Introduction
In the 1950s, Selye et al. [1] presciently characterized the effects of aldosterone on nonepithelial tissues and postulated that spironolactone is protective in conditions of aldosterone excess. The cloning of the human mineralocorticoid receptor (MR) by Arriza et al. [2] exactly 30 years ago, spurred interest in the nonclassical aspects of aldosterone including the role of aldosterone in cardiac remodeling and fibrosis [3]. MRs are members of a superfamily of intracellular ligand-operated steroid receptors that regulate transcription of multiple genes and other transcription factors resulting in a complex repertoire of effects. The remarkable success of clinical trials in MR inhibition through their effects on the cardiovascular system have driven research on the physiological and pathological role(s) of nonepithelial MR expression [4,5,6]. An important new dimension is the evolving appreciation of the role MR plays in immune cells as it relates to target organ damage (Fig. 1). In this review, we attempt to review the most significant developments related to MR modulation of immune expression and new studies over the last decade that have paved the way for renewed understanding of MR-mediated cardiorenal disease.
Fig. 1
Mineralocorticoid agonism or elevated aldosterone levels have a deleterious effect on organ systems and cells relevant to cardiometabolic diseases.
MR Structure and Expression
The MR receptor is a 984-amino acid intracytoplasmic receptor divided into 3 domains: the N-terminal domain that regulates transcriptional activity of the receptor; the DNA-binding domain involved in the binding of the specific response element found on the promoter of MR target genes; and finally, a ligand-binding domain responsible for the selectivity of hormone binding. MR also binds to a number of chaperones that play a pivotal role in maintaining MR in an appropriate conformation for ligand binding. Upon hormone binding, the MR dissociates from chaperone proteins, undergoes nuclear translocation, and interacts with numerous molecular partners in a coordinated and sequential manner to ensure appropriate transcriptional regulation. In the nucleus, MR recruits co-regulators (cofactors and/or corepressors) to induce the transactivation and regulation of hundreds of target genes [7]. These genes present a palindromic DNA sequence common for GR and MR called the glucocorticoid response element within their promoter. Although MR is regulated transcriptionally, posttranscriptional mechanisms of regulation are important and include phosphorylation and sumoylation. Very recently, ubiquitination, another posttranslational modification of MR, has been reported [8].
MR Activation/Antagonism and Specificity-Conferring Mechanisms
MR has been shown to bind to aldosterone at low concentrations (high picomolar) and with high affinity. MR also binds with equally high affinity to cortisol, corticosterone, deoxycorticosterone, and progesterone [9]. Since circulating physiologic glucocorticoid levels are ∼1,000-fold higher than those of aldosterone on a normal diet, the issue of MR selectivity to aldosterone has been a topic of contention for decades. Studies by Funder and Minireview [9] suggested that 11β-HSD type 2 (11β-HSD2), a high-affinity (nanomolar KM), low-capacity NAD-dependent dehydrogenase is expressed alongside MR, where its activity reduces the availability of glucocorticoids, permitting aldosterone to bind to the MR with relative exclusivity. However, the idea that the presence of 11β-HSD2 is enough to provide unfettered access to aldosterone, through “debulking” cortisol (conversion to cortisone) would require a tremendously efficient system that converts vast excesses of cortisol to cortisone in the area proximal to the MR. This mechanism is not supported by in vivo evidence in the cardiovascular, immune, and central nervous systems. Indeed, the preponderance of evidence suggests little or no 11β-HSD2 activity in the heart, inflammatory cells, and regions of the central nervous system; yet there is extensive evidence to support MR binding in these organs [10]. In addition, in vivo competition studies in adrenalectomized animals show high MR selectivity in these organs. For instance, cortisol has ∼30% of the apparent affinity of aldosterone in the heart. These studies firmly suggest that specificity-conferring mechanisms, other than pure enzymatic mechanisms are essential for selective aldosterone action. 11β-HSD1, the enzyme that converts inactive cortisone to cortisol in humans, has low affinity for glucocorticoids (micromolar KM) relative to 11β-HSD2, and functions both as an oxidoreductase (transfers electrons from one molecule to another) and as a dehydrogenase. The latter activity is dependent on the supply of NADPH through coupled expression of the enzyme hexose-6-phosphate dehydrogenase. Although there is plentiful evidence that myocardial cells express 11β-HSD1, reactivation of glucocorticoid is apparently limited under physiological conditions both in mice and humans. In an in vivo study in humans, the stable isotope tracer 9, 11, 12, 12-[2H]4-cortisol underwent little metabolism across the human heart [11]. Administration of the MR antagonist canrenoate in the same patients resulted in the elevation of cortisol collected from the coronary sinus, suggesting displacement of endogenous glucocorticoids. These data support the view that the cardiac MR is normally occupied by glucocorticoids rather than by aldosterone. A model that provides an explanation for glucocorticoid-mediated MR signaling in the setting of a protected MR (presence of 11β-HSD2) is the concept that the activity of the enzyme 11β-HSD2 results in a decrease in the NAD/NADH ratio (owing to generation of NADH) which alters the redox state, resulting in blocking activity of MR. There is direct evidence for redox stress/state regulating the activation of other nuclear transactivating factors, and it is likely that similar changes in redox state are operant for cortisol [10]. There are undoubtedly other aspects such as conformation of the ligand-binding interactions and co-regulator recruitment that may contribute to between-ligand (cortisol vs. aldosterone) differentiation in signaling [7,12].
MR Activation in Kidneys and Cardiovascular Tissues
The mechanism for MR activation in tissue injury continues to evolve and suggests a complex repertoire of effects involving a multitude of mediators that are cell and context dependent. While in both animal models and humans, there is evidence that both plasma and urinary aldosterone concentrations are increased in a variety of cardiometabolic conditions, MR activation may occur in the absence of elevated aldosterone levels [13]. Recently, several studies have suggested that MR activity is also affected by factors other than its ligands including PKA, Rac-1, ubiquitin conjugating enzymes and other factors involved in the regulation of diverse nuclear receptors [14,15,16,17]. MR is widely expressed in the cardiovascular system such as in the endothelium, smooth muscle cells, and fibroblasts, and is a major determinant of endothelial function, smooth muscle tone, vascular remodeling, fibrosis, and blood pressure (BP) [18,19,20,21,22,23,24,25]. Endothelial, vascular smooth muscle, and cardiomyocyte-specific overexpression/deletion studies in animals and studies in humans, support a role for MR activation in promoting vascular oxidative stress, inflammation, proliferation, migration, vasoconstriction, vascular remodeling, and fibrosis [26,27,28,29,30,31,32,33,34], (online suppl. Table for all online suppl. material, see www.karger.com/doi/10.1159/000480652).
In the kidneys, the classical effects of MR activation are to increase epithelial sodium channel (ENaC) density in the distal convoluted tubule via increased expression and activation of serum and glucocorticoid regulated kinase-1 (SGK1). Phosphorylated SGK1 in turn “inhibits an inhibitor” of ENaC, NEDD4, a protein involved constitutively in the ubiquitination of ENaC [35]. Chronically, SGK1 may also play a role by promoting ENaC transcription through inhibition of H3K79 methyltransferase, which blocks transcription of ENaC. Mineralocorticoid-sensitive inflammation and fibrosis involves the upregulation of the inflammatory transcription factor NFκB, which in turn stimulates the expression of diverse mediators including connective tissue growth factor. SGK1 also inhibits the degradation of the transforming growth factor beta (TGFβ)-dependent transcription factors Smad2/3, further promoting a profibrotic signal [36].
Aldosterone promotes the proliferation of renal fibroblasts and mesangial cells via transactivation of epidermal growth factor receptor and platelet-derived growth factor receptor, induces myofibroblastic transdifferentiation of mesangial and tubular epithelial cells, and directly stimulates the synthesis of profibrotic cytokines and matrix proteins [37,38,39,40]. The profibrotic response of aldosterone at least in animal models, clearly requires sodium. Studies by Shibata et al. [15,41] have shown that salt can lead to the activation of MR, even in the absence of ligand resulting in a profibrotic response in the kidney and heart. Recent studies have additionally implicated an important role for the immune system in aldosterone-mediated fibrosis and tissue injury. As detailed below, the activation of the immune system appears to be an important mediator of MR-mediated effects and is a requisite for its profibrotic effects.
Role of the MR in Macrophage/Monocytes
MR appears to play a central role in regulating macrophage phenotype and function broadly through transcriptional reprogramming of monocytes/macrophages. Many of the phenotypic effects reported to be regulated by MR may reflect a broad repurposing of cellular function. Thus, while the effects of MR activation/antagonism are reported discretely, they may reflect related and connected effects. In this regard, deletion of MR in myeloid cells (MR knock out or MRKO) has been very useful in ascribing MR-dependent mechanisms in macrophages. Table 1 details the cell-specific and phenotypic effects of conditional tissue-specific deletion of MR in cardiovascular cells, including in myeloid cells.
Transcriptional Reprogramming of Macrophages
PPARγ, PPARδ, and KLF4 are major regulators of alternate activation and are required for the maintenance of alternatively activated macrophages (Fig. 2) [42]. Macrophages in mice can be rendered pro-inflammatory (M1) in the presence of aldosterone, an effect prevented by MR antagonism which favors an anti-inflammatory, alternatively activated (M2) phenotype [43]. Conversely, MRKO in myeloid cells recapitulated the effects of MR antagonism, by shifting the phenotype to M2 (alternatively activated macrophage) and downregulating pro-inflammatory and profibrotic genes (TGFβ and PAI-1). In vivo, myeloid MRKO reduced aortic and cardiac macrophage recruitment, cardiac hypertrophy, fibrosis, and fetal gene reprogramming in response to AngII and L-NAME (model of MR activation) suggesting that myeloid MR is crucial to adverse, fibrotic cardiovascular remodeling [43]. Gene expression analysis revealed significant similarity between MRKO and PPARγ activation. These findings were similar to another study investigating macrophages from the heart in myeloid MRKO and wild-type (WT) animals treated with vehicle or DOCA/salt. A pro-inflammatory and profibrotic profile in response to DOCA salt was prevented in the heart of mice with myeloid MR-null macrophages [44]. Further, MRKO in macrophages diminished the activation of both AP1 and NFκB in restenosis models with effects dependent on SGK1, consistent with other studies [45,46].
Fig. 2
Mineralocorticoid receptor agonism (ligand binding, left side) increases the classical activation of macrophages, while antagonism MRA promotes an alternative activation (right side).
Regulation of Myeloid Inflammatory Numbers and Chemotaxis
MRKO macrophages demonstrate reduced migration de novo in response to a chemokine gradient with restenotic injury, resulting in lower macrophage content in MRKO animals vs. WT [47]. Corning Transwell® assays with conditioned media derived from LPS-stimulated MRKO macrophages induced markedly less migration of vascular smooth muscle cells and lower expression of pro-inflammatory cytokines, compared to conditional media from control macrophages [47]. Several in vivo studies involving hypertension and stroke models have demonstrated a reduction in macrophage content in mice transplanted with MRKO myeloid cells [43,48]. Similarly, in a study of cardiac hypertrophy (transaortic constriction), a reduction in macrophages in the heart with myeloid MR deletion was noted [49]. However, two studies using a severe hypertension model (unilateral nephrectomy with 0.9% salt and L-NAME) and a uninephrectomized mouse model of DOCA salt excess, demonstrated no change in the number of tissue macrophages in the heart [44,50]. In many of these studies, macrophage recruitment seems to play a critical role in BP response, with evidence suggesting a CCL2-dependent movement of myeloid cells to the heart required for myeloid MR-dependent effects [51]. However, all studies demonstrated rather consistent reduction in tissue fibrosis and inflammation suggesting that MR deficiency critically regulates fibrosis [43,47,48,50].
Regulation of ROS and Inflammatory Kinases
Aldosterone has been shown to activate components of NAPDH oxidase in various cell types [27,28,52,53,54], and reductions in NADPH oxidase have been noted in response to MR blockade [54,55,56]. The degree to which these are direct, nongenomic effects is difficult to understand and is currently uncertain [57]. Rac1, a Rho family small GTPase, is a novel modulator of MR activity and demonstrated the pathological role of Rac1-mediated MR activation in the kidney and in salt-sensitive hypertension [58]. In prior studies, overexpression of constitutively active mutant Rac1 in rat cardiomyocytes promoted nuclear accumulation of MR and increased MR-dependent transcriptional activity regardless of the ligandlevel implicating a potential contribution of Rac1-MR signaling in cardiac diseases [16,41]. Rac1 associates with Nox isoforms such as Nox4 (present in endothelial cells) rather than Nox2 (present in macrophages and neutrophils), at least in the myocardium and contributes to heart failure in response to pressure overload hypertrophy. Thus, the activation of Rac1 and subsequent activation of MR in addition to ROS generation through Nox4 may contribute to tissue injury and transition to heart failure [41]. cJun N-terminal kinases (JNK) may also be a downstream target of MR, as bone marrow-derived macrophages exposed to LPS (classic type 1 proinflammatory mediator) significantly increased the phosphorylation of JNK, while phosphorylation of JNK is attenuated in MR-null bone marrow-derived macrophages. Analysis of other MAPK pathways such as p38 and ERK1/2 showed equivalent phosphorylation. In this study there were no differences in phosphorylation of the NFκB pathway and IκBα.
Evidence for Inflammasome Activation in Myeloid Cells in Response to Aldosterone and MR Involvement
Chronic inflammation caused by inflammasome activation is involved in many diseases including atherosclerosis, diabetes, and obesity (Fig. 3). Recently, a role for inflammasome activation in kidney injury via MR activation has been proposed; aldosterone stimulates various components of the inflammasome complex and products of inflammasome activation (IL18) lead to podocyte injury while blockade of MR reverses these effects [59]. Mice deficient in apoptosis-associated speck-like protein (ASC) had reduced renal fibrosis and inflammation without affecting macrophage numbers. Bone marrow transplantation using ASC-deficient mice marrow reduced inflammasome activation, implicating myeloid cell-derived ASC in tubulointerstitial damage and subsequent fibrotic changes in the kidney [60]. The mechanism of activation was attributed to mitochondrial-driven ROS as mitochondrial-directed antioxidant mito-TEMPO interrupted caspase activation in response to aldosterone in cultured macrophages [60]. A model of anti-glomerular basement membrane glomerulonephritis (anti-GBM GN) was used to interrogate the contribution of podocyte versus myeloid MR. The absence of MR in podocytes did not reduce immune injury in anti-GBM GN. In contrast, injury glomerular crescents, myofibroblast accumulation, and gene expression of profibrotic molecules (COL1A1, FN1, PAI-1) were all decreased in MyMRKO mice versus WT [61].
Fig. 3
Aldosterone stimulation of adipose tissue macrophages may potentiate local tissue inflammation exacerbating insulin resistance, diabetes, and atherosclerotic processes.
Role of Central Nervous System MR in Regulation of Peripheral Inflammation
MR activation in the brain has been linked to sympathetic hyperactivity and an increase in peripheral tissue aldosterone levels, while central MR blockade attenuates sympathetic hyperactivity [62,63]. In an interesting study, the time course of macrophage infiltration and apoptosis in the heart in response to central MR blockade (intracerebroventricular infusion of eplerenone, 5 μg/day) was evaluated post-myocardial infarction. Central MR blockade significantly decreased CD80-positive pro-inflammatory M1 macrophages and increased CD163-positive anti-inflammatory M2 macrophages in the infarct. Central MR blockade also reduced apoptosis of myocytes by 40-50% in the peri-infarct zone [64].
Role of the MR in T Cells
T lymphocytes play an important role in target organ damage in hypertension and atherosclerosis. Indeed, MR in T cells is critical in mediating fibrosis in the heart and kidney. T cell deficient in MR reduces ventricular remodeling in hypertension caused by trans-aortic constriction. This was associated with reduced T cell activation markers and inflammation in heart. Activation of MR resulting in increased Th17 T cells could contribute to cardiac fibrosis. Conversely, treatment with IL-17 blocking antibodies prevented DOCA/salt induced cardiac and renal fibrosis in rats [65]. Recently, it has also been shown that MR may interact with a critical transcription factor in T cells, NFAT1, and activator protein-1 to control interferon gamma in T cells and regulate BP and target organ damage in an AngII-infusion murine model [66]. MRA (mineralocorticoid receptor antagonism) by eplerenone and T cell-specific MR ablation (TMRKO) in mice resulted in reduced abdominal aortic constriction (AAC)-induced cardiac hypertrophy, with reduced measures of cardiac fibrosis (% fibrotic area, βMHC, collagen I/III, connective tissue growth factor, and TGFβ1; Table 1) [67]. Measures of cardiac function (e.g., LV end-systolic volume) were partially preserved in TMRKO-AAC versus WT-AAC and LV-dilation/LVH was attenuated. Post-ACC cardiac neutrophil and monocyte/macrophage (CD11b+Ly6G+; CD11b+Ly6Chi respectively) content was dramatically lower in TMRKO mice.
Role of the MR and Effect of MR Antagonism in the Treatment of Cardiovascular and Renal Diseases
Pharmacological and clinical studies over >20 years have defined the importance of the MR in hypertension and heart failure which will not be discussed here. There are studies that demonstrated an impact of MRA in patients with risk factors, with improvement in surrogate outcomes related to LV mass and hypertrophy (Table 2).
Effect of MRA in Cardiac Hypertrophy, Fibrosis, and Diastolic Dysfunction
Online supplementary Table details studies involving MRA that have demonstrated efficacy in reducing fibrosis and hypertrophy in a variety of animal models irrespective of aldosterone levels. A consistent effect of MRA is its impact on fibrosis and reduction of left ventricular hypertrophy. In humans, MRA reduced LVH in patients on top of ACE inhibition [68]. While these effects may rely on BP reduction, data from animal models seem to support an effect that may occur independently of BP. A small study in obese patients demonstrated that MRA (spironolactone) for 6 months can improve diastolic dysfunction, subclinical markers of systolic dysfunction (global longitudinal strain), a surrogate marker of myocardial fibrosis (integrated backscatter, echo) and circulating markers of fibrosis (PICP) [69]. Although results from the Treatment of Preserved Cardiac Function Heart Failure with an aldosterone antagonist trial were negative, subset analysis suggests benefits in patients with evidence of definitive heart failure who were medication compliant [70,71,72].
Effect of MRA in Atherosclerosis
Proof-of-concept experiments from our group using eplerenone in a rabbit model of atherosclerosis provided one of the first lines of evidence that MRA may improve vascular function and redox stress independent of aldosterone levels. New Zealand white male rabbits were fed 1% cholesterol chow (HL) or normal chow for 6 weeks to induce endothelial dysfunction and then randomized to receive eplerenone or placebo (100 mg/kg) for 6 additional weeks [56]. Eplerenone normalized peak endothelium-dependent relaxation and reduced O2- in the aorta of high cholesterol fed animals. A number of studies have demonstrated an impact of MRA in reducing atherosclerosis in mouse models, including reduction of inflammatory cell infiltration, increased M2 markers, smooth muscle proliferation, and reduced pro-inflammatory cytokines in plaques (online suppl. Table). Studies in monkeys have also demonstrated important effects of eplerenone in reducing aortic intimal volume (intravascular ultrasound) and improving acetylcholine-induced vasorelaxation [73]. In models of experimental thrombosis, aldosterone enhances thrombosis while spironolactone reverses this effect [74]. In recent studies, LDLR-/- chimeric mice with bone marrow cells from floxed (control) mice or from myeloid MR-/- demonstrated reduced atherogenesis, suggesting that MR in myeloid cells likely promotes atherogenesis. Further chimeric ApoE-/- mice with myeloid MRKO also exhibited reduced atherogenesis in response to AngII, an effect mediated in part by reduced foam cell formation and enhanced cholesterol efflux [45].
While the role of MRA in secondary prevention in patients with post-myocardial infarction and symptoms of heart failure is well known, there are data suggesting that use of MRA early post-MI in patients with STEMI and LV dysfunction may be beneficial [75]. In the REMINDER study (n = 1,012), in patients with STEMI without HF, eplerenone reduced the composite end point of CV mortality, rehospitalization, extended hospital stay, due to HF, sustained ventricular tachycardia or fibrillation, ejection fraction ≤40%, or elevated BNP/NT-proBNP at 1 month. The end point was primarily driven by persistent elevation of BNP/NT-ProBNP in the placebo group. In contrast to earlier studies such as EMPHASIS-HF, this was a low risk population without HF or low EF with a low event rate (0.4% morality rate through the trial). Further the drug was administered early on after presentation, with the first dose of study drug administered within 24 h of the onset of symptoms of acute MI and preferably within 12 h. There is limited data supporting a role for aldosterone in the progression of atherosclerosis. In human studies, polymorphisms of the aldosterone synthase gene (Cyp11β2) have been associated with plaque size on MRI. Plasma aldosterone levels have been associated with nonfatal cardiovascular events and CV death. In a study of 848 patients, plasma aldosterone was the only independent predictor of plaque progression (carotid ultrasound) in the first 2 years of the study [76].
Effect of MRA on Proteinuria and Progression of Chronic Kidney Disease
The beneficial impact of renin-angiotensin-aldosterone system (RAS) blockade with ACE-I and ARB in both diabetic and nondiabetic chronic kidney disease (CKD) has been demonstrated in multiple animal models and human studies (online suppl. Table). Two previously published meta-analysis studies published initially in 2009 and updated in 2014 demonstrated that the addition of MRA to RAS blockade reduced BP and proteinuria in CKD [77,78]. An updated meta-analysis that included previously unpublished data as well as including data from 3 studies which were not considered in the previous meta-analysis supported previous findings [79]. A total of 19 trials (1,646 patients) were included, of which 8 were done in patients with diabetic nephropathy. Fourteen (889 patients) compared spironolactone plus ACE-I or ARB with ACE-I or ARB alone, and 5 trials (757 patients) compared eplerenone plus ACE-I or ARB to ACE-I or ARB alone. The follow-up period of included trials was <1 year and the mean baseline eGFR was >35 mL/min/1.73 m2, therefore the impact of addition of MRA to RAS blockade on long-term renal outcomes or mortality in the later stages of CKD cannot be evaluated. In random effects meta-analysis, addition of MRA to RAS inhibitors resulted in a reduction in systolic BP from baseline of -5.7 and diastolic BP of -1.7 mm Hg, respectively. The GFR fell by -3.2 mL/min/1.73 m2. MR antagonism reduced the weighted mean protein/albumin excretion by 38.7%. MRA was associated with 3-fold increased risk of hyperkalemia above the predefined trial limit. Diabetic CKD patients, however, were not at a greater risk of developing hyperkalemia than patients with CKD of alternative etiology (p = 0.38). Number needed to harm for 1 year of treatment, calculated from trials reporting at least one case of hyperkalemia, was 10 (95% CI 5-27). The addition of MRA to RAS blockers led to a moderate increase from baseline potassium compared to ACE-I and/or ARB alone, both at end-of-trial visit (0.19 mmol/L [95% CI 0.07-0.31]; 16 trials; n = 1,356; I2 = 83.8%).
MRA and Insulin Resistance and Type 2 Diabetes
A number of reviews have already detailed in vitro, experimental and human evidence linking aldosterone/MR activation with IR [80,81,82]. The visceral adipose RAS system synthesizes aldosterone, expresses MR, and predicts IR in both humans and animal models [82]. Adipocyte overexpression of MR results in metabolic syndrome and enhanced vascular contractility, and suggests an independent contribution outside of MR in inflammatory cells in adipose [83]. In patients with nondiabetic stages 2-5 CKD, treatment with spironolactone ameliorated insulin resistance. In the same study, insulin resistance in nephrectomized rats was improved with spironolactone presumably via adipose overexpression of the rate limiting enzyme for aldosterone, CYP11β2 and the downstream effector of MR, SGK-1 [84]. Spironolactone has also been shown to prevent insulin resistance in response to diuretics [85]. However, treatment of individuals with uncomplicated obesity over 6 weeks with spironolactone 50 mg, did not appear to improve insulin sensitivity index assessed by Matsuda method. It is possible that this study was performed in metabolically healthy obesity, although the insulin sensitivity index was <5 indicating potential insulin resistance [86]. MR activation may affect IR through multiple mechanisms that include attenuation of insulin signaling in the heart, vasculature, and skeletal muscle. This may include impairment of expression of insulin receptor and substrate, decreased GLUT4 expression, abnormal phosphorylation of IRS, and activation of multiple stress kinases downstream of insulin receptor/IRS leading to the attenuation of insulin signaling [87]. Recently, caveolin-1 appears to be an additional mediator of MR action. Caveolin-1 knockout mice exhibit features of insulin resistance and oxidative stress with the effects being ameliorated by MR blockade. In humans, individuals with a specific mutation of caveolin-1 also appear to be more insulin-resistant [88].
Conclusion
Based on the central role MR plays in the pathogenesis of target organ damage, there is optimism that the use of MRA could benefit patients with a variety of cardiometabolic diseases to prevent complications. The advantages of MRA use for a broad spectrum of patients are far beyond theoretical and are supported by a vast body of data over the last 5 decades. However, there are challenges in the use of these agents. The identification of patients who may truly benefit from MRA is an important issue, as demonstrated in Treatment of Preserved Cardiac Function Heart Failure [71,89]. Additionally, hyperkalemia is a concern, particularly in patients with advanced CKD. Whether the use of nonsteroidal MRA's can minimize hyperkalemia, while allowing continued benefit of MRA is an exciting area of investigation. Quantitative whole-body labeling studies with [14C]-labeled finerenone, a novel nonsteroidal MRA, show equal distribution in heart and kidney tissues in contrast to disproportionate renal deposition for steroidal MRAs such as eplerenone or spironolactone, an aspect believed to be important in the lower incidence of hyperkalemia despite comparable IC50 (24 nM for spironolactone vs. 18 nM for finerenone) [90]. Different dose strengths of finerenone have been investigated in 823 randomized patients with type 2 diabetes mellitus (T2DM) and diabetic kidney disease receiving standard of care (i.e., ACEIs/ARBs) and either once-daily finerenone or placebo [91]. FIGARO-DKD (NCT2545049, n = 6,400) and FIDELIO-DKD (NCT2540993, n = 4,800) are 2 randomized, double-blind, placebo-controlled, parallel-group, multicenter, phase 3 studies that investigate the safety and efficacy of finerenone in the reduction of cardiovascular morbidity and mortality, and progression of CKD in subjects with T2DM and diabetic kidney disease. Apararenone, a novel nonsteroidal MRA (MT-3995), is being tested in nonalcoholic steatohepatitis (NCT2923154) and in diabetic nephropathy (NCT2676401). The Mineralocorticoid Receptor Antagonism in Diabetic Atherosclerosis study will test the utility of MR antagonism in patients with T2DM with CKD, at high risk for cardiovascular complications [92]. The co-primary efficacy end point will be percentage change in total atheroma volume in thoracic aorta and left ventricular mass at 52 weeks in patients treated with spironolactone versus placebo. Secondary outcomes include 24-h mean systolic BP, central aortic BP, and insulin resistance at 6 weeks. A novel measure in the study will be changes in candidate miRNAs that regulate expression of NR3C2 (MR gene) as well as measuring monocyte/macrophage polarization in response to therapy with spironolactone. These studies may extend the utility of MRA and make these agents attractive adjuncts to statins in the prevention of cardiometabolic complications.
Disclosure Statement
The authors would like to acknowledge the support of R01HL127422-02 awarded to Dr. Rajagopalan in this grant.
PubMed ID
