Abstract
Primary aldosteronism, or Conn syndrome, is the most common endocrine cause of hypertension. It is associated with a higher risk of cardiovascular, metabolic and renal diseases, as well as a lower quality of life than for hypertension due to other causes. The multi-systemic effects of primary aldosteronism can be attributed to aldosterone-mediated activation of the mineralocorticoid receptor in a range of tissues. In this review, we explore the signalling pathways of the mineralocorticoid receptor, with a shift from the traditional focus on the regulation of renal sodium–potassium exchange to a broader understanding of its role in the modulation of tissue inflammation, fibrosis and remodelling. The appreciation of primary aldosteronism as a multi-system disease with tissue-specific pathophysiology may lead to more vigilant testing and earlier institution of targeted interventions.
Introduction
Primary aldosteronism (PA), or Conn syndrome, is the most common endocrine cause of hypertension and is characterized by the autonomous production of the mineralocorticoid aldosterone, affecting 5–15% of hypertensive patients in the primary care setting (Monticone et al. 2018, Libianto et al. 2020) and up to 30% in people with resistant hypertension (Kayser et al. 2016). However, there is a large discrepancy between estimates of prevalence and actual rates of diagnosis. Screening rates are often ~1–2%, even in populations who are at high risk of having PA, e.g. resistant hypertension (Jaffe et al. 2020) or hypertension with concurrent hypokalaemia (Hundemer et al. 2022). Even in patients with onset of hypertension <40 years, the median duration of hypertension at the time of diagnosis of PA was 10.5 years (3.5–18 years) (Alam et al. 2021). It is therefore not surprising that less than 0.1% of 1.1 million Canadian adults with hypertension (Liu 2021) and less than 0.1% of an Australian primary care hypertensive population received a diagnosis of PA (Yang et al. 2018).
PA is potentially curable by adrenalectomy in patients with a unilateral aldosterone-producing adrenal adenoma or can be effectively treated with mineralocorticoid receptor (MR) antagonists (MRAs). Targeted treatment of PA offers benefits above and beyond blood pressure control by mitigating the systemic effects of aldosterone-mediated MR activation (Fig. 1). In this review, we explore the spectrum of clinical manifestations of PA and their molecular basis with a shift from the traditional focus on the MR as a regulator of renal sodium–potassium exchange to a broader understanding of its role in the modulation of tissue inflammation, fibrosis and remodelling in the cardiorenal system, as well as roles in adipose tissue and brain. The appreciation of PA as a multi-system disease with tissue-specific pathophysiology that can be mitigated by MR blockade may lead to more vigilant testing and earlier institution of targeted interventions for millions of affected patients around the world.
Multisystemic consequences of primary aldosteronism and targeted treatment. CV, cardiovascular; LDL, low density lipid; LV, left ventricular; Na+, sodium.
Citation: Journal of Endocrinology 259, 1; 10.1530/JOE-22-0249
Primary aldosteronism: a multisystem disease
End-organ damage caused by inappropriate MR activation is particularly devastating in the cardiovascular system. In a meta-analysis of 31 studies including 3838 patients with PA and 9284 patients with essential hypertension, patients with PA had a significantly higher risk of atrial fibrillation (odds ratio, OR 3.52), stroke (OR 2.58), heart failure (OR 2.05), left ventricular hypertrophy (OR 2.29) and coronary artery disease (OR 1.77) at a median of 8.8 years after diagnosis (Monticone et al. 2018). The increased incidence of cardiovascular events in people with PA was demonstrated in a retrospective cohort study of 602 people with PA, which found that patients receiving inadequate MRA therapy experienced more cardiovascular events (adjusted hazard ratio, HR 2.83) and higher rates of mortality (adjusted HR 1.79) than the matched cohort of 41,853 patients with essential hypertension (Hundemer et al. 2018). Even in a population-based cohort, the incidence of cardiovascular diseases was higher in people with biochemical markers of aldosterone excess (Hu et al. 2021). Cardiac MRI has demonstrated that pathological aldosterone excess increased extracellular myocardial matrix and intracellular mass in patients with PA, suggesting increased interstitial fibrosis, even following adjustment for mean blood pressure (Redheuil et al. 2020). This is consistent with the finding of more diffuse blood pressure-independent myocardial fibrosis in patients with PA compared to matched patients with essential hypertension (Freel et al. 2012). At the microvascular level, endothelial function is impaired in PA with reduced reactive hyperaemia and flow-mediated vasodilation (Kishimoto et al. 2018). Circulating biomarkers of endothelial dysfunction, including von Willebrand factor (vWF), intercellular adhesion molecule 1 (ICAM-1) and oxidized low-density lipoprotein (ox-LDL) have also been found to be higher in patients with PA compared to those with essential hypertension matched for age, sex, blood pressure and duration of hypertension (Liu et al. 2014).
In the kidney, aldosterone excess stimulates sodium reabsorption and volume expansion, thereby increasing renal perfusion pressure together with glomerular hyperfiltration (Ribstein et al. 2005), resulting in a higher mean eGFR in hypertensive patients with PA compared to those without PA. A meta-analysis of 23 studies including 4239 patients with PA and 8474 without PA also demonstrated an increased risk of albuminuria (OR 2.09) and proteinuria (OR 2.68) despite matched systolic blood pressure (Monticone et al. 2020). Both eGFR and urinary albumin excretion decreased significantly following 12 months of targeted treatment of PA, consistent with reversal of glomerular hyperfiltration. In addition to hyperfiltration, aldosterone excess has also been shown to promote renal inflammation and fibrosis with evidence of progressive glomerulosclerosis, tubulointerstitial inflammation and scarring in renal biopsies from patients with PA (Grady et al. 1996, Blasi et al. 2003).
Hyperaldosteronism may also have an impact on metabolic parameters. A systematic review found an increased risk of diabetes (OR 1.33, 95% CI 1.01–1.74) and metabolic syndrome (OR 1.53, 1.22–1.91) in subjects with PA compared to those with essential hypertension (Monticone et al. 2018). Consistent with this, treatment of PA has been shown to increase insulin secretion and decrease insulin clearance after 6 months, in a study of nine volunteers with PA (Adler et al. 2020). The metabolic dysfunction may be reflected in circulating biomarkers as demonstrated in a separate study where 20 patients with PA were found to have lower LDL and HDL but higher GlycA, a pro-inflammatory glycoprotein biomarker of enhanced chronic inflammation, when compared to 501 patients with untreated hypertension (Berends et al. 2019). Plasma aldosterone concentration has also been associated with metabolic syndrome, hepatic steatosis, triglyceride concentration and the levels of very-low-density lipoprotein particles in the absence of PA (van der Heijden et al. 2020).
The quality of life (QoL), in both physical and mental domains, is lower in patients with PA compared to the general population. This is likely a result of the reported increase in psychological symptoms including anxiety, demoralization, stress, exhaustion, depression, irritable mood and nervousness in patients with untreated PA (Velema et al. 2017). Plasma aldosterone concentration has been positively associated with white matter lesions on brain MRI in a hypertensive population even after adjusting for blood pressure (Yuan et al. 2021). These imaging characteristics are indicative of cerebral small vessel disease, which is associated with an increased risk of depression, dementia and stroke.
Overall, these multi-system effects of hyperaldosteronism (Fig. 1) reflect the deleterious effects of excess aldosterone, which via interaction with the MR in a range of tissues promote tissue inflammation, fibrosis and injury independently of blood pressure levels (Fig. 2).
The cellular effects of mineralocorticoid receptor activation in response to excess aldosterone that is inappropriate for salt status. Aldo, aldosterone; K+ potassium; MR, mineralocorticoid receptor; Na+, sodium; VSMC, vascular smooth muscle cell.
Citation: Journal of Endocrinology 259, 1; 10.1530/JOE-22-0249
Mechanism of disease: mineralocorticoid receptor and aldosterone signalling
The receptor for aldosterone, the MR, is the exclusive mediator of aldosterone action and hence of the pathophysiology resulting from PA. The central importance of the MR has been clearly demonstrated in mice homozygous for inactivating mutations in the MR gene (Berger et al. 1998) (MRKO) where the classic features of aldosterone deficiency, salt-wasting, hyperkalaemia, dehydration and neonatal lethality are observed. The MR is a member of the steroid receptor subfamily of the nuclear receptor superfamily, which is defined by a highly conserved central cysteine-rich, DNA-binding domain (DBD). At the C-terminus is the ligand-binding domain (LBD), which has a highly conserved tertiary structure whereas the N-terminal domain (NTD) has little or no homology with the NTD in other steroid receptors (Fig. 3). These structural and functional domains in the MR are all highly conserved across evolution.
Schematic diagram of the domain structure of the 984 amino acid human mineralocorticoid receptor, with the hinge region between the DBD and LBD. Below the linear schematic is the crystal structure of two DBD monomers with the hormone response element shown below the DNA. Four zinc atoms coordinate the zinc fingers, the two alpha-helices that interact with the major groove of the DNA. Aldosterone is shown in the ligand pocket of the LBD tertiary structure. The crystal structures were drawn using SWISS-MODEL Workspace/ GMQE. DBD, DNA-binding domain; LBD, ligand-binding domain; NTD, N-terminal domain.
Citation: Journal of Endocrinology 259, 1; 10.1530/JOE-22-0249
The DBD forms two α-helices, one of which lies in the major groove of chromosomal DNA and binds to a common consensus sequence in the DNA, the hormone-response element (HRE) (Hudson et al. 2014). DNA binding by the ligand-activated MR is obligatory, at least for sodium homeostasis, as transgenic mice homozygous for an MR DBD mutation that precludes DNA binding exhibit a phenotype identical to that of the MR knock-out mice (Cole et al. 2015). Several studies have sought to characterize the MR cistrome using ChIP-seq (chromatin immunoprecipitation with massive parallel sequencing). A study using a transformed human renal cell line identified 974 MR-binding sites, the majority of which, somewhat surprisingly, did not include the canonical consensus HRE (Le Billan et al. 2015). Conversely, in a murine epithelial cell line (Ueda et al. 2014) and in rat hippocampus (van Weert et al. 2017), the HRE sequence was identified.
The NTD is unstructured (Kumar & McEwan 2012), enabling a broad range of interactions with other transcription factors and the transcription complex, with this activity designated (trans)activation function-1 (AF-1). A functional interaction has been described between the N- and C-termini for both the MR as also seen for the androgen receptor (AR) (Pippal et al. 2009). The LBD consists of 11 α-helices that form a distinct three-layered antiparallel structure with the ligand-binding pocket buried in the lower third of the structure (Li et al. 2005). Ligand binding induces a conformational change in the LBD leading to the formation of AF-2, a surface pocket that interacts with an LxxLL motif (L is leucine, x is any amino acid) in coactivator molecules (Li et al. 2005).
The MR is unique in having two physiological agonist ligands, aldosterone and cortisol (corticosterone in rodents). However, they are not equivalent in that each induces subtly different conformations in the LBD with functional consequences reflected in the characterization of MR coactivators that are aldosterone specific (Fuller et al. 2021). The primary physiological arbiter of aldosterone versus cortisol MR occupation and hence activation of the MR in epithelial tissues is 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2), which converts cortisol/corticosterone to the inactive metabolites, cortisone/11-dehydrocorticosterone (Odermatt & Kratschmar 2012). HSD11B2 protection of the MR has also been shown, predominately in pre-clinical animal models, to be operative in vascular beds (McCurley et al. 2012) and discrete subpopulations of hypothalamic neurones (Gasparini et al. 2019), whereas the MR, in monocyte/macrophages, cardiomyocytes, adipocytes and hippocampal neurones, is unprotected and hence occupied by cortisol/corticosterone under physiological conditions (Ricketts et al. 1998, Thieringer et al. 2001, Geerling & Loewy 2009, Iqbal et al. 2014).
The MR is found only in vertebrates; it diverged with the GR as a gene duplication from the ancestral corticoid receptor >450 million years ago (Bridgham et al. 2006), yet aldosterone first appears as an active steroid in amphibians. In most vertebrates, progesterone and spironolactone are MRA; however, fish MR is activated by both progesterone and spironolactone (Baker & Katsu 2020). This evolutionary switch of the MR response to progesterone from agonist to antagonist reflects a single amino acid change in the MR LBD (Fuller et al. 2019), which occurs at the time of the appearance of aldosterone synthesis in terrestrial vertebrates. The physiological significance of the MR as a progesterone receptor (PR) remains to be determined.
As the term mineralocorticoid implies, the classic effects of aldosterone involve the regulation of electrolyte flux across transporting epithelia. The genes regulated by the MR either mediate sodium transport per se or modulate components of the transport pathway. Sodium entry at the apical membrane is through an amiloride-sensitive electrogenic sodium channel (ENaC), with efflux at the basolateral membrane via the sodium pump with ATP generation needed to drive the process (Rossier et al. 2015). ENaC is a relatively short-lived protein complex that is ubiquitinated on residues in the N terminus of the α and γ subunits; a proline–proline–proline–X–tyrosine (PY) motif in the C terminus of ENaC interacts with Nedd4-2, a ubiquitin protein-ligase, whose role is to target the channels for proteasomal degradation (Staub et al. 1997). Although aldosterone can induce ENaC subunit synthesis, the initial aldosterone-induced increase in sodium flux appears to be mediated by an increased number of ENaC complexes in the apical membrane. Aldosterone treatment in vivo rapidly increases the levels of serum and glucocorticoid-regulated kinase (sgk-1) in the kidney and colon with a time course consistent with an effect of aldosterone on transcription (Bhargava et al. 2001). Sgk-1 directly interacts with Nedd4-2 to block its binding with ENaC and, as a consequence, slows ENaC degradation (Snyder et al. 2002). Regulation of ENaCα-subunit gene expression involves sgk-1 through relief of Dotla-Af9-mediated transcriptional repression (Zhang et al. 2007). Nedd4-2 is also regulated by Usp2-45, a de-ubiquitinylation enzyme that is itself regulated by aldosterone (Fakitsas et al. 2007). The glucocorticoid-induced leucine zipper (GILZ) protein is also aldosterone-induced; it interacts with and inhibits Raf-1 leading to repression of ERK-signalling, a negative regulator of ENaC, as well as directly interacting with sgk-1 and Nedd 4-2 (Rashmi et al. 2017).
Efflux of Na+ at the basolateral cell membrane is mediated by Na+/K+-ATPase activity in response to the increased intracellular sodium concentration. In the late phase of the aldosterone response, levels of Na+/K+-ATPase mRNA, protein and activity are all increased (Sansom & O'Neil 1985). Channel-inducing factor (CHIF) is upregulated in response to aldosterone (Brennan & Fuller 1999) through a primary transcriptional response to increase the affinity of Na+/K+-ATPase for sodium (Beguin et al. 2001).
Aldosterone also regulates potassium transport, primarily through the Na+K+-ATPase-mediated basolateral membrane exchange of sodium for potassium but also through other channels particularly through increases in the apical membrane channel density of ROMK (renal outer medullary K channel) (Manis et al. 2020). The intercalated cells within the collecting duct play specific roles in both potassium and hydrogen efflux in response to aldosterone. The β-intercalated cells mediate Cl− absorption and HCO3− secretion, largely through the anion exchanger pendrin which is stimulated by angiotensin II and aldosterone (Wall et al. 2020). The response of the β-intercalated cell to aldosterone is modulated by the phosphorylation of serine 843 in the ligand-binding domain of the MR which then precludes aldosterone binding (Shibata et al. 2013). Dephosphorylation in response to angiotensin II provides a mechanism by which the aldosterone-mediated response to volume depletion promotes sodium reabsorption with limited potassium depletion. These classic actions of the MR in the renal epithelia lead to the features of sodium retention, extracellular fluid volume expansion and occasional hypokalaemia observed in PA. Additional tissue-specific mechanisms of disease contribute to the broader clinical impact of PA.
Tissue-specific mechanisms of disease
The kidney
In the kidney, the MR is expressed in many cell types in addition to the high levels of expression found in the epithelia of the distal nephron. These include other segments of the nephron filtration system, the specialized macula densa cells and podocytes within the glomerulus, interstitial fibroblasts, endothelial and vascular smooth muscle cells (VSMC) and in tissue-resident and -infiltrating immune cells (monocytes/macrophages and T cells). Pharmacological studies and experimental animal models paired with clinical observations suggest that inappropriate activation of the MR in both epithelial and non-epithelial cell types underpin the pathogenesis of end-organ damage (Nishiyama et al. 2005, Briet & Schiffrin 2010, Huang et al. 2014).
While chronic administration of aldosterone in experimental animals, or sustained high levels of aldosterone release as occurs in patients with PA, increases glomerular filtration rate (Ribstein et al. 2005), an independent role for aldosterone in driving renal injury beyond the development of hypertension is also well defined. In stroke-prone spontaneously hypertensive rats (SHRSP) drinking 1% saline solution, both MRAs (spironolactone) and the ACE inhibitor captopril provided therapeutic benefits reducing vascular injury, malignant nephrosclerotic lesions and proteinuria, whereas replacement of aldosterone reinstated the full pathological phenotype, verifying the detrimental effect of aldosterone (Rocha et al. 1999).
Other studies have characterized the impact of aldosterone infusion in rodent models and defined its role in podocyte injury, proteinuria and promotion of renal inflammation and fibrosis via actions on multiple cell types including podocytes, infiltrating macrophages and stromal cells (Blasi et al. 2003, Huang et al. 2009). Moreover, an increasing number of transgenic mouse models have revealed a range of MR-dependent cellular mechanisms that contribute to the onset of renal dysfunction in the presence of high circulating aldosterone. For example, aldosterone-induced renal injury is reduced in mice in which plasminogen activator inhibitor (PAI-1), galectin-3 and interleukin-18 (IL-18) are genetically deleted or inflammasome activation in macrophages and other cell types is inhibited (Calvier et al. 2015, Kadoya et al. 2015, Tanino et al. 2016). These studies are consistent with the protective effects of MRA treatment or selected pathway antagonists and support a central role for these pathways in MR-mediated renal fibrosis. Other cellular pathways activated in kidneys from aldosterone-infused animal models include osteopontin, oxidative stress (NOX4, NOX2), connective tissue growth factor, NF-κB activation and TGF beta, many of which are also relevant to aldosterone/MR-mediated disease processes in other tissues (Queisser et al. 2011). MR-dependent signalling pathways driving these cellular changes include Rho-kinase, phosphoinositide 3-kinase (PI3K), extracellular signal-regulated kinase 1/2 (ERK1/2), c-jun N-terminal kinase (JNK) or small body size mothers against decapentaplegic-2 (SMAD2). Aldosterone can also directly promote fibrotic responses in cultured human kidney cells through the proliferation of mesangial cells and renal fibroblasts via mechanisms that involve epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) pathways or myofibroblastic transdifferentiation (Huang et al. 2009).
Additional mechanisms for renal injury involve aldosterone-mediated oxidative stress resulting in DNA strand breaks and chromosomal damage in renal cells from DOCA/salt-treated rats, which can be reduced by co-treatment with an MRA (Schupp et al. 2011). Another pathway involved in aldosterone-induced tissue injury in experimental animals is nuclear factor-erythroid-2-related factor 2 (Nrf2). Upregulation of this transcription factor appears to oppose aldosterone-induced, MR-mediated induction of cellular antioxidative defence in pig kidney epithelial cells (LLCPK) and Madin–Darby canine kidney (MDCK) cells (Queisser et al. 2011). Ligand-independent activation of the MR can also have pathogenic actions that can be addressed by MRA therapy. Infusion of glucocorticoids, angiotensin II (AngII) or high salt feeding in Dahl salt-sensitive rats can induce renal injury in aldosterone-deficient rodents, which is inhibited by MRAs (Rafiq et al. 2011, Luther et al. 2012). Of note, a link between aberrant RAC1-MR pathways in salt-sensitive hypertension in rodents has been described and argues for a direct role of RAC1 in the independent and synergistic activation of the MR in the kidney and underscores the importance of inappropriate sodium status for aldosterone in promoting MR-dependent tissue injury (Nagase & Fujita 2013, Tapia-Castillo et al. 2015).
Studies of the cellular and molecular impact of aldosterone in the human kidney are by their nature difficult, hence, much of our current understanding necessarily comes from animal models. Several recent studies have sought to characterize urinary extracellular vesicles as an indirect readout of renal tubular functional changes (Kong et al. 2022, Wu et al. 2022) and the source of unique proteomic signature of aldosterone excess (Bertolone et al. 2023), although these still require validation.
The heart
Direct cellular actions of the MR in multiple cell types in the heart and vascular system underlie many of the pathogenic actions of excess aldosterone. While the MR has numerous physiological actions regulating chronotropy and inotropy of cardiomyocytes, the MR is perhaps better characterized as a driver of a wide range of pathological actions that underpin compensatory changes in the heart and cardiac dysfunction including cardiac hypertrophy, tissue remodelling and metabolic dysfunction (Brilla & Weber 1992, Young et al. 1994). While these early pharmacological studies were performed in rats, they recapitulate the tissue remodelling and response to MRAs observed in clinical studies (Young & Rickard 2015). A number of clinical and experimental studies have reported elevated cardiac tissue levels of MR in heart failure; however, inappropriate MR activation, for example, in the presence of a moderately high sodium diet, is sufficient to activate multiple cellular systems that promote pathogenic remodelling. Analysis of early timepoint studies of aldosterone-, or another potent mineralocorticoid agonist deoxycorticosterone (DOC)-, infused rodent models identified oxidative stress and inflammation as key precursors for the tissue remodelling process seen at later timepoints (Rickard et al. 2012, 2014).
Similarly, cardiac tissue inflammation can be detected early following aldosterone infusion in experimental animals over 1 or more weeks (Rickard et al. 2009, Young et al. 1994). For example increased chemokines and other chemoattractant factors are directly regulated by aldosterone such as Gal3, NGAL, CCL2, CX3CL1, CCL5 and osteopontin, as well as proinflammatory/profibrotic factors, CTGF, MMP12, PAI1, PDGF and regulators of extracellular matrix turnover including MMP2/MMP2, TIMP1 and ADAMTS1 (Latouche et al. 2012, Rickard et al. 2012, Messaoudi et al. 2013). Aldosterone infusion in rats can also exacerbate infarct size and tissue injury in a model of myocardial infarction (Mihailidou et al. 2009), while DOC/salt infusion in mice enhances ischemia–reperfusion injury (Bienvenu et al. 2015), which can lead to poor cardiac function in both males and females. The use of cardiomyocyte MR null animals as well as MRAs in isolated rat cardiomyocytes identified, or verified, aldosterone-mediated MR regulation of calcium, sodium and potassium channels and ion cotransporters, which are critical for control of membrane repolarization, calcium handling during the action potential and hydrogen ion export (Bienvenu et al. 2022). These studies highlight potential mechanisms for the increased risk of atrial fibrillation, left ventricular hypertrophy and heart failure in patients with untreated PA (Monticone et al. 2018).
Cell selective gene deletion or over-expression of the MR in mouse models has also enabled the identification of many aldosterone-independent mechanisms that are relevant for cardiac function, cardiac hypertrophy and remodelling (Ouvrard-Pascaud et al. 2005, Fraccarollo et al. 2011, Rickard et al. 2012). The circadian clock was also identified as a novel cellular system regulated by the cardiomyocyte MR as well as exogenous mineralocorticoids in experimental animals (Rickard et al. 2012, Fletcher et al. 2017). These findings are consistent with earlier reports from in vitro studies of the period homologues 1 and 2 as MR-responsive genes (Tanaka et al. 2007). Importantly, cardiac tissue remodelling in pre-clinical models is independent of blood pressure changes; tissue injury is present in both the hypertrophied left ventricle as well as the right ventricle which, except in the case of pulmonary hypertension, is not subjected to an elevated afterload and a hypertrophic response. In vitro studies using a rat cardiomyoblast cell line overexpressing the MR demonstrated that aldosterone induced a range of known MR target genes (SGK1 and FKPB5) together with profibrotic markers (metalloprotease Adamts1, PAI-1 and tenascin X) support the direct regulation of these genes by aldosterone via the MR (Latouche et al. 2010). Several of these targets were also inhibited by selective GR antagonists, suggesting that the contribution from the GR to the cardiac pathology could be considered for patients with adrenal tumours that produce both aldosterone and cortisol (Latouche et al. 2010). However, while several of these MR targets together with troponin T3, serine-protease inhibitor Serpina-3 collagen 1 and fibronectin 1 are also regulated in transgenic mice with overexpression of the MR in cardiomyocytes, they are not regulated by overexpression of the GR in cardiomyocytes (Latouche et al. 2010).
The vasculature
The MR is expressed in both endothelial cells and VSMC where HSD11B2 is co-expressed at low levels in the mouse (Christy et al. 2003) and humans (Caprio et al. 2008). Many pathogenic actions of inappropriate MR activation in the vessel wall contribute to hypertension and impaired endothelial function (Liu et al. 2014, Kishimoto et al. 2018) in the setting of PA or with aldosterone infusion in pre-clinical rodent models (Nguyen Dinh Cat et al. 2010, Rickard et al. 2014, Moss et al. 2019). Activation of the MR in VSMC promotes structural remodelling of the vessel wall in part via the proliferation of VSMC and an increase in vascular tone (McCurley et al. 2012), whereas endothelial cell MR is a key regulator of eNOS, iNOS and nitric oxide production in experimental models (Rickard et al. 2014, Mueller et al. 2015). MR-dependent cell stress uncouples eNOS signalling leading to the production of reactive nitrous species, which in turn dysregulates VSMC relaxation. Pathogenic activation of the MR in human vascular endothelial cells by aldosterone also regulated the expression of the NADPH oxidase Nox4 while enhancing the surface expression of ICAM1 protein and promoting leukocyte adhesion to the coronary vessel wall (Caprio et al. 2008).
Studies from several laboratories have performed cell-selective deletion of the MR from either endothelial cells or VSMCs in mice. MR expressed in the VSMC is required for NO and Ca (2+) signalling pathways and contractile protein activity, but when inappropriately activated, contributes to vascular oxidative stress, vascular contraction and hypertension in these models (McCurley et al. 2012). In mice null for the MR in VSMC, there is reduced vascular myogenic tone, agonist-dependent contraction and expression with increased activity of L-type calcium channels (McCurley et al. 2012). Whereas mice lacking the MR in endothelial cells are without a phenotype, when challenged by DOC/salt or L-NAME/Angiotensin II, expression of cell adhesion molecules (VCAM/ICAM/PECAM) is substantially reduced or absent. This prevents the recruitment of monocytes/macrophages into tissues and reduces the proinflammatory and fibrotic response characteristic of these models (Rickard et al. 2014, Mueller et al. 2015). Transgenic mouse models have also shown that cellular pathways involved in MR-dependent pathogenesis include dysregulation of junction proteins and altered expression of the endothelial form of the sodium channel (EnNaC) (Jia et al. 2018). In a mouse model of aldosterone infusion or injury caused by diet-induced obesity, the role of EnNaC in renal tubular injury and renal dysfunction can be demonstrated by genetic deletion of αEnNaC in endothelial cells (Tarjus et al. 2019). Direct induction of EnNaC by aldosterone activation of the MR underlies increased EC stiffness and decreased NO-mediated vascular relaxation compared to littermate controls. These studies also determined that aldosterone and insulin signalling interact to regulate EnNaC via the mTORC2/SGK-1 signalling pathway, consistent with reports of MR regulation of mTORC in the mouse heart and SGK-1 in the nephron and several other tissues in these mice (Huang et al. 2006). Very recent studies have demonstrated the requirement of EnNaC for DOCA-salt-induced endothelial cell and arterial stiffening in a rodent model via mechanisms that involve the mTOR signalling pathway (Zhang et al. 2022).
Endothelial MR contributes to vascular inflammation in atherosclerosis in a sex-specific manner in mouse models of hypertension and end-organ remodelling. MR inhibition attenuated vascular inflammation in males but not females in the AAV-PCSK9 mouse atherosclerosis model (Moss & Jaffe 2015). Mice lacking MR in endothelial cells show reduced leukocyte–endothelial interactions, plaque inflammation and expression of E-selectin and ICAM-1, providing a potential mechanism whereby the MR promotes vascular inflammation in male mice. In females, however, plaque inflammation and leukocyte–endothelial interactions are reduced compared to males, most likely due to an inhibitory effect of the oestrogen receptor on the MR, and deletion of the endothelial MR has no effect in this model. Lysine-specific demethylase 1 (LSD-1), caveolin and striatin are other novel targets regulated by aldosterone (Baudrand et al. 2014). LSD1 is an epigenetic regulator that is involved in the pathogenesis of salt-sensitive hypertension in humans and experimental models and has been demonstrated to modulate aldosterone transactivation outcomes, while caveolin-1 is an anchoring protein and the main component of caveolae. Cooperative MR and CAV-1 actions on eNOS and vascular relaxation, for example, are not present with CAV1 knockout or MRA administration to experimental models (Pojoga et al. 2015). Striatin promotes an interaction between signalling molecules and rapid effects of the MR in the cardiovascular system have been demonstrated in both human and rodent models. These actions are consistent with the hypothesis that aldosterone promotes adverse cellular effects via both genomic and rapid/nongenomic actions, and the latter may involve caveolae- or striatin-mediated intracellular signalling (Pojoga et al. 2015).
These preclinical studies offer numerous insights into the underlying mechanisms involved in the enhanced vascular stiffness and higher carotid intima-media thickness (Petramala et al. 2022, Can et al. 2023), atherosclerotic burden (Lottspeich et al. 2021) and endothelial dysfunction (Farquharson & Struthers 2002) seen in patients with PA vs EH. Of note, serum markers such as endothelial cell-specific molecule 1 (ESM1 or endocan) differ between PA and other forms of hypertension, supporting the direct actions of aldosterone on the vasculature in PA as well as in preclinical models (Can et al. 2023). However, not all clinical studies have identified differences in biomarkers of endothelial dysfunction and microvascular endothelial function in PA vs EH.
Immune cells
Over recent years, there have been consistent reports that cells of the innate and adaptive immune system in humans and experimental animals express the MR and are responsive to aldosterone, including monocytes/macrophages, dendritic cells and T-cells (van der Heijden et al. 2022). Of note, the role of MR signalling in myeloid monocyte/macrophage responses to cardiovascular disease in vivo has been assessed by several groups in macrophage MR-null mice via the lysozyme M-Cre recombinase. Deletion of MR from macrophages affords complete protection from cardiac fibrosis and hypertension in the DOC/salt model of cardiovascular disease and in nitric oxide depletion-induced cardiac fibrosis (i.e. short-term L-NAME/AngII-and 8-week chronic L-NAME/salt treatment). Despite the overall cardioprotective effects, several differences have been noted in the various studies which most likely reflect the particular mouse disease model used (Usher et al. 2010, Shen et al. 2017). These studies show that MR signalling in the myeloid cell population is required for the proinflammatory phenotype and that the loss of MR promotes an alternative macrophage phenotype that shares some common markers with certain ‘M2’ macrophage subsets. Aldosterone-driven activation of the MR in cells of the adaptive immune system has been demonstrated for both CD8+ and CD4+ T cells and dendritic cells and T-reg cells, and these interactions have been recently reviewed (Ferreira et al. 2021). Examples include demonstration that aldosterone activates CD8+ T cells in the presence of dendritic cells in vitro and in vivo (Herrada et al. 2010). Dendritic cells activated by aldosterone in vitro polarize CD4+ T cells to a Th17 phenotype and aldosterone-blunted activation and polarization of T-reg cells (Caillon et al. 2019). Mice in which the MR was knocked out in T cells showed decreased cardiac fibrosis and hypertrophy following abdominal aortic constriction (Li et al. 2017), as well as reduced cardiac inflammation, myeloid cell numbers and cytokine expression (Sun et al. 2017). Finally, a potential role of the MR in B cells is suggested by single-cell sequencing, although MR gene expression is much lower in human B cells than in T cells (https://www.proteinatlas.org/). Modulation of B cell function via the MR in patients with PA remains unexplored.
Overall, the modulation of multiple cell types in the immune system by aldosterone contributes to the inflammatory outcomes associated with metabolic and cardiovascular disease in PA. Use of MRA, inhibitors and antibodies targeting cytokine receptors and cytokine production may offer specific novel treatments for hypertension via targeting immune cell activation.
Adipose tissue
In rodents, both white adipocytes and brown adipocytes express the MR (Zennaro et al. 1998, Caprio et al. 2007) with either no or very weak expression of HSD11B2 making it likely, except in conditions of aldosterone excess, that the ligand regulating the MR in vivo is cortisol/corticosterone. Stimulation of preadipocytes in culture by either aldosterone or MRAs demonstrates that aldosterone can drive adipogenesis with stimulation of adipogenic transcription via activation of C/EBP-α and PPARγ and also key adipokines (Infante et al. 2017). In vivo, however, adipogenesis is most likely controlled by glucocorticoids, and the potential transcription cooperatively of the co-expressed MR and GR in both adipocyte cell types remains unclear. Compellingly, knock-down of MR or MR blockade by MRAs inhibits preadipocyte differentiation; however, tissue-selective MR gene knockout in mature white adipocytes had few metabolic consequences in vivo suggesting a limited role in adipocyte physiology in mice or perhaps compensation by a still functional GR (fully reviewed in (Feraco et al. 2020)). In patients with PA, activation of the MR in adipose depots will drive aspects of metabolic dysfunction characterized by increased adipogenesis, increased lipid storage, increased proinflammatory adipokines and reduced thermogenesis, all leading to an increased risk and extent of metabolic syndrome (Thuzar & Stowasser 2021). Clinical studies with PA patients have indicated that high plasma aldosterone may promote adipose dysfunction, leading to an inflammatory state and metabolic syndrome (Wu et al. 2018). In addition, excess aldosterone may drive reduced leptin and adiponectin expression in visceral adipose in patients with aldosterone-producing adrenal adenomas (Letizia et al. 2015). Compellingly, human clinical studies demonstrate that MRAs can reverse some of these features by enhancing brown adipose function and show promise as potential treatments for the metabolic effects of PA (Thuzar et al. 2019).
The brain
The MR is expressed at high levels in neurones in the limbic areas of mammalian brains, in particular, the hippocampus, central amygdala and lateral septum (Reul & de Kloet 1986), where in the absence of HSD11B2 and given that the penetration of the blood–brain barrier by aldosterone is substantially less than that of most steroid hormones, the MR acts as a receptor for cortisol (Geerling & Loewy 2009). Most data for molecular mechanisms of MR and aldosterone actions in the brain are derived from animal studies and are thus the focus of the following discussion unless otherwise noted. A small number of nuclei in the nucleus of the solitary tract (NTS) co-express MR and HSD11B2 to regulate salt appetite in response to aldosterone (Gasparini et al. 2019). They occupy a subregion of the NTS with a diminished blood–brain barrier which may afford exposure to circulating aldosterone. These neurones also express the angiotensin receptor so MR activation appears to interact synergistically with AngII to promote salt appetite (Resch et al. 2017). It would seem likely that in PA this would counteract the physiological decrease in salt appetite and intake that should otherwise follow from sodium retention and volume expansion.
In those regions unprotected by HSD11B2, the MR appears to mediate diverse behavioural responses including memory and affect (de Kloet & Joels 2017). Polymorphisms in the human MR gene have been associated with altered responses to psychosocial stress (DeRijk et al. 2011, Cole 2021) and human MR gene locus variants have recently been associated with autism spectrum disorder, a condition characterized by altered levels of stress and responses to anxiety, although whether these MR variants are causative in autism is not known (Cukier et al. 2020, Cole 2021). Several recent studies have found that the mental health-related QoL of patients with PA is compromised (Ahmed et al. 2011, Velema et al. 2017, Buffolo et al. 2020). The question of whether the high aldosterone levels that may occur in PA directly impact the brain MR and directly contribute to the decreased QoL in PA remains to be clearly determined. An interesting nuance in this question is whether the MRAs used for medical treatment of PA have a greater impact on the brain MR than aldosterone and therefore impact cortisol signalling in these brain regions. An evaluation of the effects of spironolactone in this context is however inevitably compromised by its agonist effect at the PR and antagonism at the AR.
Systemic effects of targeted treatment of primary aldosteronism
To abolish inappropriate activation of the MR, MRAs are used to antagonize the effect of excess aldosterone, or unilateral adrenalectomy is offered to eliminate aldosterone hypersecretion in patients with a single aldosterone-producing adrenal adenoma. Adrenalectomy is superior to MRA treatment in reducing all-cause mortality and major adverse cardiovascular events including coronary artery disease, stroke, arrhythmia and congestive heart failure, as demonstrated in a meta-analysis of 9 cohort studies with 8473 patients (31.3% had adrenalectomy, 687% had MRAs) (Chen et al. 2022). The cardiovascular benefits are evident from imaging studies which showed a reduced left ventricular mass as well as myocardial collagen content (Ueda et al. 2022) and decreased carotid intima-media thickness (Holaj et al. 2015) in patients treated with surgery or MRA. In patients with medically treated PA, adequate dosing of MRAs is important for achieving cardiovascular benefits. In a large cohort study of 602 patients with PA and 41,853 patients with essential hypertension, a significant reduction in cardiovascular events was only demonstrated in patients whose renin activity was normalized by adequate MRA dosing (Hundemer et al. 2018). Similar benefits in CV risk reduction and regression of left ventricular mass index have been reported in patients whose renin normalized with MRA treatment (Köhler et al. 2021, Nomura et al. 2022).
The impact of treatment on renal function in patients with PA may appear paradoxical. A meta-analysis of 21 studies showed a comparable decrease in renal function, as measured by the eGFR, following both MRA and surgical treatment of PA (Monticone et al. 2020). Rather than causing renal damage, this is most likely due to the unveiling of underlying renal impairment previously masked by aldosterone-induced glomerular hyperfiltration (Kobayashi et al. 2019). The benefits of MRAs and surgery are seen in the reversal of microalbuminuria (Sechi et al. 2009, Fourkiotis et al. 2013) and proteinuria (Wu et al. 2011) associated with untreated PA.
The impact of PA treatment on metabolism is less consistent. Surgical treatment of PA has been shown to improve insulin secretion, first-phase insulin reaction and insulin sensitivity, as well as reduced fasting glucose and new-onset diabetes (Loh & Sukor 2020). Surgical treatment has also been shown to restore insulin action in contrast to MRAs (Sindelka et al. 2000, Loh & Sukor 2020). However, both surgery and MRAs were shown to increase insulin resistance at 1-year post-treatment in another study, possibly related to concurrent weight gain (Lin et al. 2020). Importantly, improvement in QoL is observed in patients as early as 3 months after surgical treatment with the benefit being greater and earlier in onset in surgically vs medically treated patients (Sukor et al. 2010, Ahmed et al. 2011, Velema et al. 2018, Tan et al. 2021). Patients’ mental health also improves with PA treatment based on a series of relatively small prospective studies that demonstrated reduced psychological symptoms of depression and anxiety following targeted PA treatment (Velema et al. 2017, Tan et al. 2021).
The outcomes of medical treatment for patients with PA have been based exclusively on the use of steroidal MRAs, spironolactone and eplerenone. The use of spironolactone can be limited by its non-specific actions at the AR and PR while eplerenone is less potent and often more expensive or not accessible. Newer non-steroidal MRA, such as finerenone, are now available for a range of indications other than PA, having shown cardiovascular and renal benefits in heart failure (Rico-Mesa et al. 2020) and diabetic nephropathy (Pitt et al. 2021, Filippatos et al. 2022). Finerenone has higher potency for the MR than spironolactone but no affinity for other steroid hormone receptors. Esaxerenone is another non-steroidal MRAs with greater potency than spironolactone that has been approved for the treatment of diabetic nephropathy in Japan (Ito et al. 2020a,b). Both agents would seem to be ideal for the treatment of PA, given their high affinity for MR with minimal off-target adverse effects, but only esaxerenone has been evaluated in patients with PA. It was found to be highly effective at lowering blood pressure without causing gynecomastia or mastodynia (Satoh et al. 2021), and when compared with spironolactone, it had a similar effect on body composition (Ishikawa et al. 2022). However, there are no studies on the impact of these non-steroidal MRAs on cardiovascular, renal and metabolic endpoints in patients with PA.
Conclusion and future directions
The diverse actions of the MR highlight the importance of diagnosing and treating PA not just for blood pressure control but to reduce cardiovascular, renal and metabolic risk and improve QoL. The prominent role of the MR in mediating tissue inflammation and fibrosis in numerous organ systems is a particular concern for the millions of hypertensive patients around the world who are never screened for aldosterone excess. A concerted effort to improve screening for PA via expanded public health programs is needed so that the benefits of PA discovery research can be translated into improved health outcomes for the wider community. Active engagement with primary care physicians has been shown to increase screening for PA in a recent Australian study (Libianto et al. 2022). In parallel with increased testing, improvements in diagnostic tests and targeted treatments are needed. Current advances in nuclear medicine imaging with radio-labelled ligands that target the steroidogenic pathway (Wu et al. 2023) or bind receptors expressed by aldosterone-producing adrenal adenomas (Hu et al. 2023) may improve the non-invasive detection of surgically curable PA. Increased use of liquid chromatography-tandem mass spectrometry for the measurement of aldosterone and steroid metabolites may also facilitate the accurate diagnosis of PA, especially when integrated with machine learning (Constantinescu et al. 2022). The cellular pathways affected by inappropriate MR activation may be interrogated to identify novel biomarkers of PA or treatment targets, while newer non-steroidal MRAs currently being used for diabetic nephropathy and heart failure should be trialled in the PA population where they may be expected to significantly improve patient outcomes.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. Morag Young is on the editorial board of Journal of Endocrinology. Morag was not involved in the review or editorial process for this paper, on which she is listed as an author
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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