone complex helps the MR to improve its affinity for ligands and support a dynamic equilibrium between cytosolic and nuclear localization, which can be shuttled in both directions, depending on the presence or absence of ligands. After binding of ligand in the cytosol, MR localization is then shifted to the nucleus by two different modes of MR trafficking. A rapid shifting (t1/2 4–10 min) that is mainly regulated by HSP90, as confirmed by using an HSP90 inhibitor such as geldanamycin. However, a slower transport to the nucleus (t1/2 40–60 min) has now been described as well. Interestingly, accumulation of MR in the nucleus is still possible in the presence of geldanamycin mediated, in part, by a slower transport mechanism that may be reflective of MR diffusion.11 Other associated proteins in the cytosol are involved in MR transport such as dynein/dynactin and the immunophilin FKBP52. To favor the cytoplasmic transport of MR to the nucleus, FKBP52 links the MR–HSP90 complex to dynein/dynactin motors, thus improving nucleocytoplasmic trafficking.13 Next, the MR trafficking to the nucleus is possible through an active transport that involves nuclear pore complexes and the binding of MR to importin α. Finally in the nucleus, MR signaling by homodimerization occurs after dissociation from chaperone HSP90.11 Of interest, it has also been postulated that MR is capable of forming heterodimers with other steroid receptors, in particular the GR and ER, which offers additional transcriptional regulation.12

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2.2 Cell Membrane Mineralocorticoid Receptor Currently, a large body of evidence supports the view that aldosterone effects are mediated via the classic cytosolic MR protein in various cell types but at least a small fraction of MR is also located in the membrane. In analogy to the estrogen receptor (ER), it was hypothesized that MR localized to the membrane and could be responsible for different activation pathways than those mediated via MR’s nongenomic or rapid aldosterone effects.14 For example, using coimmunoprecipitation and fluorescence imaging techniques, it was demonstrated that MR colocalized with epidermal growth factor receptor (EGFR), a tyrosine kinase receptor at the plasma membrane, inducing extracellular signal–regulated kinase (ERK) phosphorylation. In addition, other downstream signaling molecules potentially modulated by MR–EGFR cross talk include NADPH oxidase, the proto-oncogene c-Src, protein kinase C, calcium, reactive oxygen species, and small GTPase.15 In the cell membrane, small invaginations called caveolae are not only a structural platform for receptors and enzymes but also act as functional modulators for different cellular pathways.9 The main component of plasma membrane caveolae, caveolin 1 (cav-1), has an important role in signal transduction and intracellular trafficking and interacts with several steroid receptors, such as the ER. Interestingly, Pojoga and colleagues have shown that cav-1 colocalizes and coimmunoprecipitates with the MR in renal and cardiac tissues16 and that MR–cav-1 complexes can be modulated and are more abundant during Na+ loading (Fig. 1).9 Also, since some studies have found that some of the rapid aldosterone-mediated effects are not blocked by MR antagonism, identifying an alternate aldosterone receptor in the membrane is an ongoing area of research.17 Likewise, Gros et al. have proposed that MR-independent effects of aldosterone are mediated by the G protein-coupled estrogen receptor (GPER).18 Interestingly, GPER expression is required for rapid MR-independent effects of aldosterone in VSMC, and can be abolished by a GPER antagonist, decreasing ERK½ phosphorylation.15 Also the cross talk of MR with the angiotensin II (AngII) receptor type 1 (AT1R) and the vascular endothelial growth factor (VEGF) receptor are under current research.

2.3 Coregulators of Aldosterone Signaling Over the past decade, we have learned that rapidly activated signaling cascades that can act as coactivators and corepressors modulate aldosterone-induced transcription. These heterogeneous groups of coregulators may enhance

FIGURE 1.1  Schematic figure of aldosterone signaling. From Baudrand R, Pojoga LH, Romero JR, Williams GH. Aldosterone's mechanism of action: roles of lysine-specific demethylase 1, caveolin and striatin. Curr Opin Nephrol Hypertens. 2014 Jan;23(1):32-7. Review.

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or repress nuclear receptor-mediated transactivation of target genes and are currently crucial to our understanding of the complexity of MR signaling, especially in relation to ligand- and tissue-specific activation. Coactivators are usually large complexes associated with target genes that perform or regulate enzymatic reactions needed for gene expression such as initiation of transcription, histone modification, or RNA splicing. Steroid receptor coactivator 1 (SRC-1) was the first nuclear receptor coregulator recognized. SRC-1 is a coactivator that binds to the activation function 2 (AF-2) region in the MR LBD and recruits histone acetylation complex to initiate transcription. Other MR coactivators described are the peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) interacting with AF-2 in LBD and the transcription-intermediary factor (TIF-1) binding to the NTD region.12 On the other hand, several corepressors have been described regulating histone activity, apoptosis, and repressing transactivation. For example, both nuclear receptor corepressor (NCoR) and silencing mediator of retinoid and thyroid hormone receptor (SMRT), decrease ligand-dependent MR transactivation by inducing histone deacetylase activity via LBD interaction.19 Although many other proteins have been identified as potential coregulators by in vitro screening, additional data is needed, especially related to the clinical relevance for new and more specific MR antagonists.

2.4 Mineralocorticoid Receptor Interaction With the Estrogen Receptor There is growing evidence of a functional and physical interaction of MR and the ER as mentioned above. Lisanti’s group showed evidence that cav-1 acts as a positive modulator of estrogen signaling and that cav-1 interacts with ER-α in cotransfected 293T cells.20 Caveolins are principal molecules within the caveolae that compartmentalize various cellular functions in the plasma membrane. In ECs, Chambliss et al. reported that ER-α localized to the caveolae where it coupled with the endothelial nitric oxide (NO) synthase (eNOS) and its activity.21 Karas’ group then identified striatin, a cav-1-binding protein, that anchored the ER-α, eNOS, and the Gαi complex to the membrane to mediate the rapid nongenomic effects of estradiol on eNOS activation.22 Of interest, Pojoga et al. showed coimmunoprecipitation studies suggesting the presence of a cav-1/MR interaction in vascular tissue that was most likely mediated via the evolutionary conserved cav-1-binding motif within the N-terminal region of MR.16 In addition, they showed that cav-1 mediated the rapid/nongenomic effects of aldosterone on ERK½ phosphorylation in human ECs. Coutinho et al. expanded on these findings and showed that cav-1 and MR formed a complex with striatin in human and mouse vascular tissue.23 They showed that striatin mediated aldosterone’s rapid, nongenomic effects and that aldosterone preincubation could enhance estrogen’s rapid, nongenomic effect on eNOS activation (phosphorylation) in ECs in part by increasing striatin levels. This effect was specific for aldosterone as knockdown of striatin in vascular cells had no significant effect on epidermal growth factor activation. Thus MR, ER-α, striatin, and cav-1 form a complex of receptors in the membrane that may also include the androgen receptor among others. However, the interaction of MR and ER-α is not entirely clear and additional in vivo and in vitro studies in male and female animal models and humans are critically needed in this area. To this end, Barrett Mueller and colleagues showed that MR and ER-α can coimmunoprecipitate from HEK293 cells that were cotransfected with these receptors.24 However, striatin failed to be detected in this complex. Nonetheless, they reported that ER-α can block MR-mediated genomic activation and demonstrated that estradiol treatment prevented aldosterone-stimulated ICAM-1 increases and leukocyte adhesion in EC lines that express ER-α.

2.5 Mineralocorticoid Receptor Ligands and Their Selectivity From an evolutionary perspective, to survive the transition from aquatic life to a land environment with limited salt availability and day–night cycles, new complex mechanisms have been developed for Na+ retention and circadian regulation. Phylogenetic analyses showed that adrenocortical hormone secretion and steroid receptors coevolved during the different stages of vertebrate evolution, possibly to improve receptor selectivity and helping diversification and adaption to new environments.25 This novel information sheds further insight on many mysteries of adrenal physiology, such as prereceptor regulation and the versatility of MR that can be activated by ligands other than aldosterone, such as cortisol or deoxycorticosterone. Furthermore, these phylogenetic studies have demonstrated that genes encoding the machinery for cortisol secretion preceded those for aldosterone secretion.5 Since cortisol, which has high MR affinity, is more abundant than aldosterone, 11β-HSD2 evolved as a gatekeeper for inappropriate MR activation by cortisol, thus improving tissue

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selectivity, especially in the kidney. This prereceptor regulation is crucial for modulating receptor activation and ligand specificity. On the other hand, the close homology of the MR and GR is explained by a shared ancestral corticoid receptor (CR).5,25 Despite a similar structure at a receptor level, mineralocorticoid selectivity is also achieved by ligand-induced conformational changes, as aldosterone dissociates more slowly from the MR and induces greater transactivation than cortisol at any given concentration. Finally, at the postreceptor level, several coregulators have been recognized to play a key role in tissue specificity and ligand specificity, endorsing aldosterone-, rather than cortisol-mediated, activation of the MR.10

3.  GENOMIC ACTIONS OF ALDOSTERONE 3.1 Classical Target Tissues Classically, aldosterone’s genomic actions involve the modulation of gene expression in epithelial organs that regulate water permeability (kidney, colon, salivary and sweat glands). These effects are initiated by aldosterone binding to the MR, followed by heat shock protein dissociation from the receptor and MR translocation from into the nucleus26,27 (discussed in detail in Chapter 25 by Dr. Celso Gomez-Sanchez et al.). Here, the MR binds to HRE in target gene promoters, followed by the recruitment of relevant transcription factors, coactivators and/or corepressors, which allows for the control of gene expression.28,29 The final effectors of aldosterone actions in epithelial tissues are pumps, transporters, and ion channels that are directly produced by the genomic actions of the MR, leading to a sustained increase of their plasma membrane density. Examples of such aldosterone-controlled effectors include the epithelial Na+ channel (ENaC) acting on the apical side, the Na+/K+-ATPase acting on the basolateral side,30 the thiazide-sensitive Na/Cl cotransporter (NCC)31 in the distal convoluted tubule, and the Na+/H+ exchanger (NHE)32 in the proximal colon. Aldosterone and MR also control K+ secretion through the regulation of apical K+ channel ROMK and fluid absorption through aquaporin 2 water channels. By modulating the cell surface expression of these proteins in epithelial cells, aldosterone leads to a sustained increase in (1) transepithelial Na+ and water reabsorption and (2) K+ excretion. Another classical target of aldosterone action in the epithelia is the serum and glucocorticoid-regulated kinase 1 (SGK1). SGK1 expression is upregulated after only 30 min of aldosterone stimulation, leading to an increase in Na+/K+-ATPase expression and activity.33,34 Further, SGK1 has been shown to inactivate ENaC degradation pathways, by mechanisms that include the phosphorylation and subsequent inhibition of the ubiquitin ligase Nedd4-2.35 However, SGK1 knockout studies in response to either short-term Na+ restriction or chronic aldosterone administration suggest that—while SGK1 is essential for optimal processing of ENaC—it plays a noncritical role for the aldosterone-mediated increase in Na+ channel activity in the cortical collecting duct.36

3.2 Nonclassical Target Tissues 3.2.1 Cardiac Tissue The notion that the activation of the aldosterone/MR pathways has damaging effects on the cardiovascular system has been known for many decades; however, only recently it has been shown that these effects are independent of changes in BP levels, but rather dependent on the level of Na+ intake. Inappropriate levels of aldosterone during Na+ loading lead to detrimental consequences on the heart, such as vascular and perivascular inflammation, fibrosis, and hypertrophy. The initial event in aldosterone and Na+-mediated injury is vascular inflammation and is later followed by interstitial fibrosis and cardiomyocyte damage.37–40 Myocardium-specific changes in response to aldosterone salt include modified expression for markers of inflammation such as cell adhesion molecules (mainly VCAM-1) and inducible cyclooxygenase, cytokines, and chemokines (TGF-β1, osteopontin, MCP-1). All these alterations could be prevented by selective MR blockade, and without effects on BP.37–40 Similar inflammatory changes in the coronary vascular bed and the beneficial action of eplerenone have also been reported in uninephrectomized rats treated with an 11β-HSD2 inhibitor and salt,41 suggesting that local glucocorticoid excess may play a direct role in the etiology of coronary vascular inflammatory responses to salt loading. Further, selective MR blockade decreased the cardiac dysfunction, interstitial fibrosis, and the oxidative stress in a mouse model of heart failure.42 However, cardiomyocyte-specific MR gene ablation in mice was able to prevent the cardiac dysfunction induced by transverse aortic constriction, but not the perivascular and interstitial fibrosis, proinflammatory gene expression, myocyte hypertrophy, and apoptosis.43 This may be

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explained, at least in part, by two recent studies that suggest that myeloid MR activation is critical for BP control and for hypertrophic and fibrotic responses in the mouse heart and aorta.44,45 The mechanisms underlying these aldosterone/MR-mediated cardiac pathologies have been deciphered in cell culture and molecular biology studies, and sometimes confirmed in transgenic animal models. Thus, aldosterone has been shown to induce rat cardiac myofibroblast proliferation by activation of the oncogene K-Ras and mitogen-activated protein kinase (MAPK) pathways.46 Moreover, these cells act as mediators of the elastogenic process by a putative MR-independent mechanism, contributing to the progression of the fibrotic damage.47 In addition, in rat neonatal cardiomyocytes, aldosterone triggered myocyte growth, accompanied by hypertrophy marker overexpression (e.g., atrial natriuretic peptide, α-actin).48 Recent studies have also proposed lipocalin 2, a small circulating glycoprotein associated with heart failure, atherosclerosis, and renal dysfunction, as a novel target for the genomic actions of aldosterone in cardiovascular tissues.49 Indeed, subsequent studies have demonstrated that lipocalin 2 mediates the vascular profibrotic effects of aldosterone.50 In a microarray study performed on a cell line of cardiomyocytes stably expressing MR, physiological concentrations of aldosterone induced the early (2 h) upregulation of a panel of genes involved in extracellular matrix regulation, inflammation, and signal transduction.51 Further, aldosterone was confirmed as a regulator of some of these transcripts (PAI-1, Adamts1) in cardiac tissues from double transgenic mice with conditional, cardiomyocytespecific MR overexpression.52 Moreover, the myotoxic effect of aldosterone could be observed in transgenic mice with cardiomyocyte-specific overexpression of 11β-HSD253 (which allows for glucocorticoid inactivation in this tissue, and thus—for increased MR occupancy by aldosterone). These mice develop fibrosis, hypertrophy, and subsequent heart failure,53 consistent with a direct role of aldosterone in these pathologies. Interestingly, aldosterone also induces increased excitability and beating frequency in cardiomyocyte cell culture,54–56 likely mediated by the modification of ion fluxes through the membrane.56–58 As a partial in vivo confirmation of these data, Ouvrad-Pascaud et al.59 demonstrated, in a conditional cardiomyocyte-specific MR overexpressed mouse model, that the transgenic animals display ventricular extrasystoles and increased sensitivity to triggering ventricular arrhythmias. 3.2.2 Endothelium The position of the endothelial layer at the interface between the blood stream and the vascular wall makes it a crucial organ for maintaining vascular homeostasis in the face of continuous exposure to stimuli. Early studies have documented that MR is expressed in the endothelium and that MR levels are increased in hypertensive animal models.52,60–62 Thus, it is not surprising that numerous aspects of endothelial physiology are affected by aldosterone. Recently, a mouse model with conditional and inducible endothelium-specific MR overexpression highlighted the involvement of the endothelial MR in BP regulation and vascular reactivity,63 although these effects may depend on the vascular bed type.64,65 The underlying mechanisms for these physiological effects include aldosterone-mediated changes in expression at the endothelial level (reduced expression for the inflammatory cytokine C–C chemokine receptor type 5, CCR5, and for the fibrotic marker connective tissue growth factor, CTGF). Further, Schaefer et al. recently documented transcriptional changes in EC isolated from endothelium-specific MR-deficient mice,66 which include decreased cyclooxygenase 1 (COX-1) and NADPH oxidase subunit p22phox expression in response to aldosterone administration. Moreover, aldosterone was shown to mediate the early increase in angiotensin-converting enzyme67 and osteopontin68 expression in rat aortic EC, suggesting an inflammatory modulation of the cardiovascular RAAS. Further, the intercellular adhesion molecule 1 (ICAM1) has been shown to be modestly but significantly overexpressed at 24 h in aldosterone-treated human coronary EC, with a resulting increase in leukocyte adhesion.61 In addition, aldosterone reduces endothelial glucose 6-phosphate dehydrogenase expression and activity, with a consequent depletion of NADPH, increased oxidative stress, reduced NO bioavailability, and vascular dysfunction.69 Aldosterone/ MR also increased endothelial-derived contractile factors via increased synthesis of endothelin,70 while MR antagonism prevented the posttranslational modifications of the endothelin 1 receptor type B, thus allowing vasodilation to counterbalance the vasoconstriction induced by endothelin 1-mediated endothelin 1 receptor type A stimulation, and leading to better local hemodynamics.71,72 3.2.3 Vascular Smooth Muscle Cells The idea of a direct effect of aldosterone on VSMC initially stemmed from in vitro studies documenting the inhibitory effect of MR blockade on AngII-mediated proliferation,73 corroborated by in vivo studies showing that aldosterone/salt administration leads to increased arterial stiffness and thickness of the tunica media due to accumulation of fibronectin in uninephrectomized rats.74 In the wake of these findings Jaffe et al. gave a comprehensive description of the in vitro genomic effects of aldosterone on the VSMC demonstrating that they express not only a functional MR but also 11β-HSD2, the enzyme that allows for glucocorticoid inactivation, and thus increases the specificity of

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the aldosterone/MR interaction.75 Further, they showed in microarray studies with qRT-PCR confirmation, that in these cells aldosterone upregulates genes involved in vascular fibrosis, calcification and inflammation,75 and that MR activation promotes the osteoblastic differentiation and mineralization of VSMC.76 Recently, constitutive or inducible inactivation of VSMC-specific MR gene demonstrated that VSMC MR is involved in BP regulation at baseline and in response to AngII infusion, but not in response to aldosterone/salt.77,78 Overall, MR activation in the VSMC impacts ion channel regulation77,79,80 and the expression of profibrotic markers75,81,82 in these cells. 3.2.4 Adipose Tissue Clinical and bench studies have highlighted aldosterone as a potential risk factor for diabetes and metabolic syndrome (MetS), through mechanisms at least partially independent of hypertension.83 Recent experimental studies point to a new role for aldosterone/MR activation in adipose tissue.84–87 Thus, MR has been shown to mediate the plasticity of white adipocytes, with MR blockade acting as a promoter of “browning” of the white adipose tissue, thus increasing the metabolic activity of the adipose.88 Studies in rodent models of metabolic dysfunction (db/db, ob/ob, or diet-induced obese mice) indicate that MR antagonism improved glucose tolerance and decreases insulin resistance, and plasma levels of triglycerides and reversed obesity-related changes in adipose tissue gene expression (e.g., increased expression of PAI-1, leptin, and proinflammatory cytokines tumor necrosis factor (TNF)-α, and MCP-1).89–91 In contrast, Baudrand et al.92 recently showed, in a cav-1-­deficient animal model of metabolic dysfunction, that eplerenone improves some (but not all) pathways of glucose and lipid homeostasis. Adipose transcripts associated with MR-dependent metabolic impairment included resistin, aldose reductase, and retinol binding protein 4 (RBP-4)—all molecules associated with insulin resistance and/or diabetes.92 However, pharmacological approaches cannot discriminate between direct consequences of MR blockade in the adipose tissue and those related to global MR antagonism in other organs affected by MetS (e.g., cardiovascular, pancreatic, hepatic or muscle tissues), where MR has been shown to be expressed and/or involved in cardiometabolic pathologies. The specific role of adipocyte MR was recently addressed using a novel transgenic mouse model, with inducible MR overexpression limited to adipocytes.93 The conditional upregulation of MR in adipocytes led to increased weight and fat mass, insulin resistance, and metabolic syndrome features in this model, without affecting BP. Interestingly, this study identified the prostaglandin D2 synthase as a novel MR target in mouse adipocytes, and confirmed that in human adipose depots, MR and prostaglandin D2 synthase expression levels correlate.93 In a second study by the same group, adipocyte-MR overexpression lead to reduced vascular contractility, increased generation of adipocyte-derived hydrogen peroxide, activation of vascular redox-sensitive PKG-1, and downregulation of Rho kinase activity.94

4.  NONGENOMIC ACTIONS OF ALDOSTERONE 4.1 Rapid Signaling Cascades The characterization of novel aldosterone/MR signaling molecules including: cav-1, striatin and GPER, has refocused the interest of various groups on the nongenomic effects of aldosterone and MR activation. The existence of a rapid, nongenomic effect of aldosterone was proposed in 1963 from studies in humans by Klein and Henk that demonstrated increased cardiac output, vascular resistance and BP following 5 min of 1 mg aldosterone administration.95 Studies in isolated dog erythrocytes by Spach et al. later showed rapid effects of aldosterone on unidirectional Na+ transport.96 We now know that aldosterone has rapid, nongenomic effects on various signaling molecules that are mediated via MR activation and others that are not. Aldosterone’s effects on Na+ transport are mediated, in part, by rapid increases in ENaC activity97 and increased activity of the Na+/H+ exchanger NHE-1.98 More specifically, aldosterone activates EGFR and MAPK, ERK1/2, leading to increased calcium influx and activation of NHE-1. In addition, there is growing evidence that ERK and its signaling molecules including, RAS and RAF, are activated within 10 min of aldosterone administration.23,99–101 Furthermore, there is evidence that the serine/threonine kinase, Akt, shows rapid MR-dependent phosphorylation thus implicating the phosphoinositide 3-kinase (PI3K) pathway in MR activation.102,103 Moreover, aldosterone has been reported to activate MR and rapidly increase the production of reactive oxygen species (ROS) in VSMCs, cardiomyocytes, and ECs.23,104–106 MR-mediated ROS production is mediated in part, through regulation of NOX isoforms, AKT, and NADPH in the presence of oxygen in various cell types (Fig. 1). Consequently, these data suggest an important role for aldosterone and MR activation in regulating diverse cellular functions including transcription, metabolism, growth, proliferation, and protein synthesis that may initiate at the membrane. In support of this concept there is evidence that MR is present in the plasma membrane as discussed above.107–109

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4.2 Striatin Striatin, a scaffolding protein that is abundant in neurons, interacts with mediators of vesicular trafficking and cav-1 and is localized to caveolae. The Pallas group has shown growing evidence that striatin facilitates the formation and cross talk of a membrane signaling complex.110 Striatin contains a caveolin-binding motif, a coiled-coil structure, a Ca2+-calmodulin-binding site and a large WD-repeat domain.111 This WD-repeat domain interacts with GPCR - Gαi protein and Protein Phosphatase 2A allowing for rapid activation of several transduction molecules including eNOS and mitogen-activated protein kinases. Proteomic analyses of the growing striatin family complexes has led to the naming of these as striatin-interacting phosphatase and kinase (STRIPAK) complexes.112 Various groups have now identified STRIPAK function and cellular signaling in the pathophysiology of numerous diseases including, cardiovascular, cancer, diabetes and cerebral cavernous malformations. This is a rapidly expanding area of investigation and these pathways and associated diseases have been recently reviewed in detail.110,113 Striatin has been shown to be a key intermediary of the effects of estrogen receptor-α (ERα) activation and critical for the rapid/nongenomic effects of estrogen on Akt and eNOS activation in ECs.22 In fact, Lu and colleagues have shown that blockade of the ERα-striatin complex has no effect on ERα-mediated gene transcription in human ECs. Striatin’s N-terminal segment interacts with the DBD of ERα in ECs that organizes ERα-eNOS membrane signaling leading to rapid nongenomic activation of eNOS. Of interest, overexpression of striatin leads to increased ERα in membrane fractions containing EGFR. More recent information from this group shows the in vivo relevance of the ERα-striatin complex.114 In vivo blockade of the ERα-striatin complex was performed using a novel mouse model that was created to produce a blocking peptide against the complex. They demonstrate loss of estrogen-mediated protection against vascular injury following carotid artery wire injury in these mice. The association between ERα and striatin raised the possibility that striatin may be a mediator of the rapid/ nongenomic effects of other steroids. To this end, Romero’s group reported that activation of MR leads to increases of striatin levels in the vasculature and that MR is likewise complexed with cav-1 and striatin in vascular tissue.115 They determined the in vivo effects of salt restriction on striatin levels in vascular tissue that were associated with increased striatin levels in heart, aorta and kidneys. These results also showed that striatin is present and co-­ precipitates with the MR in mouse aortas, heart, and ECs. They reported that aldosterone in vitro can stimulate increases of striatin mRNA and protein levels in both human and mouse ECs; events that are not observed when cells are incubated with estradiol. The in vivo relevance of these studies was confirmed using two mouse models of MR activation: (1) intraperitoneal aldosterone administration and (2) a model of chronic aldosterone-mediated cardiovascular damage following treatment with N(G)-nitro-l-arginine methyl ester plus AngII. In both models they observed increased abundance of striatin protein in heart tissue. More recent studies from the Romero and Williams’ groups extended these original observations and identified striatin as an important component of the rapid/nongenomic effects of aldosterone/MR activation.23,102 They documented that striatin is necessary for aldosterone’s rapid effects on ERK½ and AKT phosphorylation, and ROS production (Fig. 1).23 Indeed striatin is present in several cardiovascular tissues, kidney, and the adrenal cortex23,102 and is an important regulator of some of ALDO’s nongenomic mechanism of action in human and mouse ECs but not its genomic effects on SGK1 or WNK4.23,102 Thus, these studies suggest a novel mechanism for nongenomic regulation of aldosterone/MR activation and provide evidence further supporting the contention that striatin is an important component of MR activation in the cardiovascular system. Studies were then initiated to specifically address MR’s nongenomic effects in vivo. First a striatin-deficient mouse (STRN±) was developed and characterized.102 These mice had increased salt-sensitive BP, increased aldosterone levels on a liberal salt diet, altered vascular vasodilator responses, and developed hypertension in the presence of reduced striatin levels in cardiovascular, kidney, and adrenal tissue. To determine the potential clinical relevance of these findings, Williams’ group then tested the association between polymorphic variants of the striatin gene and salt sensitivity of BP in hypertensive subjects. HapMap-derived tagging single nucleotide polymorphisms identified an association of rs2540923 with salt sensitivity of BP.102 These data show that genetic variants of striatin are associated with salt sensitivity of BP in humans and mice. Thus, striatin plays an important role in aldosterone’s mechanisms of action/secretion, vascular function, and salt intake. Other than the work of the Karas’ group and Romero’s group, there remains little information on the physiological role of striatin in the cardiovascular system. Transcriptional profile of heart tissue has revealed the presence of striatin.116 Meurs and colleagues localized striatin to the intercalated discs within cardiac myocytes from boxer dogs.117 They also identified a deletion in the 3′ untranslated region of the STRN gene that was associated with

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arrhythmogenic right ventricular cardiomyopathy in these dogs that was associated with reduced striatin expression and protein levels. However, much more remains to be done to thoroughly comprehend the role of striatin in the cardiovascular system. Taken together the available evidence would suggest that striatin mediates a novel level of interaction between signaling molecules, steroids, and the cardiovascular system that may be important to understand steroid function in the vasculature.

4.3 G Protein-Coupled Estrogen Receptor GPER was first described as an estradiol receptor that mediated its rapid effects via MAPK, PI3K, and EGFR activation. GPER is expressed in numerous cells/tissues including cardiomyocytes, VSMCs, endothelium, lung, and liver.18,118–121 GPER has also been reported to mediate aldosterone’s rapid cellular effects on ERK signaling in VSMCs, ECs, and more recently in the cardiomyocyte cell line, H9C2.122,123 However, the mechanisms for aldosterone’s rapid effects via GPER are not clear. Potential pathways have been recently reviewed and described in detail by Feldman and Limbird.124 To this end, there is evidence that aldosterone activates GPER at physiological levels. However, binding of aldosterone to GPER has not been clearly established.125,126 Others have proposed a direct interaction of GPER and MR126 and cross talk via second messengers and/or modification of striatin127 as an alternative mechanism of action. Of importance, in vivo cardiovascular effects for GPER activation have been reported. G1 agonists specifically activate GPER leading to vasodilation of mouse carotid vessels: an event that was absent in vessels from GPER knockout mice.128 Vasodilation by GPER activation has also reported vessels from mRen2.Lewis rats.129 GPER activation lowers BP acutely.128 However, GPER ablation leads to increase in mean BP in female mice.130 However, more studies are needed to clarify these signaling mechanisms and the role of biological sex, aldosterone, and GPER in cardiovascular diseases.

5.  EPIGENETIC EFFECTS In recent years, growing evidence has focused on the role of epigenetics in biological processes. Epigenetics considered all phenotypic variations throughout life by mechanisms that alter gene expression, that importantly, are independent of changes in DNA sequence. These epigenetic modifications lead to dynamic modulations of gene expression by different molecular processes including DNA methylation, histone modification, and microRNA.9 To date, determining the multiple environmental–genetic interactions that trigger these epigenetic changes in MR signaling is a matter of active research. Histones can undergo epigenetic modifications such as methylation or acetylation, thus changing chromatin structure and gene regulation. It was recently described that lysine-specific demethylase 1 (LSD1) is involved in the pathogenesis of salt-sensitive hypertension in both animals and humans with a key role of MR.131,132 LSD1 is a flavin-dependent amine oxidase that can act either as a transcription corepressor, if demethylation occurs at the lysine 4 of histone H3 (H3K4) site, or as a transcription coactivator if demethylation is switched toward H3K9 site.9 In a translational approach, Williams et al. showed that LSD1 heterozygote knockout mice (LSD1+/−) and African American subjects with polymorphic variants of LSD1 had a similar phenotype that included salt-sensitive hypertension, supporting a role of LSD1 as an epigenetic mediator of Na+ effects on MR and BP (Fig. 1).132 Moreover, Lee and colleagues recently described that histone deacetylases HDAC-3 and HDAC-4, via epigenetic modifications, can regulate the activation of MR-dependent transcription.133 Finally, aldosterone-mediated vascular pathogenesis by MR was recently described to be associated with miR-29b.134

6.  MINERALOCORTICOID RECEPTOR MODULATORS 6.1 Sodium The multiple regulatory system of aldosterone/MR axis serve primarily to ensure efficient Na+ and water homeostasis in the setting of a low-salt environment. Nowadays, excessive Na+ intake in modern industrialized societies results in inappropriate suppression of the aldosterone/MR axis, leading to hypertension, cardiovascular damage, kidney dysfunction, and cardiometabolic disorders. With Westernized diets, the kidney has to deal with excessive amounts of Na+. Of note, the average minimum daily requirement of Na+ is approximately 0.5–1 g per day; however, the estimated average Na+ intake of a typical US citizen ranges closer to 10 g per day.135

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Accumulating studies reveal that aldosterone/MR plays a significant role in the development of salt-sensitive hypertension and associated end-organ damage. For example, experimental studies have demonstrated an important role of Na+ in the pathways leading to MR activation, despite classical suppression of aldosterone production. Interestingly, in transgenic obese hypertensive rats, 4 weeks of salt loading resulted in severe hypertension, proteinuria, and this phenotype was, at least in part, explained by Na+-induced activation of MR.136 Others have shown that the protective effects of a low Na+ diet could be related to lower MR levels and related changes in adipokines.137 Consistently, the effects of excessive dietary salt intake in BP and proteinuria in salt-sensitive rats were significantly attenuated by an MR antagonist such as eplerenone.138 In addition to the well-described effects on BP and kidney function, new data indicate that a high Na+ diet is also associated with increased prevalence of metabolic syndrome and insulin resistance, by several potential mechanisms under study.135,139

6.2 Caveolin-1 Caveolae, small invaginations in the cellular membrane, are not only a structural platform for receptors, channels, and enzymes but also act as functional modulators of a wide selection of cellular pathways. In cardiovascular and renal tissues, caveolae are particularly abundant and mediate a number of critical signal transduction mechanisms. The main component of plasma membrane caveolae, cav-1 has recently drawn growing attention due to its effects on cellular physiology, from receptor and ion channel activation, to signal transduction and intracellular trafficking. Owing to its role in water and Na+ homeostasis, aldosterone is a prime candidate to explain phenotypic abnormalities associated with salt-sensitive hypertension. Besides the classical, genomic effects of aldosterone via transcriptional effects of the MR in the nucleus, new evidence suggests that aldosterone can have rapid, nongenomic effects in cardiovascular and renal tissues. Such effects have been characterized to occur via MR activation at the plasma membrane, or via interaction with other receptor pathways typically initiated in caveolae, including the AT1R, the EGFR, or the GPER.14 Interestingly, two groups have shown that—during Na+ loading—cav-1 and MR levels are increased in both polar and nonpolar aldosterone target cells (such as cardiac and renal tissues),140,141 while MR expression is decreased in cardiac and vascular tissues from cav-1 knockout mice,142 consistent with impaired MR signaling in the absence of cav-1. In addition, Pojoga et al. have shown that the MR (like other steroid receptors) colocalizes and coimmunoprecipitates with cav-1 in these tissues16 and that MR–caveolin complexes are more abundant during Na+ loading.140 These data are consistent with an interplay between cav-1 and MR in modulating mechanisms of salt sensitivity in aldosterone target tissues. Indeed, Pojoga et al. demonstrated that cav-1-deficient mice display profound vascular dysfunction that can be ameliorated by dietary Na+ restriction or MR blockade.142,143 Importantly, other pathways modulated by cav-1 have also been implicated in mechanisms of aldosterone signaling and/or salt sensitivity, such as enzymes involved in oxidative stress responses, G protein-coupled receptors, as well as ion channels and transporters. Thus, it was recently shown that MR blockade rescues the cardiovascular phenotype in Dahl salt-sensitive rats via improvements in oxidative stress mediated by eNOS and NADPH oxidase.144 These enzymes are not only known regulators of the redox potential inside cells (via their interaction with cav-1) but also key players in the etiology of cardiovascular145 and renal146 diseases. Furthermore, cav-1 has been shown to be a key player in polyubiquitylation events that control Rac1 intracellular levels and activity.147 Importantly, recent evidence suggests that dietary Na+ activates the small GTPase Rac1 in Dahl rat kidney tissues, leading to aldosteroneindependent MR activation, oxidative stress, and target organ damage.85,148 Salt sensitivity is also often associated with abnormal ion transport in cardiovascular and renal tissues. There is now abundant evidence that cav-1 targets to caveolae and modulates aldosterone-sensitive molecules such as ENaC,149 Na+/K+-ATPase,141,150,151 Na+/H+ exchanger NHE-1,152 the Na+/K+/2Cl− cotransporter (NKCC2)153 or the large conductance Ca2+- and voltage-activated K+ channels (BKCa).154 Initially demonstrated in kidney cells, these effects of cav-1 on aldosterone/MR signaling have been recently extended to nonrenal tissues. While many of these influences are exerted via changes in cav-1-mediated endocytosis, it has become clear that cav-1 can also facilitate direct signaling at the membrane. Interestingly, a recent report suggests that the α-subunit of the Na+/ K+-ATPase acts as a cell surface receptor for the nongenomic action of steroids,151 in a cav-1-dependent manner. Although the study was focused on the effects of progesterone in cultured oocytes, it can be speculated that similar interactions hold true for aldosterone in cardiovascular and renal tissues in vivo. Furthermore, cav-1 plays a critical role in maintaining appropriate urinary Na+ excretion and BP homeostasis under conditions of Na+ loading.141

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Taken together, these data suggest that caveolae and cav-1 act as modulators of salt sensitivity via an interplay with MR activation in aldosterone target tissues. Interestingly, Baudrand et al.92 recently brought translational evidence for a pathophysiological role of cav-1 in aldosterone/MR-mediated metabolic dysfunction. Thus, cav-1 deficiency in mice and cav-1 gene variation in humans impacted aldosterone metabolic signaling via several pathways of glucose and lipid homeostasis. In contrast, hyperinsulinemia and hypertriglyceridemia associated with cav-1 ablation or cav-1 genotype seemed to be mediated by MR-independent mechanisms. Future studies in humans are needed to elucidate the clinical relevance of MR blockade in patients with genotype-mediated cav-1 insufficiency.

6.3 Rac1 It is well known that Na+ loading not only increases BP but causes cardiovascular and kidney damage in animals and humans. One of the best-studied phenotypic trait related to Na+ is salt-sensitive hypertension, defined as an increase in BP in response to salt loading, with an estimated prevalence of 50%–60% within hypertensives.9 Why BP responds differently to Na+ loading is explained by both environmental and genetic factors. Recently, Shibata and Fujita described a new signaling cross talk between MR and Rac1, that is a novel modulator of MR signal transduction that is related to Na+ intake.155 Rac1 is a member of the Rho family of small GTPases involved in signal transduction pathways that control proliferation, adhesion, and migration of cells. GTPases are molecular switches in important cellular processes including signal transduction, vesicle trafficking, and nuclear protein import.155 The interaction between MR and Rac1 was shown to be an alternative pathway that potentiates MR activity, both in vitro and in vivo.148 An in vitro study assessing nuclear trafficking using green fluorescent protein (GFP)–tagged MR showed that transfection of active Rac1 could induce nuclear translocation of MR-GFP even in the absence of aldosterone, and it further increased nuclear accumulation in the presence of aldosterone. Moreover, overexpression of active Rac1 significantly potentiates aldosterone-induced MR transcriptional activity. Of note, the aldosterone/MR complex signaling is closely related to dietary Na+ intake. Excessive Na+ intake can cause MR activation,136 leading to the unfavorable synergistic action of aldosterone and high salt intake, being Rac1 a new described player in salt-induced MR activation and hypertension.

7.  NOVEL MINERALOCORTICOID RECEPTOR ANTAGONISTS Since aldosterone/MR pathway is a potential key player in cardiometabolic disorders, targeted pharmacological therapy is expected and is currently under active investigation. First, to decrease the ligand, aldosterone synthase (CYP11B2) inhibitors have been developed that reduce aldosterone levels but are not selective and can result in decreased cortisol production.156 Currently, next-generation CYP11B2 inhibitors are under development, with improved selectivity index and potent reduction of aldosterone levels in humans.157 In relation to MR antagonists (MRA), their use in clinical practice have decades with the introduction of spironolactone, that is a potent MR competitor but poorly selective.158 Then was released eplerenone, a second generation MRA with improved selectivity but shorter half-life and less potency than spironolactone. Both drugs have excellent evidence for hypertension, and cardiac diseases with a reasonable safety profile despite hyperkalemia is not uncommon. Because of hyperkalemia risk and with the understanding of MR signaling, new drug discovery programs in the last decade within several pharmaceutical companies are studying novel nonsteroidal MRAs with potentially different tissue selectivity and blocking mechanisms. For example, finerenone can bind to the LBD of MR but also to the C-terminal AF-2 domain of MR, thus not only blocking aldosterone–MR interaction but also modifying several coregulators of MR signaling.159

8. CONCLUSIONS Recent reports have demonstrated that nongenomic and genomic signaling by steroid hormones are inextricably linked, such that many important transcriptional changes in response to these hormones require both processes to be functioning normally. This is of particular relevance to kidney function as detailed above where aldosterone rapidly regulates Na+ transport then induces long-term effects by regulating expression of important cellular Na+ transporters including ENaC and the Na+/K+ ATPase and its associated signaling molecules including SGK1. In the case of aldosterone, nongenomic

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signaling can arise from the classical “nuclear” MR on or near the cell surface and from other important cell membrane signaling molecules such as GPER or EGFR. These nongenomic signals can modulate aldosterone-mediated transcription via many pathways, including nuclear localization of the classical MR or changes in phosphorylation of nuclear signaling molecules. Understanding how genomic and nongenomic signaling work together to regulate important biological processes will help us better design novel means of regulating these processes and therefore may improve our ability to treat aldosterone- and/or MR-dependent conditions, such as cardiovascular and metabolic dysfunction. It is important to note that the number of signaling pathways that are activated by aldosterone and/or MR activation further support the concept that aldosterone has additional roles beyond the classical Na+ and volume homeostasis functions and in part may explain its role in areas such as insulin resistance, endothelial function, fibrosis, and inflammation among others. Clearly, further studies are needed to elucidate the relevance of these molecules in aldosterone function, and MR activation in women and men as these new molecular pathways may be relevant in improving our current strategies for targeted treatment and/or prevention of cardiovascular diseases including hypertension.

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