Mineralocorticoid receptor signaling: Crosstalk with membrane receptors and other modulators

Steroids 91 (2014) 3–10

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Mineralocorticoid receptor signaling: Crosstalk with membrane receptors and other modulators S. Meinel, M. Gekle, C. Grossmann ⇑ Julius Bernstein Institute of Physiology, Martin Luther University Halle-Wittenberg, Germany

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Article history: Received 11 November 2013 Received in revised form 16 May 2014 Accepted 28 May 2014 Available online 11 June 2014 Keywords: Mineralocorticoid receptor Epidermal growth factor receptor Angiotensin II receptor Receptor tyrosine kinases Signaling Modifications

a b s t r a c t The mineralocorticoid receptor (MR) belongs to the steroid receptor superfamily. Classically, it acts as a ligand-bound transcription factor in epithelial tissues, where it regulates water and electrolyte homeostasis and controls blood pressure. Additionally, the MR has been shown to elicit pathophysiological effects including inflammation, fibrosis and remodeling processes in the cardiovascular system and the kidneys and MR antagonists have proven beneficial for patients with certain cardiovascular and renal disease. The underlying molecular mechanisms that mediate MR effects have not been fully elucidated but very likely rely on interactions with other signaling pathways in addition to genomic actions at hormone response elements. In this review we will focus on interactions of MR signaling with different membrane receptors, namely receptor tyrosine kinases and the angiotensin II receptor because of their potential relevance for disease. In addition, GPR30 is discussed as a new aldosterone receptor. To gain insights into the problem why the MR only seems to mediate pathophysiological effects in the presence of additional permissive factors we will also briefly discuss factors that lead to modulation of MR activity as well. Overall, MR signaling is part of an intricate network that still needs to be investigated further. Ó 2014 Elsevier Inc. All rights reserved.

1. Introduction The mineralocorticoid receptor (MR) belongs to the steroid receptor superfamily together with receptors for progesterone, estrogens, androgens and glucocorticoids. In classical target tissues like epithelia of the kidney, colon, sweat and salivary glands, the MR is activated by aldosterone and subsequently increases sodium and water reabsorption, enhanced potassium secretion and thereby contributes to the maintenance of blood pressure. Meanwhile it has been shown that the MR is expressed in cells of nonepithelial tissue like heart and vasculature, where it can lead to pathophysiological changes initiated by inflammation or an altered micromilieu followed by fibrosis, hypertrophy and remodeling. Regarding the mechanisms of MR activation and MR action, there are still several unsolved questions. (i) What are the different mechanisms of activation considering the high glucocorticoid concentrations and the fact that the MR seems to be activated in the absence of altered hormone concentrations? Glucocorticoids like cortisol can bind to the MR with an affinity that is comparable to that of aldosterone. In classical MR target epithelial tissues an ⇑ Corresponding author. Address: Julius-Bernstein-Institut für Physiologie, Universität Halle-Wittenberg, Magdeburger Strasse 6, 06097 Halle/Saale, Germany. Tel.: +49 345 557 1886; fax: +49 345 557 4019. E-mail address: [email protected] (C. Grossmann). http://dx.doi.org/10.1016/j.steroids.2014.05.017 0039-128X/Ó 2014 Elsevier Inc. All rights reserved.

enzyme called 11-beta hydroxysteroid dehydrogenase 2 is responsible for inactivating cortisol to cortisone that no longer binds to the MR. Especially in cells that do not express this enzyme, like cardiomyocytes, MR-specific signaling is not well understood. (ii) How is differential control of gene expression by MR and GR achieved despite the fact that only common response elements have been described? In its inactive state, the MR is primarily located in the cytosol associated to a multicomponent complex. Binding of aldosterone then leads to nuclear translocation, where it binds as a homodimer to glucocorticoid response elements (GRE) and regulates gene expression and ultimately protein expression. Given that MR and GR share a common hormone response element (HRE) makes it difficult to explain MR-specific effects and therefore the existence of additional MR binding sites has been postulated [1]. (iii) What determines whether MR activation elicits physiological or pathophysiological effects? From these questions the hypothesis of further non-canonical signaling pathways can be derived. Strong indications for the existence of complementary MR signaling pathways came from reports of MR effects that occur independently of transcription. For example, as early as 1984 a rapid, actinomycin D-independent effect of aldosterone on sodium flux in arterial smooth muscle cells has been described [2] and later rapid effects on MAP kinase phosphorylation, cAMP/CREB and PKC signaling have been demonstrated

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and termed non-genomic effects [3]. Of course these non-genomic effects may also affect gene transcription indirectly because for example CREB acts as transcription factor [4,5]. Taken together these findings suggest that there is an intense cross-talk between MR outside the nucleus and other signaling components that is crucial for its non-canonical actions. These interactions include different membrane receptors, namely receptor tyrosine kinases and the angiotensin 1 receptor that are especially thoroughly investigated and will be the focus of this review. Furthermore, interaction of the MR with micromilieu factors like reactive nitrosative species have been described to lead to pathophysiological relevant activation of the MR and therefore contribute to disturbed tissue homeostasis (see Figs. 1 and 2). 2. MR interaction with receptor tyrosine kinases Receptor tyrosine kinases are cell surface receptors mainly for growth factors. They are not only responsible for cell growth, differentiation and death but are also involved in pathological changes like tumor growth or vascular remodeling [6]. Activation of these receptors occurs not only by binding of ligands but also by a mechanism called transactivation (see below). Recently it has been shown that functional receptor tyrosine kinases are also located in the nucleus, where they potentially interact with transcription factors, for example the activated nuclear MR. However, little is known about the functional impact of nuclear receptor tyrosine kinases as well as about the interaction with the MR [7]. The receptor tyrosine kinases considered are epidermal growth factor receptor (EGFR), insulin receptor (IR)/insulin-like growth factor receptor (IGF-1 receptor), platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR). 2.1. EGFR The EGFR is an important protagonist in a variety of physiological and pathophysiological settings including fetal development, proliferation, differentiation, migration, vasoconstriction and cancer. The EGFR (ErbB1) belongs to a family of membrane tyrosine kinases additionally including ErbB2, ErbB3 and ErbB4. In the presence of their ligands, the members of this family act as homo- or heterodimers resulting in activation of different signaling pathways including Ras/Raf-1/MAPK, c-Src, PI3/Akt and phospholipase Cc. Furthermore, the EGFR can act as a mediator of angiotensin II, endothelin-1 and aldosterone-induced effects [8–11]. With respect to the MR, it has been shown to interact with the EGFR either via transactivation in a non-genomic [4,12] or in a genomic way via altered expression. In the renocardiovascular system it has been demonstrated that this transactivation can promote fibrosis [10,11,13]. 2.1.1. Modes of Interaction between MR and EGFR An MR-dependent increase in EGFR expression was found in the heart, aorta and the kidney [14–18]. As underlying mechanism an MR-specific SP1-dependent responsive element was identified, which differs from classical GRE elements and shows no respon-

Fig. 1. Scheme of MR domains. The N-terminal region A/B is responsible for cofactor binding and is the most variable among steroid receptors. The C domain consists of the DNA binding domain (DBD) and is followed by the hinge region D. The C-terminal E/F region possesses a ligand binding domain (LBD) and is involved in the dimerization of steroid receptors.

Fig. 2. Scheme of MR crosstalk with other signaling pathways. Interactions between MR signaling and different membrane receptors like angiotensin II receptor I (AT1R) and different receptor tyrosine kinases exist. These include the epidermal growth factor receptor (EGFR), the insulin-like growth factor receptor (IGF-1R), the platelet-derived growth factor receptor (PDGFR) and the vascular endothelial growth factor receptor (VEGFR). Furthermore, MR signaling may be modulated by micromilieu factors, possibly through posttranslational modification and by crosstalk with other signaling components.

siveness to the glucocorticoid receptor (GR) [15]. MR-induced enhancement of EGFR expression increases the amount of the EGFR molecules available for transactivation by MR and other receptors of vasoactive substances [14–16,18]. Downstream signaling molecules affected by the non-genomic MR–EGFR crosstalk or mediating it are versatile and include NADPH oxidase, c-Src, PKC (protein kinase C), PKD (protein kinase D), Ca2+, reactive oxygen species, Rho/Rhokinase and ki-Ras-2a (Kirsten rat sarcoma viral oncogene homolog) [4,12,19–22]. Conversely, EGFR/ERK signaling can also influence genomic activity of MR by affecting its nuclear translocation [4]. 2.1.2. Physiological effects Crosstalk between the MR and the EGFR is of particular importance because of its contribution to physiological effects on the one hand and also pathophysiological effects on the other hand. An important physiological implication is the MR–EGFR-induced reabsorption of sodium. Previous studies of McEneaney et al. established the EGFR as a mediator of the signaling between aldosterone-induced MR and PKD leading to an increased trafficking and activity of the epithelial sodium channel (ENaC) in renal collecting duct M1 cells [12,23]. In human RPTEC cells (primary renal proximal tubule epithelial cells) the activity and surface expression of NHE3 (sodium-proton-exchanger 3) is stimulated via MR–EGFR crosstalk, which also activates NHE1 in MDCK cells, where it regulates cellular pH and volume [19,24,25]. The MRinduced NHE1 stimulation in rat ventricular myocytes is known to be abolished by spironolactone, eplerenone and the EGFR kinase inhibitor AG1478, suggesting that it is mediated by EGFR transactivation. This enhanced NHE1 stimulation was shown to be accompanied by formation of ROS and phosphorylation of the exchanger [26]. 2.1.3. Pathophysiological effects 2.1.3.1. Remodeling. Besides the physiological relevance of the interaction between aldosterone-induced MR and the EGFR, the pathophysiological actions gain more and more importance. Studies in different tissues associate the MR–EGFR interaction with vascular dysfunction, proliferation, inflammation, aging and fibrosis.

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Dorrance et al. first suggested a role of MR–EGFR interaction in vascular dysfunction and remodelling. They showed that after middle artery occlusion in spontaneously hypertensive rat stroke prone (SHRSP) the MR antagonist spironolactone lowered EGFR mRNA levels and reduced cerebral infarct size by prevention of remodelling of the cerebral vasculature [27]. Furthermore, the mineralocorticoid deoxycorticosterone acetate (DOCA) can also lead to changes in vascular function with increased basal tone and EGF-induced contraction in hypertensive DOCA–salt rats. Inhibition of PI3kinase and the use of the EGFR kinase inhibitor AG1478 suppressed these alterations in the vasculature [28]. Additionally, an increase in EGFR-mRNA levels accompanied by an EGFinduced arterial contraction has been reported in hypertensive rats [29,30]. Changes in the inner and outer diameter and also in the thickness of the vessel after DOCA have been demonstrated as well [14]. In the same work Dorrance et al. suggested that mineralocorticoids possibly lead to proliferation of vascular smooth muscle cells (VSMC). Further studies describe VSMC as well as mesangial cell proliferation as a result of MR-dependent EGFR transactivation [12,20,31–35]. A mitogenic response in VSMC as a result of the synergistic effects of aldosterone and angiotensin II on EGFR transactivation has also been reported. Therefore, simultaneous application of both ligands led to proliferation of VSMC mediated by phosphorylation of EGFR, ERK1/2, ki-Ras-2a and MKP-1 [21]. The impact of MR-dependent EGFR transactivation on mesangial cell proliferation has been described by Huang et al. The first pathway includes phosphorylation of the PI3kinase, Akt, mTOR and p70S6K1 whereas the second mechanism is mediated by ki-Ras2a and the MAPK signaling cascade [36]. Data from Griol-Charhbili et al. also indicate that, in vivo, EGFR deficiency mice (wa-2-mice) in comparison to wildtype mice show the same responsiveness to angiotensin II and phenylephrine. Treatment with aldosterone–salt led to EGFR-mediated vascular dysfunction but not to remodeling processes [37]. These data were complemented by the investigations by Messaoudi et al. using dominant negative EGFR mice (DN-EGFR mice), where angiotensin II-mediated cardiovascular remodeling was prevented in comparison to control littermates (CT). They showed that cardiac hypertrophy and mRNA expression of markers of cardiac remodeling such as collagen I, II, or III caused by an aldosterone–salt–uniephrectomy induced chronic MR activation was similar between DN-EGFR and CT mice. They postulated that in vivo, the EGFR is involved in angiotensin II- but not aldosterone–salt-induced cardiac remodeling and dysfunction [38]. 2.1.3.2. Inflammation. In addition to the depicted proliferative aspects the MR–EGFR crosstalk plays an important role in inflammatory processes in the renocardiovascular system [39,40]. Proinflammation in vessels was detected after an aldosterone-induced increase in 12-, 15-lipoxygenase expression that is prevented by EGFR inhibition via AG1478 and MEK inhibition via U0126. Lipoxygenase causes production of hydroxyeicosatetraenoic acid derivates (12- and 15-HETE as well as HPETE), which are known to enhance vascular contractility, growth, migration and oxidation of low density lipoprotein (LDL) [41]. In epithelial cells Oberleithner et al. described the aldosterone-stimulated increase of ENaC insertion into the cell membrane leading to a short term swelling and long term stiffening of these cells accompanied by reduced NO production [42]. In correlation with the observation that insertion of ENaC in kidney cells is mediated via PKD depending on EGFR phosphorylation, a similar mechanism in the endothelium seems conceivable [12,23]. 2.1.3.3. Aging. Another interesting aspect of the MR–EGFR crosstalk is the contribution to aging processes. The proinflammatory phenotype of VSMC of younger adult rats was shown to be induced by an aldosterone-dependent increase in EGFR expression.

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Simultaneously, in aged rat aorta rising mRNA and protein amounts of the MR resulted in an increase in EGFR protein expression. This suggests that EGFR-mediated aldosterone signaling aggravates proinflammation associated with arterial aging in VSMC [17]. The group of Min et al. described a similar relation between MR-dependent mechanisms and vascular aging. They proposed a synergistic signaling of MR and angiotensin II/angiotensin II – receptor leading to EGFR- and ki-Ras-2a-activated proliferation on the one hand or senescence mediated by an increase of NADPH oxidase activity and activation of NFjB and AP-1 signaling on the other hand [21,43]. 2.1.3.4. Fibrosis. A contribution of aldosterone to fibrosis in the renocardiovascular system has been published by many groups, but so far mainly indirect evidence for an involvement of the EGFR exist [44–46]. Spontaneously hypertensive rats showed enhanced proline incorporation as an index for collagen synthesis. This was mediated by an MR-induced activation of c-Src and NADPH oxidase, resulting in phosphorylation of ERK1/2 and p38 as well as a c-Src dependent increased EGFR activation [4,12,22,47]. As collagen synthesis in renal fibroblasts is known to be enhanced after MR-induced ERK1/2 phosphorylation, it is postulated that EGFR transactivation is a key mediator of this pathway [48]. It is well known that TGFb is a central mediator of fibrogenesis in the kidney. Chen et al. demonstrated that EGFR inhibition blocks the angiotensin II-induced renal fibrosis via TGFb [49]. In contrast, MR stimulated fibronectin synthesis in NRK 49f cells (kidney fibroblast cell line) was induced via activation of c-Jun NH2-terminal protein kinase (JNK) and phosphorylation of the AP1 transcription factor c-jun and thereby independent of EGFR transactivation although treatment with aldosterone enhanced EGFR phosphorylation. Furthermore, MR-independent phosphorylation of Src family kinase induces IgF1 receptor phosphorylation, which leads to ERK1/2 stimulation and to enhanced fibronectin synthesis. Therefore, it is postulated that aldosterone-dependent fibronectin synthesis in fibroblasts is mediated by MR-dependent and MRindependent pathways [50]. Zhang et al. described an induction of fibronectin synthesis in rat mesangial cells after incubation with aldosterone via ERK1/2 and NHE1 stimulation, which are both targets of the MR–EGFR crosstalk as mentioned above [51]. Indications that aldosterone predisposes cells for other stressors like reactive oxygen species were derived from studies in HAoSMC (human aortic smooth muscle cells) and also HEK293 cells (human embryonic kidney cells). In HAoSMC an H2O2 – induced increase in collagen I, III and IV was augmented by aldosterone and inhibited by MR-antagonists and EGFR kinase inhibitors [52]. These results could be confirmed in HEK293 cells [53]. In summary, aldosterone-induced EGFR transactivation promotes physiological effects (sodium chloride transport) and pathophysiological events like vascular remodeling, inflammation, aging and fibrosis depending on the cell type. Physiological effects are elicited in epithelial cells and pathophysiological effects seem to be associated with mesenchymal cell types (VSMC, cardiomyocytes, fibroblasts). 2.2. Insulin/IGF-1 receptor signaling 2.2.1. Physiological effects – sodium chloride transport It is well known that MR as well as IGF-1 enhance sodium transport and that both pathways can lead to activation of PI3K and Akt [54,55]. In the renal epithelial cell line A6, transactivation of the IGF1-R by aldosterone via MR and GR was postulated. Transactivation implies that the receptor phosphorylation and thereby activation occurs independently of a ligand and Holzman et al. showed that 1.5 lM of aldosterone is able to rapidly induce phosphorylation of the IGF-1 receptor, IRS-1 and Akt via PI3K activation [56].

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2.2.2. Pathophysiological effects – insulin resistance The MR has been linked to reduced insulin signaling and insulin resistance [57]. The underlying mechanism comprises an increased proteosomal degradation of IRS-1 with attenuated phosphorylation of Akt in VSMC, skeletal muscle and adipocytes [58–60]. For adipocytes this effect was described to be GR and not MR mediated [60]. The suggested mechanism involves crosstalk of different downstream signaling components. By enhancing ROS production, aldosterone/MR can modulate redox sensitive kinases like Rho kinase and p70 S6 kinase, which causes enhanced serine and reduced tyrosine phosphorylation of IRS-1 and therefore proteasomal degradation [61]. Impaired insulin signaling through enhanced IRS-1 degradation has been associated with tissue remodeling in renal glomeruli [62]. Additionally, insulin resistance in the vasculature was reported to be mediated by increased IGF-1 signaling through an upregulation of IGF-1R (insulin-like growth factor 1 receptor) and IGF-1R/insulin receptor hybrids (but not IR alone) [63,64]. 2.3. PDGFR The PDGFR consists of an extracellular domain with five Ig-like domains and an intracellular tyrosine kinase domain. Two types of PDGFR (alpha and beta) exist that bind to different ligands of the PDGF family and can form homo- or heterodimers. The MR but also angiotensin II and AT2R1 can rapidly transactivate PDGFR, leading to activation of c-Src and a proinflammatory response in VSMC, namely enhanced ICAM-1 and VECAM1 expression [65]. Costimulation with aldosterone and angiotensin II leads to a synergistic activation of c-Src mediated by PDGFR and EGFR, which stimulates NADPH oxidase. Eventually, redox sensitive Rho kinase enhances VSMC migration [22]. Other known down-stream targets of the PDGFR are Akt and ERK1/2 which can mediate vascular and renal remodeling by modulating VSMC and renal fibroblast proliferation [66]. Furthermore, PDGFR-b has been shown to transactivate the EGFR via stimulation of ADAM17 activity [67] and also the FGFR [68]. Recently, PDGF was identified as a factor promoting nuclear MR translocation and MR-induced gene expression, suggesting a complex interaction and possibly a positive feedback loop between MR and PDGFR signaling that is involved in pathological remodeling processes of the vasculature [69]. 2.4. VEGFR There are three VEGF receptors that possess five ligands, VEGFA-D and placenta growth factor. In injured vessels the MR can enhance the expression of placental growth factor (PlGF) and its receptor VEGFR1, also known as Flt1 [70]. VSMC proliferation, media collagen deposition and vessel media area are augmented by aldosterone in a wire injury model. These effects are decreased in PlGF knockout mice, suggesting that MR-induced vascular remodeling is mediated by PlGF/VEGFR1 in injured vessels. Conversely, aldosterone and MR inhibit tube formation on Matrigel in HUVEC and angiogenesis in vivo by downregulating PPARc and VEGFR2 in vascular endothelial cells [71]. While VEGFR2 is closely linked to induction of angiogenesis, the role of VEGF1 in angiogenesis has been more ambiguous. VEGFR1 shows strong ligand binding but only little kinase activity and therefore has been proposed as an antagonist for VEGFR2 signaling, which makes the interpretation of the MR–VEGFR data more complex. Chronic aldosterone infusion can lead to a decrease in the number of endothelial progenitor cells and a downregulation of VEGFR2 and VEGF in these cells. These effects could be inhibited by spironolactone [72,73]. Overall, blockade of MR has been shown to improve angiogenesis and therefore the outcome in models of myocardial and brain ischemia, by upregulating angiogenic factors like bFGF and

VEGF [27,74–76]. However, aldosterone has also been shown to enhance neovascularization after ischemia-mediated angiotensin II crosstalk and increased production of VEGF. Therefore, the overall effect on angiogenesis is still under debate [77]. Likewise, transgenic animals overexpressing aldosterone synthase in the heart showed less diabetes-associated cardiac alterations, including less decrease in VEGFa expression and capillary density as well as reduced superoxide anion production [78]. Consequently, the impact of the MR on VEGFR and VEGF may depend on the observed basal level, i.e. the condition of the animal/patient.

3. MR Interaction with the angiotensin II receptor 1 (AT1R) The AT1R is a G protein-coupled receptor that mediates the vasoconstrictor effect of angiotensin II, which is, next to aldosterone, the second effector molecule of the renin–angiotensin–aldosterone system. Angiotensin II enhances systemic aldosterone levels by stimulating adrenal aldosterone synthesis. The possibility of local aldosterone production has been suggested although experiments with adrenalectomized animals suggest that this system is only of minor, if of any, importance [79–81]. In addition to their role in salt water and blood pressure homeostasis, angiotensin II and aldosterone can both mediate pathological effects in the cardiovascular system and in the kidneys. There is evidence for a crosstalk at different levels between the signaling of aldosterone/ MR and angiotensin II/AT1R. Angiotensin II-induced pathological effects are partly mediated by MR as has been suggested in vivo for cardiac damage, vascular changes and oxidative stress [82– 86]. Of note, angiotensin II seems to mediate glomerular injury and renal interlobular artery hypertrophy through MR even in aldosterone synthase knockout mice, i.e. independently of aldosterone [86]. In cell culture a synergism of aldosterone and angiotensin II in mediating VSMC proliferation, migration and cellular senescence was shown, especially when applying low doses [22,32,43,87]. As underlying mechanism for cellular proliferation, a synergistic rapid ERK1/2 activation, mediated by EGFR transactivation and generation of reactive oxygen species (ROS) was described [22,32,43,87]. EGFR transactivation by AT1R or MR could also activate pathophysiologically relevant transcription factors like NFKB and AP1 [82]. As a second mechanism a synergistic activation of c-Src through EGFR and PDGFR transactivation was demonstrated. c-Src phosphorylation was followed by activation of NADPH oxidase and RhoA/Rho kinase and influenced cell migration [22]. Cellular senescence was mediated by AT1R activation, oxidative stress and enhanced ki-ras2A expression [43]. In coronary artery VSMC, angiotensin II was able to stimulate nuclear localization and transcriptional activation of the MR, which could be inhibited by AT1 receptor and MR blocker and was not mediated by local production of aldosterone [88]. It was speculated that this effect may be mediated by posttranslational modifications, for example phosphorylation. Conversely, in the aldosterone/salt rat model, an AT1R antagonist was able to prevent the rise in collagen I and III [89,90]. In murine mesenteric vascular smooth muscle cells, siRNA against or inhibitors of AT1aR were able to block aldosterone-induced ERK1/2, JNK and NF-KB phosphorylation while AT1bR blockade only decreased aldosterone-induced NFKB activation [91]. In apolipoprotein E-deficient mice treated with aldosterone pro-oxidative effects of aldosterone in macrophages and mouse aortic segments were only completely blocked by combined treatment with MR and AT1R antagonists and not by one antagonist alone [92]. Likewise, the effect of a cholesterol-rich diet on formation of atherosclerotic lesions in these mice was more efficient when treating the mice with a combination of an MR and an AT1R antagonist instead of applying only one inhibitor [93]. Vasoconstriction by

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aldosterone in murine mesenteric arteries was suppressed in AT1aR knockout mice [94]. Genomically, aldosterone increases the expression of MR, AT1R and the expression and activity of angiotensin converting enzyme, generating angiotensin II from angiotensin I [92,95–97]. Additionally, in a mice ischemia model, angiotensinogen mRNA was found to be elevated after treatment with aldosterone and AT2R mRNA was downregulated, leading to enhanced neovascularization [77]. Overall, the angiotensin II and aldosterone signaling pathway are intertwined and interactions are complex. 4. Aldosterone effects mediated by GPR30 (GPER) Rapid effects in response to aldosterone but independent of the MR were described decades ago, but since then the underlying molecular mechanism and even their existence have been debated controversially [3,98]. First indications that MR-independent effects of aldosterone are mediated by the G-protein-coupled estrogen receptor GPR30 came from Gros et al. showing that GPR30 expression is required for rapid MR-independent effects of aldosterone in VSMC [99]. These findings were confirmed in rat aortic vascular endothelial cells with robust GPR30 expression and no detectable MR expression. In this model aldosterone as well as the GPR30 agonist G1 rapidly increased ERK1/2 phosphorylation, mediating pro-apoptotic, anti-proliferatory and vasodilatory effects. The effects were abolished by the GPR30 antagonist G15 [100]. Additionally, a GPR30-dependent angiotensin II/aldosterone interaction in human coronary microarteries was demonstrated by Batenburg et al. showing that steroids including aldosterone affect the angiotensin II-induced vasoconstriction in a biphasic manner. While nanomolar aldosterone concentrations led to enhanced vasoconstriction via transactivation of GPR30 and EGFR, micromolar aldosterone levels reversed this effect due to endothelial NOS activation [101]. More recently, Brailoiu et al. reported that aldosterone-induced bradycardia can be blocked by the GPR30 antagonist G36 but neither by spironolactone or eplerenone. They demonstrated that aldosterone increased cytosolic Ca2+ concentration via GPR30 activation in cardiac vagal neurons of the nucleus ambiguous leading to a decrease in the heart rate [102]. Despite these results, the overall role of GPR30 as an aldosterone receptor is still very controversial and requires further investigations. 5. Other modulators of mineralocorticoid receptor signaling 5.1. Micromilieu modulators Besides being influenced by interactions with membrane receptors, MR signaling is also modulated by the surrounding micromilieu and posttranslational modifications. It has been demonstrated that aldosterone-induced MR activation per se is not sufficient to mediate pathological changes in the renocardiovascular system, but that such effects have to be promoted by an appropriate micromilieu [103,104]. The influence of shifts in redox state as well as altered amounts of reactive oxygen (ROS) and/or reactive nitrogen species (RNS) on pathophysiological MR activation has been demonstrated in the past [52,105]. For example, nitric oxide (NO) can reduce MR receptor activity in the presence of corticosteroids via repressed receptor-DNA interaction. Besides the ligand-dependent activation, there are also modulators of the MR that act ligand-independently. Treatment with peroxynitrite (ONOO) in the absence of ligand induced MR transactivation activity whereas genomic GR activity was not affected [106]. Nagase et al. demonstrated that oxidative stress causes MR activation in rat cultured cardiomyocytes and thereby may also contribute to pathophysiological effects. They showed that BSO (L-buthionine sulfoximine),

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an inhibitor of the glutathione synthesis, redox-dependently increased the amount of active Rac1, a member of the Rho family of GTPases, which leads to enhanced nuclear accumulation and transactivation of the MR independent of ligand [107–109]. Osmotic stress is another factor postulated to be an important molecular determinant for cell-specific MR effects in renal failure, hypertension or mineralocorticoid resistance. Investigations in an aldosterone-sensitive cortical collecting duct cell line showed that hypotonicity causes a strong increase in MR mRNA and protein levels whereas hypertonicity strongly reduces MR transcript and protein levels. This reduction in MR levels is accompanied by expression of Tis11b, a mRNA–destabilizing protein, which then binds to the 30 -untranslated region of the MR causing degradation of the receptor transcripts [110].

5.2. Posttranslational modifications The modulation of MR signaling is mediated by different mechanisms and includes posttranslational modifications of the MR which can influence its activity or expression. Inhibition of nongenomic MR-induced phosphorylation mediated by ERK1/2 or PKCa has been shown to increase MR transactivation activity although it remains unclear if this involves direct MR phosphorylation or indirect effects [4,111]. Data from Shibata et al. regarding MR phosphorylation in intercalated cells of the distal nephron demonstrate the importance of MR phosphorylation for ligandbinding. They identified a S843 phosphorylation site within the MR ligand-binding domain which is relevant in renal response to volume depletion and hyperkalemia. Furthermore, they showed that dephosphorylation of MRS843 enables aldosterone-induced increase in Cl reabsorption and plasma volume whereas K+ secretion is inhibited [112]. Interestingly, MR degradation also depends on aldosterone as well as posttranslational modifications. In its non-activated basal state the MR was demonstrated to be bound to different proteins including HSP90, HSP70, p23, p48, cyclophillin 40 or FK-binding protein 49 immunophillins [113–115]. MR activation leads to a disruption and dissociation of the protein complexes and additionally to translocation into the nucleus. Faresse et al. demonstrated that unactivated MR is monoubiquitylated and bound to Tsg101 (tumor suppressor gene 101). Binding of aldosterone then leads to rapid phosphorylation via ERK1/2 accompanied by the disruption of the MR/Tsg101 protein complex and removal of the monoubiquitin residue thereby promoting polyubiquitylation and degradation [116,117]. Evidence that degradation of the MR is mediated via the ubiquitin–proteasome pathway in a ligand-dependent fashion was given by Yokota et al. The group demonstrated MR accumulation accompanied with an enhanced transcriptional response to aldosterone after inhibition of the proteasome [118]. Another posttranslational modification changing MR properties is sumoylation. The MR possesses five consensus binding sites for SUMO-1 (small ubiquitin-like modifier 1). PIAS1 (protein inhibitor of activated signal transducer 1) was shown to interact with the N-terminal MR domain and thereby conjugates SUMO-1 to MR in vitro as well as in vivo. The resulting sumoylation represses the ligand-dependent transcription activity of the MR [119]. Finally, modulation of the MR also involves acetylation and deacetylation. It is well known that transcription factors could be either activated or inhibited by direct acetylation and that inhibitors of histone deacetylases (HDACi) were shown to achieve antifibrotic, anti-inflammatory or antihypertensive effects [120,121]. Recently, Lee et al. demonstrated the influence of HDAC inhibition on transcriptional activity of the mineralocorticoid receptor in DOCA-induced hypertensive rats. Their results indicate that inhibition of histone deacetylases diminishes MR transcription activity and thereby prevents development of hypertension [122].

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Besides being affected by the micromilieu and by posttranslational modifications, MR signaling can also be modulated by cytosolic signaling components like mitogen activated protein kinases (MAPK), protein kinase C (PKC) and secondary messengers like calcium and cyclic adenosine monophosphate (cAMP)/cAMP response binding protein (CREB) [5,111,123–130], which has already been reviewed elsewhere [131].

[18]

[19]

6. Perspectives

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Overall, there are still questions regarding MR signaling that have not been solved, yet. The mechanisms conferring MR specificity over GR need to be investigated in more detail to understand the biological principals as well as to develop rational intervention strategies. Besides MR-specific interactions with membrane receptors, micromilieu factors and posttranslational modifiers, these mechanisms seem to include novel MR-specific response elements, interactions with additional cytosolic or nuclear factors and indirect effects mediated by chaperone molecules like HSP90 [1,129,132] (See Fig. 2). Furthermore, the relevance of the dynamic spatio-temporal subcellular MR distribution in states of health and disease for its impact on cell function as well as its specificity have been probably underestimated in the past and need to be addressed in more detail.

[21]

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