Aldosterone and the mineralocorticoid receptor

Aldosterone is a steroid hormone and downstream effector of angiotensin II in the renin–angiotensin–aldosterone system (RAAS). Aldosterone is mainly synthesized in the adrenal cortex but is also expressed in the brain, heart, vasculature, and adipose tissues, leading to local autocrine and/or paracrine effects. The mineralocorticoid receptor (MR) is found in both epithelial and nonepithelial tissues, such as the kidney, colon, brain, heart, vasculature, and adipose tissue, and binds mineralocorticoids and glucocorticoids with equal affinity. In addition to the well-known effects of aldosterone in the kidney, including sodium reabsorption with concomitant potassium and hydrogen ion excretion that leads to blood pressure elevation, more widespread effects of aldosterone include sympathetic nervous system activation and increased oxidative stress, with inflammation, remodeling, apoptosis, and fibrosis of the cardiovascular tissues. The biological activity of MR is mediated by the differential expression of proteins resulting from the interactions of multiple complicated transcriptional and translational mechanisms [1]. In addition to the genomic effects of aldosterone, aldosterone also has nongenomic effects, whereby it acts rapidly on target tissues within several minutes [2].

Primary aldosteronism

Primary aldosteronism (PA) is an endocrine form of hypertension that was first described by Jerome Conn in 1955 in a young woman with an adrenocortical adenoma [3]. The characteristic features of PA are hypertension, increased aldosterone, and suppressed renin. Although PA was considered to be a rare disease associated with hypokalemia, which was a requisite for pursuing diagnostic work-up, it is now widely accepted that PA is the most common form of endocrine hypertension, with the majority of patients displaying normokalaemia [4].

The estimated prevalence of PA is 4–6% among patients with hypertension in primary care, ~10% in specialized hypertensive clinics, and 20% in patients with resistant hypertension [5], which is defined as persistent hypertension with concomitant use of three different antihypertensive drugs, including a diuretic [6].

Patients with PA have an increased risk of cardiovascular and cerebrovascular events, heart [7, 8] and renal diseases [8, 9], diabetes mellitus, and metabolic syndrome [8, 10] and a reduced quality of life [11, 12]. These observations indicate the importance of an early diagnosis and appropriate treatment of PA with specific surgical or medical treatment, as described below.

Aldosterone and the MR in cardiovascular complications in non-PA patients

Clinical studies have shown a relationship between plasma aldosterone levels and left ventricular hypertrophy (LVH), renal injury, vascular disease [13,14,15,16,17,18], atrial flutter and atrial fibrillation [19], and structural and functional alterations of medium-caliber arteries [20, 21], as well as microcirculation injuries and alterations in endothelial function [22,23,24,25,26,27,28].

In addition, the beneficial effects of pharmacological MR blockade have been clearly demonstrated in cardiovascular disease (CVD) and chronic kidney disease (CKD). The RALES [29], EPHESUS [30], and EMPHASIS-HF [31] studies have shown the benefits of MR antagonists in patients with moderate-to-severe congestive heart failure, suggesting that excessive activation of MR is involved in the pathophysiology of heart failure. Serum aldosterone levels were elevated in patients with chronic atrial fibrillation and decreased rapidly after electrical cardioversion [32]. MR antagonists showed beneficial effects in dialysis patients [33] or those who underwent cardiac surgery [34], with a reduction in the occurrence of atrial fibrillation. MR antagonists reduced the risk of rhythm disorders and cardiac arrest in patients with heart failure [35] or myocardial infarction [36]. In addition, meta-analyses showed a substantial antiproteinuric effect and a possible major renoprotective effect of MR antagonists [37, 38].

MR-associated hypertension

Resistant hypertension is associated with a poor prognosis because of organ damage caused by prolonged suboptimal blood pressure control and has associations with diabetes mellitus, CKD, and obesity [39, 40]. Resistant hypertension is increasingly common in clinical practice, and treatment focuses on maximizing the doses of antihypertensive drugs and adding drugs with complementary mechanisms of action, including a combination of calcium channel blockers, angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors, and diuretics [6] (Table 1). The concomitant use of an MR antagonist with other antihypertensives has been shown to improve blood pressure control in some patients with resistant hypertension (Table 2) [41,42,43], known as MR-associated hypertension [44] (Fig. 1).

Fig. 1
figure 1

Mineralocorticoid receptor-associated hypertension. ACE angiotensin-converting enzyme, AT1R angiotensin II type-1 receptor, 11β-HSD2 11β-Hydroxysteroid dehydrogenase type 2, 11β-HSD1 11β-Hydroxysteroid dehydrogenase type 1, MR mineralocorticoid receptor

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Table 1 Drug therapy for resistant or poorly controlled hypertension
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Table 2 Changes in home systolic blood pressure during the final visit of each treatment period
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MR-associated hypertension is classified into two subtypes, one with a high plasma aldosterone level and the other with a normal aldosterone level [44]. In the former subtype, the plasma aldosterone level is relatively high (usually ≥ 150 pg/ml) in proportion to the plasma renin activity. It is logical that MR antagonists are effective in the treatment of resistant hypertension with elevated plasma aldosterone levels; however, it is notable that several subsets of patients with resistant hypertension and normal plasma aldosterone levels can also be effectively controlled by add-on therapy with MR antagonists [44].

MR-associated hypertension with elevated plasma aldosterone levels

PA is a typical type of MR-associated hypertension with elevated plasma aldosterone levels. In addition to PA, an elevated plasma aldosterone concentration has been implicated in several other forms of hypertension.

Aldosterone breakthrough (escape) phenomenon

Renin–angiotensin system (RAS) inhibitors reduce plasma aldosterone levels in the initial treatment phase, but aldosterone levels may later reach, or sometimes exceed, pretreatment values [45, 46]. This phenomenon is known as “aldosterone breakthrough” or “aldosterone escape” and may limit the beneficial effects of RAS inhibitors. It has been shown that aldosterone breakthrough is independent of RAS inhibitor dosage [47] and does not differ with ACE inhibitor or ARB treatment [48]. Aldosterone breakthrough may be associated with cardiovascular and renal morbidity. Indeed, it has been reported to reverse the beneficial effects of an ACE inhibitor on LVH [49], and the improvement in functional capacity noted in patients with congestive heart failure treated with an ACE inhibitor was decreased when aldosterone breakthrough was present [50]. In patients with CVD and CKD exhibiting aldosterone breakthrough, the addition of an MR antagonist significantly restored the organ-protective effects of RAS inhibitors without changing blood pressure [51, 52]. These data suggested that inappropriately elevated plasma aldosterone levels play a critical role in the pathogenesis of CVD and CKD in high-risk patients who are treated with a RAS inhibitor in the long term.

Aldosterone-associated hypertension

Clinical and biochemical evidence has indicated the existence of a gray zone between patients with essential hypertension and PA, leading to a hypothesis that there is a continuum, which includes essential hypertension, low-renin hypertension, and bilateral idiopathic hyperaldosteronism (IHA) [53, 54]. Patients with an elevated aldosterone-to-renin ratio (ARR) and plasma aldosterone level are more likely to have resistant hypertension than are patients with essential hypertension, even when they do not meet the diagnostic criteria for PA [55]. Such hypertension is defined as “aldosterone-associated hypertension” and is likely to be a resistant type of hypertension.

Obesity

Aldosterone excess has been implicated in obesity-related disorders [56, 57]. Indeed, obese women have been reported to have higher aldosterone levels than age-matched lean female controls, with aldosterone levels in these two groups becoming comparable after weight loss in the obese group [57, 58]. A correlation between plasma aldosterone levels and fat mass was observed in normotensive women, raising the possibility that there is an effect of adipose tissue on aldosterone production [57]. Furthermore, aldosterone production was shown to be exclusively correlated with subcutaneous white adipose tissue [59]. In addition, leptin released from adipocytes is directly associated with the release of aldosterone from adipose tissue [60]. Interestingly, secretory products from isolated human adipocytes strongly stimulated aldosterone secretion in human adrenocortical cells, indicating that human adipocytes secrete aldosterone-releasing factors [56, 61]. These data may suggest that increased aldosterone secretion from adipose tissue and/or the adrenal gland via adipocyte-derived aldosterone-releasing factors may play an important role in MR-associated hypertension with elevated plasma aldosterone levels in the context of obesity.

Obstructive sleep apnea

Obstructive sleep apnea (OSA) is the secondary condition most frequently associated with resistant hypertension [62]. Taking into account moderate and severe forms of OSA, the prevalence of OSA among patients with resistant hypertension ranges from 45% to 80% and has been reported to be up to 95% [62,63,64,65,66]. There is growing evidence to support the role of aldosterone in OSA; specifically, high levels of serum aldosterone appear to predispose resistant hypertensive patients to OSA through a proposed mechanism of peripharyngeal fluid retention [67]. Medical management using spironolactone, an MR antagonist, improved OSA symptoms in patients with resistant hypertension [68]. In addition, both surgical and medical treatments for PA were associated with improvements in OSA severity [69].

Sleep disorders

A growing number of epidemiologic studies have indicated that shift workers, long-distance transmeridian flight crews, and patients with sleep disorders show a higher than average prevalence of hypertension-derived CVD [70,71,72]. Moreover, a clinical trial demonstrated an increase in blood pressure in healthy volunteers following placement in an environment that induced circadian rhythm abnormalities [73]. Melatonin is involved in the physiological control of circadian rhythms, as well as in the activities of hormones and cytokines [74,75,76]. Most sleep disorders are associated with a disrupted circadian rhythm, in which the reduction of melatonin secretion leads to biological clock dysfunction. Mice lacking the core clock genes Cry1 and Cry2 displayed abnormalities of circadian rhythm and salt-sensitive hypertension due to chronic overproduction of aldosterone by the adrenal gland [77]. These data suggest that sleep disorders are associated with the pathogenesis of MR-associated hypertension.

MR-associated hypertension with normal plasma aldosterone levels

Diabetes mellitus

Hypertension is present in more than 50% of patients with diabetes mellitus and contributes significantly to both microvascular and macrovascular diseases in diabetes mellitus. ACE inhibitors or ARBs are recommended as first-line antihypertensive therapies for diabetes mellitus, and both drugs have been shown to have renoprotective effects [78, 79]. However, blood pressure control using ACE inhibitors or ARBs is often difficult in patients with diabetes mellitus, and treatment with multiple drugs with different mechanisms is necessary for blood pressure reduction [80]. Indeed, spironolactone has been shown to have beneficial effects in patients previously treated with ACE inhibitors or ARBs [81, 82]. Furthermore, the addition of spironolactone to a regimen that includes a maximal dose of an ACE inhibitor showed greater renoprotection than the addition of an ARB in the context of diabetic nephropathy, indicating that MR is overactivated in selected diabetic patients, even in the absence of high plasma aldosterone levels [79, 83].

Chronic kidney disease

There is considerable evidence to suggest that RAAS plays an important role in the pathogenesis and progression of renal diseases. Blockade of RAAS by ACE inhibitors or ARBs is considered the most effective therapy for slowing the progression of CKD. Therefore, ACE inhibitors or ARBs have become first-line therapies for the management of patients with proteinuric CKD in a manner similar to diabetes mellitus. It is speculated that a decrease in sodium excretion may cause extracellular volume expansion to decrease the levels of renin and aldosterone in CKD. However, elevated aldosterone levels have been demonstrated in both animals with kidney dysfunction [84] and patients with CKD [85], which could be explained by multiple factors that promote hyperaldosteronism in CKD [86]. Many CKD patients have obesity and/or OSA, conditions associated with elevated aldosterone levels. CKD patients often have hyperkalemia, which directly stimulates aldosterone secretion. Furthermore, elevated renin secretion due to renal ischemia or glomerulonephritis may increase aldosterone levels via increased angiotensin II production. Therefore, the addition of an MR antagonist to an ACE inhibitor or ARB is recommended because of the possible activation of MR, in addition to aldosterone breakthrough caused by ACE inhibitors or ARBs in CKD [83, 87, 88]; indeed, beneficial effects of MR antagonists in CKD have been reported [38, 86, 89]. Accordingly, it is suggested that direct activation of the MR in pathological states is associated with CKD, even in the absence of a prominent increase in plasma aldosterone levels [44].

Polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common disease affecting ~10% of women of reproductive age. PCOS is characterized by oligoanovulation and clinical/biochemical signs of hyperandrogenism, and although several phenotypes have been described, they share a common feature of insulin resistance [90]. Beyond reproductive disorders, even at an early stage, PCOS patients have a clustering of cardiovascular risk factors, such as hypertension, insulin resistance, obesity, diabetes mellitus, dyslipidemia, endothelial dysfunction, and low-grade chronic inflammation [91]. Serum aldosterone levels and ARR, though normal and not consistent with PA, were reported to be higher in PCOS women than in age- and body mass index-matched healthy controls and to correlate with blood pressure and some metabolic and cardiovascular markers [92, 93]. Insulin resistance is considered a cause of the increased aldosterone levels, even though they remain within normal limits, in PCOS [44].

MR overstimulation by other factors

Glucocorticoids

The affinity of MR for aldosterone and glucocorticoids is similar, but the plasma glucocorticoid level is 1000 times greater than that of aldosterone [94]. Although 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) transforms glucocorticoids into inactive metabolites, several studies have indicated that physiological levels of glucocorticoids activate MR under pathophysiological conditions [95]. Furthermore, high serum cortisol levels are observed in Cushing’s syndrome, and glucocorticoids are increased in subjects with obesity, diabetes mellitus, and inflammation [96]. These data suggest that inappropriate activation of MR might be induced by glucocorticoids during the development of lifestyle-related diseases [97]. Consistent with this hypothesis, glucocorticoid-induced MR activation mediates renal injury in high-salt-treated adrenalectomized rats [94].

RAC-1

It has been shown that excessive salt intake induces renal injury, which is ameliorated by blockade of MR, suggesting that renal MR is pathologically activated even when the plasma aldosterone level is suppressed. A recent study showed that the small guanosine triphosphatase (GTPase) Rac1 increases the nuclear translocation of MR, resulting in enhanced MR activity [98, 99]. Rac1 is activated by several factors, including cytokines [100], mechanical stress [101], dietary high-salt intake [102], and oxidative stress [103], all of which are risk factors for CVD and CKD. Therefore, it is considered that during the development of CVD and CKD, MR is activated by Rac1-dependent pathways, which further increases the risk of CVD and CKD.

Alteration of MR status

MR activation by aldosterone-independent mechanisms has been implicated in some pathophysiological conditions. These mechanisms could involve alteration of MR activity, which may cause MR-associated hypertension. These mechanisms were reported to include increases in MR gene transcription, MR sensitivity, MR stabilization, and/or MR overstimulation via activating mutations of the MR gene [44].

Management of MR-associated hypertension

Surgical adrenalectomy

In patients with unilateral PA, adrenalectomy is the first-choice procedure. This procedure is now primarily performed laparoscopically, which has resulted in a lower complication rate and shorter hospitalizations [104,105,106]. After surgery, a biochemical cure may be achieved; however, the postoperative blood pressure normalization rate is ~30% due to the duration and severity of hypertension and the presence of essential hypertension.

Data from direct comparisons of surgical adrenalectomy and medical treatment with MR antagonists in the treatment of PA are limited due to bias related to the varied demographics and clinical presentation of unilateral versus bilateral disease. However, a small number of studies have shown better long-term cardiovascular outcomes, renal outcomes, and mortality with surgical adrenalectomy than with MR antagonist therapy [107,108,109]. In patients with unilateral PA who are willing and able to safely undergo surgery, adrenalectomy may be recommended as the preferred treatment approach.

Dietary sodium restriction

Because MR-associated hypertension is a form of salt-sensitive resistant hypertension, dietary sodium restriction should be encouraged in patients with both PA and MR-associated hypertension. Restriction of dietary sodium intake can result in volume contraction, leading to an increase in both renin and angiotensin II. Increased angiotensin II leads to decreased distal sodium delivery, thereby limiting the pathologic consequences of aldosterone-MR-epithelial sodium channel (ENaC)-mediated distal sodium reabsorption.

MR antagonists

Lifelong MR antagonist therapy is recommended for patients with bilateral PA, as well as those with unilateral PA who are unable to or unwilling to undergo surgical adrenalectomy. MR antagonists decrease ENaC-mediated sodium reabsorption and consequent volume expansion and reduce potassium and hydrogen ion excretion, subsequently leading to a substantial reduction in blood pressure (or a decrease in antihypertensive medication) and an improvement in potassium balance.

As a therapeutic approach for resistant hypertension with high plasma aldosterone levels, MR antagonists are recommended as first-line drugs [44]. In medical treatment for resistant hypertension, a combination of a calcium channel blocker, an ARB or ACE inhibitor and a diuretic is generally used [6]. Furthermore, when the target blood pressure cannot be achieved using these three drugs, additional administration of an MR antagonist is recommended (Table 1) [6]. In particular, ARBs or ACE inhibitors are frequently used as first-line drugs to control hypertension in patients with MR-associated hypertension, including obesity, diabetes mellitus, CKD, and PCOS [87, 88]. Based on the pathogenesis of MR-associated hypertension, MR antagonists should be given as an add-on agent for the treatment of resistant hypertension with normal plasma aldosterone levels.

Regarding individual MR antagonists, spironolactone is a nonselective, competitive MR antagonist that is structurally similar to progesterone and metabolized to active metabolites in the liver. Additionally, spironolactone also acts as an antagonist to the androgen receptor, a weak antagonist to the glucocorticoid receptor and an agonist to the progesterone receptor. These receptor-mediated actions also result in adverse effects of spironolactone, including hyperkalemia, hyponatremia, gynecomastia, impotence, menstrual disturbances, hirsutism, and decreased libido, which are regarded as clinically relevant problems.

Eplerenone is derived from spironolactone and is considered a selective MR antagonist that has limited cross-reactivity for the androgen and progesterone receptors and thus lacks many of the significant sexually related adverse effects known to be associated with the use of spironolactone. However, its affinity for MR is low, and it exhibits weak MR antagonism. In Japan and the United States, eplerenone is contraindicated in hypertensive patients with diabetes mellitus and concomitant albuminuria, microalbuminuria, or proteinuria or in patients with a creatinine clearance of <50 mL/min due to the considerable risk of increased serum K+ levels seen in clinical studies [110, 111].

Esaxerenone is a novel oral, nonsteroidal, and selective MR antagonist that undergoes hepatic metabolism and has a long half-life. The MR affinity of esaxerenone is 4- and 76-fold greater than that of spironolactone and eplerenone, respectively, and the half-maximal inhibitory concentration (IC50) of esaxerenone for the transcriptional activity of human MR is 3.7, compared with 66 and 970 nmol/L for spironolactone and eplerenone, respectively [112]. Recently, the antihypertensive activity of esaxerenone 5 mg/day was shown to be superior to that of eplerenone 50 mg/day in a double-blind randomized Phase 3 study [113].

Conclusion

Hypertension in which increased MR activity is associated with blood pressure elevation and MR antagonists are effective in reducing blood pressure is considered to be MR-associated hypertension [44]. MR-associated hypertension is classified into two subtypes, one with high plasma aldosterone levels, which includes PA, and the other with normal aldosterone levels. In patients with unilateral PA, adrenalectomy may be the first-choice procedure, while in patients with bilateral PA, as well as those with unilateral PA who are unable to or unwilling to undergo adrenalectomy, MR antagonist therapy may be recommended. In addition, in patients with other types of MR-associated hypertension with high aldosterone levels, MR antagonists may be selected as a first-line therapy; in those with normal aldosterone levels, ARBs or ACE inhibitors are used as a first-line therapy, and MR antagonists may be recommended as an add-on agent. Because MR antagonist therapy may be effective as a first-line or add-on agent in these patients, an attempt to recognize these conditions may be required. Furthermore, future studies are required to investigate the pathogenesis and management of MR-associated hypertension in more detail to improve the clinical outcomes of patients with MR-associated hypertension.