Curr Hypertens Rep (2015) 17:52 DOI 10.1007/s11906-015-0567-8

HYPERTENSION AND THE KIDNEY (RM CAREY, SECTION EDITOR)

Aldosterone and the Mineralocorticoid Receptor: Risk Factors for Cardiometabolic Disorders Rajesh Garg 1 & Gail K. Adler 1

# Springer Science+Business Media New York 2015

Abstract Preclinical studies have convincingly demonstrated a role for the mineralocorticoid receptor (MR) in adipose tissue physiology. These studies show that increased MR activation causes adipocyte dysfunction leading to decreased production of insulin-sensitizing products and increased production of inflammatory factors, creating an environment conducive to metabolic and cardiovascular disease. Accumulating data also suggest that MR activation may be an important link between obesity and metabolic syndrome. Moreover, MR activation may mediate the pathogenic consequences of metabolic syndrome. Recent attempts at reversing cardiometabolic damage in patients with type 2 diabetes using MR antagonists have shown promising results. MR antagonists are already used to treat heart failure where their use decreases mortality and morbidity over and above the use of traditional therapies alone. However, more data are needed to establish the benefits of MR antagonists in diabetes, obesity, and metabolic syndrome.

Keywords Aldosterone . Mineralocorticoid receptor . Obesity . Diabetes . Metabolic syndrome . Cardiometabolic risk . Cardiovascular disease

This article is part of the Topical Collection on Hypertension and the Kidney * Gail K. Adler [email protected] 1

Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA

Introduction Excess activity of the mineralocorticoid receptor (MR) is an important pathologic factor in hypertension and heart failure. MR antagonists are effective therapy in resistant hypertension, lowering blood pressure by about 20–25/7–10 mmHg when added on to other antihypertensive agents [1, 2]. Recently, the MR has been recognized as contributing to the pathogenesis of metabolic abnormalities that lead to increased cardiovascular morbidity and mortality. While aldosterone and the MR are key regulators of blood pressure, many of the adverse cardiovascular and metabolic effects of the MR are not mediated through changes in blood pressure. This review discusses recent advances in the role of MR physiology in metabolic disorders and summarizes the use of MR antagonists to ameliorate cardiometabolic disturbances in obesity and diabetes.

Preclinical Studies Implicating MR in the Cardiometabolic Disorders of Obesity and Diabetes Multiple animal studies have shown that MR blockade reduces cardiovascular, renovascular, and cardiometabolic disorders associated with obesity and diabetes. MR and Fat Metabolism The MR, along with the glucocorticoid receptor (GR), is involved in the conversion of preadipocytes to adipocytes [3, 4]. However, excessive MR activation contributes to the pro-inflammatory phenotype of adipose tissue. Aldosterone increases production of proinflammatory cytokines and reduces expression of insulinsensitizing factors by adipocytes and pre-adipocytes [5–7]. MR blockade reduces the pro-inflammatory phenotype of fat and increases adipose expression of insulin-sensitizing factors

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in diabetic mice and in mice fed high-fat diets [7, 5]. Further, MR blockade increases the expression of brown fat-specific transcripts, increases uncoupling protein-1 levels, and reduces autophagy in white adipose tissue of mice fed a high-fat diet, suggesting that MR has a key role in regulating the browning of white adipose tissue [8••]. MR blockade improves ectopic accumulation of fat in the liver (hepatic steatosis), reduces hepatic expression of proinflammatory cytokines, and reduces the excessive gluconeogenesis in C57BL/6 mice fed a diet high in fat and fructose [9]. Similarly, aldosterone synthase-deficient mice are protected from high-fat diet-induced increases in hepatic steatosis, adipose tissue inflammation, and hyperglycemia [10]. The lack of aldosterone improves glucose-stimulated insulin secretion, increases adiponectin, but does not prevent the insulin resistance induced by the high-fat diet [10]. While the majority of preclinical studies implicate the MR in the pathophysiology of cardiometabolic diseases, the story is complex and not fully understood. For example, mice that overexpress the human MR are unexpectedly resistant to highfat diet-induced obesity [11]. The mechanism for this protection is uncertain but appears to involve impaired local glucocorticoid signaling in adipose tissue and alterations in the M1/ M2 polarization macrophages that overexpress human MR [11]. MR and Insulin The MR and all components of the reninangiotensin-aldosterone system have multiple effects on insulin signaling; these effects were recently discussed by us in other reviews [12, 13]. Aldosterone’s major influence on insulin signaling involves aldosterone-mediated decreases in IRS-1. Aldosterone also decreases GLUT4 and GLUT2 expression in the muscle and liver, respectively, and these changes are accompanied by decreases in glucose uptake in these same tissues [12]. Finally, aldosterone may inhibit insulin secretion, further exacerbating abnormal glucose metabolism [14]. MR and the Cardiovascular and Renovascular Systems in Obesity The Zucker obese rat develops cardiac diastolic dysfunction, which is improved with treatment with low-doses of the MR antagonist spironolactone [15•]. This improvement in diastolic function is accompanied by decreases in cardiac fibrosis and by improvements in endothelium-dependent vasodilatation of the coronary arterioles without improvements in blood pressure [15•]. Moreover, consistent with data described earlier in this review, spironolactone treatment also reduces adipose tissue inflammation in these rats [15•]. However, spironolactone does not improve insulin resistance or proteinuria in the Zucker obese rat [15•]. In a different animal model, mice fed a high-fat diet were shown to develop impairments in endothelium-dependent relaxation in response to acetylcholine in isolated aortic rings [16•]. Both MR blockade and endothelial-specific MR deletion improved vascular

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function [16•]. These studies suggest a role for MR in the cardiac and vascular dysfunction associated with dietinduced obesity. MR blockade also reduces renal inflammation, decreases glomerular injury, and improves albuminuria in multiple rodent models relevant to obesity and diabetes, including the db/db, ob/ob, KKA(y), and high-fat fed C57BL/6J mice models, and the streptozotocin-treated uninephrectomized rat [17•, 5, 7, 18]. The specific cell types and mechanisms involved in MR-mediated injury are under investigation. High-fat fed C57BL/6J mice develop renal injury secondary to enhanced activity of the MR/Rho/Rho-kinase pathway and inflammation [18]. In the podocyte, MR-mediated injury is enhanced by increases in the activity of guanosine triphosphate-binding protein (GTP) Rac1, a Rho-family small GTPase, Rasrelated C3 botulinum toxin substrate [19]. Myeloid cell MR potentiates renal inflammation and glomerular injury, and deletion of the MR gene from myeloid cells reduces injury in mouse models of glomerulonephritis [20]. Factors That may Modulate MR Activity The increase in MR activity associated with obesity and diabetes likely involves multiple mechanisms, including changes in the amount of either MR ligand–aldosterone or cortisol—systemically or locally, changes in the amount of MR protein, and changes in the activity or levels of proteins or factors affecting MR activity. The MR is a nuclear steroid receptor that regulates gene transcription. In addition, MR activation results in rapid, nongenomic effects, including effects on intracellular calcium, oxidative stress, and phosphorylation of kinases [21]. MR is activated by both cortisol and aldosterone with approximately equal efficacy. In some tissues, such as the kidney, the MR is found in association with an enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) 2, which converts the active cortisol to inactive cortisone [22]. In these tissues, aldosterone is the primary ligand for MR. In contrast, cortisol is thought to be the primary ligand for MR in tissues lacking 11β-HSD2, due to the 100 to 1000 times higher blood concentrations of cortisol versus aldosterone. Many tissues express 11β-HSD1 which converts the inactive cortisone to cortisol, regulating the local concentration of cortisol [22]. Increases in 11βHSD1 activity will result in increases in cortisol at least locally, and multiple investigators have proposed 11β-HSD1 as a potential link between obesity and cardiometabolic disease [23]. Hexose-6-phosphate dehydrogenase generates NADP H, a key cofactor for 11β-HSD1 enzyme activity. Adipocyte overexpression of hexose-6-phosphate dehydrogenase leads to increased local production of corticosterone and cardiometabolic abnormalities [24]. The relative contributions of GR and MR activation to the cardiometabolic phenotype remain to be determined and will likely vary depending on the specific model under study.

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In animal models of obesity and diabetes (e.g., ob/ob, db/ db, and KKA(y) mice), there are increases in circulating aldosterone levels, increases in tissue expression of MR, and/or increases in activity of GTP Rac1, which induces the actions of MR independent of ligand binding [5, 18, 7, 17•]. The mechanism for the association of increased aldosterone with obesity is an area of active investigation. Adipose tissue itself could increase aldosterone through the production of adipocyte-derived aldosterone secretagogues [25]. Further, all components of the renin-angiotensin-aldosterone system are expressed in adipose tissue, including adipocyte production of aldosterone synthase, which could affect at least local aldosterone levels [26]. It is possible that other adipocytederived factors could directly increase adrenal aldosterone production [25]. Recently, cholesteryl ester-transfer protein inhibitors were shown to increase aldosterone production in human adipocytes [27], providing one possible mechanism for why aldosterone levels were increased in the ILLUMINATE trial in individuals receiving torcetrapib [28]. Other receptors (e.g., epidermal growth factor receptor (EGFR), GR, and AT1R) affect MR activity [29–31] and, recently, we showed that ERα inhibits MR’s transcriptional functions [32••]. The MR also interacts with the caveolaeassociated proteins caveolin and striatin as well as transcriptional co-activators and co-repressors [21, 33]. For example, the recently identified tesmin interacts with the MR-aldosterone, not MR-cortisol, complex to selectively increase the transcriptional activity of MR-aldosterone by two-fold [33]. Thus, there are multiple mechanisms that may lead to increased MR activity and these mechanisms may vary depending on the specific tissue and cell. The study of cell-specific MR null mice will shed more light on the role of MR in specific organ systems [34]. For example, this approach was used to demonstrate that the endothelial MR mediates endothelial dysfunction in a mouse model of diet-induced obesity [16•]. In other non-obese mouse models, the myeloid MR has been shown to mediate renal injury and cardiac fibrosis and remodeling [35, 20, 36, 37]. Given the multiple mechanisms involved in MR activation, it is likely that the specific cardiovascular, renovascular, and metabolic benefits of MR antagonist therapy will vary depending on the animal model under study. Consuming a diet high in sodium markedly and significantly increases renal and cardiac injury in animal models of aldosterone-mediated damage [38]. This has led to the concept that excess aldosterone levels or MR activity, in the setting of a high-sodium intake, are particularly damaging to the vascular system. Whether increases in dietary sodium exacerbate MR-mediated cardiometabolic damage in obesity is not established; however, dietary sodium restriction reduced adipose tissue inflammation and improved production of insulinsensitizing adipokines in the db/db mouse [39]. Further, studies into environmental factors that may modulate MRmediated damage in specific clinical conditions are warranted.

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Evidence Implicating MR in the Cardiometabolic Disorders of Obesity and Diabetes in Humans MR in Human Obesity and Metabolic Syndrome Evidence suggesting MR-mediated injury across the spectrum of cardiometabolic disorders in humans is summarized in Fig. 1. Increases in body mass index are associated with increases in circulating aldosterone levels [40], increases in tissue expression of 11β-HSD1 [23] and, in Chinese overweight adolescents, increases in the level of Rac1 expression in monocytes [41]. Weight loss is associated with decreases in aldosterone [42]. As first suggested by Goodfriend and colleagues, the degree and location of adiposity appears to affect the relationship between aldosterone and adiposity [43]. They demonstrated an association between visceral adipose tissue and aldosterone levels [43]. A more recent study in HIV-infected women also showed an association between visceral adipose tissue and aldosterone [44]. In another recent study of HIVinfected men and women, aldosterone levels on a low-sodium diet were significantly higher in individuals with above median, versus below median, visceral adiposity, irrespective of BMI [45]. Excess MR activity is implicated in the pathophysiology of metabolic syndrome and in the cardiovascular and renovascular complications associated with this syndrome. Population studies performed in Germany [46] and in the USA in Mississippi [47] and Minnesota [48•] demonstrated a positive association between aldosterone levels and the metabolic syndrome. In the Minnesota population, aldosterone also predicted hypertension, central obesity, chronic renal disease, increased triglyceride levels, atrial fibrillation, and concentric left ventricular hypertrophy [48•]. Similarly, physiologic studies showed a positive association between aldosterone dysregulation and metabolic syndrome in normotensive and hypertensive individuals studied on controlled sodium diets [49]. Greater degrees of aldosterone dysregulation also predicted lower renal vascular function and higher Framingham cardiovascular risk score [50]. Thus, it is possible that altered aldosterone production may contribute to the effects of visceral adiposity on blood pressure and glucose homeostasis, leading to metabolic syndrome in viscerally obese individuals. We and others demonstrated the presence of high aldosterone levels in overweight and obese individuals irrespective of visceral obesity [40]. We also showed an association between aldosterone and indices of insulin resistance [51]. Further, primary hyperaldosteronism is associated with an increase in insulin resistance that is reversed after treatment of the hyperaldosteronism [52]. Weight loss is associated with a significant decrease in aldosterone levels that is associated with decreases in C-reactive protein, leptin, insulin, homeostasis assessment of insulin resistance (HOMA), and increases in adiponectin along with beneficial cardiac effects [53]. Favorable changes in obesity-related factors are associated with

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Fig. 1 Potential role for MRmediated injury across the spectrum of cardiometabolic disorders in humans. Aldo aldosterone, BP blood pressure, CFR coronary flow reserve, LVH left ventricular hypertrophy, MRA MR antagonist

reductions in aldosterone in young adults with or without metabolic syndrome [53]. Although, the MR is implicated in obesity-related complications, there are relatively few studies examining the effects of MR antagonists in obesity. In one study involving healthy, normotensive humans with obesity, spironolactone reduced blood pressure but did not affect brachial artery endothelial function or insulin resistance [54]. Another study again showed no overall effect of MR antagonist on brachial artery reactivity in obese individuals, but did show that higher body mass index correlated with a greater improvement in endothelial function with MR antagonist treatment [55]. Further, 50 mg spironolactone versus placebo for 6 weeks in obese individuals improved a hippocampal-dependant task—associate learning, which involves remembering that two previously unrelated items are associated with each other [56]. This result is consistent with preclinical studies suggesting that the hippocampal MR has a role in hippocampal memory modulation [57]. Given the wide range of MR’s effects on the cardiovascular and renovascular systems, the brain, and on metabolism, further studies examining effects of MR antagonists in obesity are warranted. In designing such studies, it is important to recognize that aldosterone levels tend to return to pretreatment levels after about 3 months of angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy. Thus, using ACEI or ARB therapies to block aldosterone production are unlikely to provide reliable evidence regarding the long-term effects of the MR in cardiometabolic disease. Since the MR can be activated through multiple mechanisms, not just increases in aldosterone, it will be important to design studies that reduce MR activity regardless of the activating mechanism.

MR and Diabetic Complications in Humans High aldosterone levels are associated with myocardial extracellular matrix expansion in patients with type 2 diabetes mellitus suggesting a role of aldosterone in early myocardial remodeling [58]. Moreover, multiple studies have shown that add-on therapy with an MR antagonist reduces albuminuria in humans with type 2 diabetes on an ACEI, ARB, or renin inhibitor [59–61]. Further, low-dose spironolactone was recently shown to exert significant lowering of blood pressure and urinary albumin creatinine ratio in high-risk patients with resistant hypertension and type 2 diabetes [62]. To evaluate the effect of MR antagonism on cardiovascular disease in type 2 diabetes, we conducted a double-blind randomized controlled study in patients with type 2 diabetes, without coronary heart disease, who were well controlled for all traditional risk factors on optimal recommended therapy including an ACEI. The addition of 25 mg spironolactone, as compared to hydrochlorothiazide or placebo, significantly improved coronary flow reserve [63••], a measure of coronary microvascular function whose impairment predicts increased risk of cardiovascular mortality in type 2 diabetes [64]. This evidence points to a beneficial effect of MR antagonism in the prevention of diabetic complications. Given the findings that MR antagonist therapy improves albuminuria and improves coronary microcirculatory function in diabetic patients, there is a need for large-scale clinical trials to determine the effects of add-on MR antagonist therapy on hard clinical endpoints—progression of renal disease and cardiovascular morbidity and mortality in patients with type 2 diabetes. MR and Cardiovascular Disease in Humans Studies, which are not specifically focused on obesity and diabetes,

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continue to support the concept that excess MR activation, independent of its effects on blood pressure, contributes to cardiovascular and renovascular disease. Patients with adrenal lesions leading to primary overproduction of aldosterone, as compared to individuals with essential hypertension, have increased prevalence of cardiovascular events (atrial fibrillation, nonfatal myocardial infarction, heart failure, stroke) as well as increased prevalence of metabolic syndrome and abnormal glucose metabolism [65–67, 68•, 69]. Large-scale clinical trials of patients with heart failure have consistently demonstrated strong cardiovascular benefits of adding MR antagonists to standard therapy [70–72]. Recently, post hoc analysis of the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial also revealed a substantial benefit of the MR antagonist eplerenone on major cardiovascular events in the subset of patients with mild heart failure, over and above high doses of standard therapies [73]. Similar observations were made in another study that enrolled patients with NYHA classes I to II HF and treated them with spironolactone [74]. Spironolactone improved diastolic cardiac function in patients with heart failure with preserved ejection fraction [75]. Further, high doses of spironolactone in acutely decompensated chronic heart failure were shown to be safe relative to serum potassium levels and to exert a positive impact on the resolution of congestion [76]. In contrast to these studies showing benefits on cardiovascular morbidity and/or mortality with MR antagonist, spironolactone was not found to improve the composite endpoint of time to cardiovascular death, aborted cardiac arrest, or hospitalization for heart failure in the 3445 patients with symptomatic heart failure and preserved ejection fraction who were studied in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) clinical trial [70]. However, post hoc analysis of this trial demonstrated marked differences between patients recruited from the Americas versus those recruited from Russia and Georgia [77]. The rate of occurrence of composite events in patients randomized to placebo was much higher in those recruited in the Americas than in those from Russia and Georgia. Spironolactone lowered the event rates in patients from the Americas; thus, raising the possibility that spironolactone may eventually be proven to be clinically useful in some patients with heart failure and preserved ejection fraction [77]. One concern about using MR antagonists in heart failure patients relates to their potential to cause high serum creatinine and hyperkalemia. However, analysis of the EMPHASIS-HF trial showed that the addition of eplerenone was associated with survival benefit in spite of worsening of renal function and a higher risk of hyperkalemia [78]. Similarly, analysis of the Randomized Aldactone Evaluation Study (RALES) and the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trials showed

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benefits of MR antagonist irrespective of hyperkalemia [79, 80]. Eplerenone was both efficacious and safe when carefully monitored, even in subgroups of patients at high risk of developing hyperkalemia or worsening of renal function [81]. Spironolactone 25 mg daily also reduced the risk of both cardiovascular morbidity and mortality among oliguric or anuric hemodialysis patients without causing serious risk of hyperkalemia [82••].

Conclusions Overall, data suggest that increased MR activity contributes to adverse metabolic, cardiovascular, cerebrovascular, and renovascular outcomes. Accumulating preclinical and clinical data suggest that obesity is associated with increased MR activation, raising the possibility that excess MR activation is a link between obesity and cardiometabolic disorders. Given the multiple mechanisms of MR activation, it is likely that the degree and effects of MR activation will vary depending on the tissue type and disease state. The MR antagonists are clearly useful in conditions like resistant hypertension and many types of heart failure, but their role in obesity and diabetes remains to be established. More studies are needed to identify those groups of patients who will benefit from MR antagonist therapies. Acknowledgments This work was supported in part by NIH grant K24 HL103845 Compliance with Ethics Guidelines Conflict of Interest Gail K. Adler declares personal fees from Pfizer, Japan. Rajesh Garg declares no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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