Download Aldosterone and end-organ damage

Clinical Science (2007) 113, 267–278 (Printed in Great Britain) doi:10.1042/CS20070123
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Aldosterone and end-organ damage
Annis M. MARNEY and Nancy J. BROWN
Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University Medical Center,
550 Robinson Research Building, Nashville, TN 37232-6602, U.S.A.
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Aldosterone concentrations are inappropriately high in many patients with hypertension, as well as
in an increasing number of individuals with metabolic syndrome and sleep apnoea. A growing body
of evidence suggests that aldosterone and/or activation of the MR (mineralocorticoid receptor)
contributes to cardiovascular remodelling and renal injury in these conditions. In addition to
causing sodium retention and increased blood pressure, MR activation induces oxidative stress,
endothelial dysfunction, inflammation and subsequent fibrosis. The MR may be activated by
aldosterone and cortisol or via transactivation by the AT1 (angiotenin II type 1) receptor through a
mechanism involving the EGFR (epidermal growth factor receptor) and MAPK (mitogen-activated
protein kinase) pathway. In addition, aldosterone can generate rapid non-genomic effects in
the heart and vasculature. MR antagonism reduces mortality in patients with CHF (congestive
heart failure) and following myocardial infarction. MR antagonism improves endothelial function
in patients with CHF, reduces circulating biomarkers of cardiac fibrosis in CHF or following
myocardial infarction, reduces blood pressure in resistant hypertension and decreases albuminuria
in hypertensive and diabetic patients. In contrast, whereas adrenalectomy improves glucose
homoeostasis in hyperaldosteronism, MR antagonism may worsen glucose homoeostasis and
impairs endothelial function in diabetes, suggesting a possible detrimental effect of aldosterone via
non-genomic pathways.
INTRODUCTION
Activation of the RAAS [renin–Ang (angiotensin)–
aldosterone system] is associated with increased morbidity and mortality among patients with hypertension
and CHF (congestive heart failure). These effects have
been attributed to the hypertrophic, proliferative, pro-
inflammatory, prothrombotic and profibrotic effects of
AngII. However, it is now appreciated that aldosterone or
MR (mineralocorticoid receptor) activation contributes
to many of these effects of AngII. In addition, although
interruption of the RAAS with ACE (Ang-converting
enzyme) inhibitors or ARBs [AT1 (AngII type 1) receptor
blockers] significantly reduces morbidity and mortality
Key words: aldosterone, angiotensin II (AngII), cardiovascular remodelling, end-organ damage, mineralocorticoid receptor, renal
injury, renin–angiotensin–aldosterone system (RAAS).
Abbreviations: Ang, angiotensin; ACE, Ang-converting enzyme; ARR, aldosterone/renin ratio; AT1 receptor, AngII type 1
receptor; BP, blood pressure; BH4, 5,6,7,8-tetrahydrobiopterin; CHF, congestive heart failure; ECM, extracellular matrix; EGFR,
epidermal growth factor receptor; ENaC, epithelial sodium channel; EPHESUS, Eplerenone Neurohormonal Efficacy and Survival;
ET, endothelin; ETA , ET type A receptor; G6PD, glucose-6-phosphate dehydrogenase; 11β-HSD2, type 2 isoform of 11βhydroxysteroid dehydrogenase; LV, left ventricular; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase;
MR, mineralocorticoid receptor; NET, noradrenaline transporter; NF-κB, nuclear factor κB; NOS, NO synthase; PAI-1,
plasminogen activator inhibitor-1; PKC, protein kinase C; PP2A, protein phosphatase 2A; RAAS, renin–Ang–aldosterone system;
RALES, Randomized Aldactone Evaluation Study; ROS, reactive oxygen species; sgk-1, serum- and glucocorticoid-inducible
kinase-1; TGF-β, transforming growth factor-β; t-PA, tissue-type plasminogen activator; uPA, urokinase plasminogen activator;
VSMC, vascular smooth muscle cell.
Correspondence: Professor Nancy J. Brown (email [email protected]).
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Figure 1 Classical MR-mediated effects of aldosterone in the principal cells of the kidney, resulting in increased potassium
excretion and sodium reabsorption
ALDO, aldosterone; Hsp, heat-shock protein; SRE, steroid-response element; CHIF, corticosteroid-hormone-induced factor. Reproduced from [128] with permission.
c (2002) American Physiology Society.
in patients with CHF, at risk of coronary artery disease
or with nephropathy, aldosterone concentrations ‘escape’
to baseline during chronic therapy.
In this article, we review results from studies in vitro
and in whole-animal models indicating that aldosterone
or MR activation causes oxidative stress and induces
endothelial dysfunction, inflammation and fibrosis. We
present these results in the context of recent clinical trials
of MR antagonists in patients with CHF, hypertension
and nephropathy. Understanding the mechanisms
through which aldosterone contributes to end-organ
damage during activation of the RAAS can lead to the development of new pharmacological strategies to decrease
end-organ damage.
ALDOSTERONE: A REGULATOR OF FLUID
AND ELECTROLYTE HOMOEOSTASIS
Classically, aldosterone regulates sodium excretion
through MR-dependent and genomic effects in the distal
nephron of the kidney [1–3]. AngII, potassium or corti
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cotropin [ACTH (adrenocorticotropic hormone)] stimulates the adrenal zona glomerulosa to synthesize aldosterone. Circulating aldosterone then binds to the inactive
cytosolic MR of target cells, resulting in dissociation
of the ligand-activated MR from a multiprotein complex containing molecular chaperones and translocation
of the ligand-activated MR into the nucleus, where it
binds to hormone-response elements in the regulatory
region of target gene promoters. In the distal nephron of
the kidney, MR induction of sgk-1 (serum- and glucocorticoid-inducible kinase-1) gene expression triggers
a cascade that leads to the absorption of sodium and
water through the ENaC (epithelial sodium channel)
and potassium excretion with subsequent volume
expansion and hypertension (Figure 1).
The MR binds cortisol and aldosterone with equal
affinity; however, in epithelial tissues, the enzyme 11βHSD2 (type 2 isoform of 11β-hydroxysteroid dehydrogenase), converts cortisol (or in the case of rodents
corticosterone) into its inactive 11-ketometabolite, such
that MRs are occupied primarily by aldosterone [4].
MRs are also expressed in the hippocampus, heart
Aldosterone and end-organ damage
(cardiomyocyte), vasculature [endothelial cells and
VSMCs (vascular smooth muscle cells)], renal cells in
addition to the principal cell of the collecting duct (e.g.
mesangial cells and podocytes) and monocytes [5–7]. The
vasculature expresses 11β-HSD2 and here aldosterone
acts as the primary ligand at the MR. In contrast, neither
cardiomyocytes nor hippocampal cells express 11βHSD2 [8]. Therefore cortisol, present in concentrations at
least 10-fold in excess of aldosterone, acts as the primary
MR ligand at these sites. Paradoxically, under normal
redox conditions, cortisol acts as an antagonist in these
tissues [9].
Just as MRs have been identified in non-epithelial
tissues, so have many of the downstream targets of MR
activation. For example, sgk-1 is abundantly expressed in
the heart [10]. Likewise, ENaC mRNA and protein are
expressed in fibroblasts, VSMCs, endothelial cells and in
cerebral vasculature [11].
ALDOSTERONE EXERTS EFFECTS
THROUGH GENOMIC AND NON-GENOMIC
PATHWAYS
In addition to its classical effects on gene expression,
aldosterone can produce rapid (occurring within minutes)
non-genomic (not blocked by inhibitors of transcription)
effects [9,12]. In both VSMCs and endothelial cells,
aldosterone causes a rapid increase in intracellular calcium
through Ins(1,4,5)P3 , diacylglycerol and PKC (protein
kinase C) [13–15]. The consequence of these rapid
effects of aldosterone in the vasculature depends on
the bioavailability of endogenous NO [14–17]. For
example, aldosterone causes vasoconstriction in microperfused afferent arterioles [15], whereas aldosterone
decreases phenylephrine- [13] or potassium- [14] stimulated vasoconstriction in rat aortic rings and rabbit
renal afferent arterioles via activation of NOS (NO
synthase).
In the heart, aldosterone increases Na+ –K+ –2Cl− cotransporter activity and decreases Na+ /K+ pump activity
through a non-genomic PKCε-dependent mechanism
[18]. In rabbit cardiomyocytes, these so-called ‘rapid’
effects of aldosterone persist for 7 days, suggesting
an interaction with non-genomic effects [18]. Because
PKCε activation also stimulates NF-κB (nuclear factor
κB) activation of MAPK (mitogen-activated protein
kinase), the genomic effects of aldosterone may influence
the genomic effects [19]. Whether the non-genomic
effects of aldosterone are also MR-independent is
uncertain. In most studies, MR antagonism with
spironolactone does not block the non-genomic effects
of aldosterone; however, the open-ring water-soluble
metabolite of spironolactone, canrenoate, or eplerenone
have been reported to block some non-genomic effects
[20].
ALDOSTERONE AND ENDOTHELIAL
FUNCTION
Impaired endothelial function, defined by vasodilation in
response to sheer stress or pharmacological agonists that
stimulate NOS, is associated with increased mortality
[21]. In animal models, aldosterone infusion causes
endothelial dysfunction via the generation of ROS
(reactive oxygen species) [22–24]. Aldosterone increases
expression of NADPH oxidase subunits p22phox and
gp91phox through an MR-dependent mechanism, whereas
aldosterone stimulates expression of p47phox mRNA
through both AT1 receptor and MR-dependent mechanisms (Figure 2) [25,26]. The resultant generation of ROS
leads to the formation of peroxynitrite and oxidation
of the NOS co-factor BH4 (5,6,7,8-tetrahydrobiopterin)
[27]. In addition, aldosterone promotes the ‘uncoupling’
of NOS by inducing dephosphorylation of Ser1177
by PP2A (protein phosphatase 2A). Aldosterone also
produces oxidative stress and endothelial dysfunction by
decreasing the expression of G6PD (glucose-6-phosphate
dehydrogenase), which reduces NADP+ to NADPH
[28].
Increased aldosterone concentrations are associated
with endothelial dysfunction in human hypertension
[29,30], and acute aldosterone administration causes
endothelial dysfunction in healthy individuals in some
studies [31,32]. Administration of an MR antagonist
improves endothelial dysfunction in patients with CHF
[33]. A few investigators have reported that aldosterone
can also cause vasodilation via a rapid MR-independent
mechanism involving PI3K (phosphoinositide 3-kinase)dependent activation of NOS [16]. The clinical relevance
of these observations is not yet known. As described
below, MR antagonism worsens vascular function in
patients with Type 2 diabetes [34].
ANGII AND ALDOSTERONE INTERACT TO
PRODUCE CARDIOVASCULAR INJURY
A wealth of data supports the interaction of AngII
and aldosterone in inducing inflammation, fibrosis and
proliferation. For example, aldosterone increases ACE
and AT1 receptor mRNA expression and AT1 receptor
binding in the vasculature and heart, whereas MR antagonism decreases AT1 receptor mRNA and density in the
heart [35,36]. AngII activates gene expression in VSMCs
by transactivating the MR [37]. At low concentrations,
AngII and aldosterone synergistically increase ERK
(extracellular-signal-regulated kinase) activity in VSMCs
through a biphasic mechanism; Horiuchi and coworkers have reported [38] that the early phase involves
EGFR (epidermal growth factor receptor) transactivation
through a rapid non-genomic mechanism, whereas the
late phase involves MR-mediated effects on the fibrotic
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Figure 2 Aldosterone induces oxidative stress and endothelial dysfunction through several mechanisms
Aldosterone stimulates the expression of NADPH oxidase subunits [129,130], and decreases the activity of G6PD, which reduces NADP+ to NADPH [28]. Aldosterone
promotes the ‘uncoupling’ of NOS by activating PP2A to dephosphorylate Ser1177 [27].
and proliferative small and monomeric GTP-binding
protein Ki-ras2A and MAPK.
AT1 receptor blockade abrogates many of the adverse
effects of aldosterone in the heart and vasculature.
Conversely, studies in vivo in rats in which the RAAS is
up-regulated suggest that AngII induces cardiovascular
injury in part through an aldosterone- and MRdependent mechanism. For example, in rats doubly transgenic for the human renin and angiotensinogen genes,
AngII stimulates AP-1 (activator protein-1) and NF-κB
expression and cardiac fibrosis via an MR-dependent
mechanism [39]. Pharmacological inhibition of aldosterone synthase also decreases cardiac hypertrophy and
renal injury in this model [40]. In humans, intravenous
infusion of aldosterone or AngII increases circulating
concentrations of inflammatory cytokines through an
MR-dependent mechanism [41].
ALDOSTERONE PROMOTES OXIDATIVE
STRESS, INFLAMMATION AND FIBROSIS
Chronic aldosterone infusion at doses that yield concentrations similar to those observed in CHF causes
myocardial fibrosis in rat models in the setting of high
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salt intake [42]. The development of fibrosis is preceded
by coronary and myocardial inflammation characterized by monocyte and macrophage infiltration and
increased expression of inflammatory markers, such
as COX-2 (cyclo-oxygenase-2), osteopontin, MCP1 (monocyte chemoattractant protein-1) and ICAM-1
(intracellular adhesion molecule-1) [43,44]. Both the inflammatory changes and subsequent fibrosis can be
blocked by MR antagonism [42,45].
Aldosterone also causes aortic fibrosis and hypertrophy in hypertensive rats through an MR-dependent
mechanism [46–48]. Similarly, aldosterone causes glomerular injury and tubulointerstitial fibrosis. In the rat
remnant kidney model, aldosterone infusion reverses
the protective effects of ACE inhibition and AT1
receptor antagonism [49]. MR antagonism decreases
the development of glomerular damage (thrombosis,
sclerosis and mesangiolysis) and arteriopathy in strokeprone SHRs (spontaneously hypertensive rats) [50] in a
renin-dependent radiation model of renal damage [51]
and in diabetes [52], independent of effects on BP (blood
pressure).
High-salt intake promotes cardiac fibrosis and vascular
injury in aldosterone-treated animal models, but the
Aldosterone and end-organ damage
pathophysiological basis for the effect of sodium has
not been fully elucidated. Changes in potassium do not
appear to contribute to aldosterone/salt-mediated injury
[53]. On the other hand, during high-salt intake, activation of the MR causes Ca2+ loading and a fall in cytosolicfree ionized Mg2+ in monocytes and cardiomyocytes,
through a mechanism involving Na+ /Mg2+ and Na+ /
Ca2+ exchangers [54]. Intracellular Ca2+ loading, in
turn, causes oxidative stress. Funder and Mihailidou
[55] have proposed that changes in intracellular redox
potential result in activation of cortisol (corticosterone)–
MR complexes in non-epithelial tissues, such as the heart.
In addition, it should be noted that, whereas high-salt
intake suppresses the activity of the circulating RAAS,
local cardiac [56], aortic [26] and renal [57] concentrations
of AngII may be up-regulated in the setting of high-salt
intake. Similarly, although high-salt intake is associated
with decreased renal sympathetic nerve activity, lumbar
sympathetic nerve activity is increased [58].
Because animal models of aldosterone-stimulated
cardiovascular and renal injury involve the systemic
administration of aldosterone, it has been difficult to
dissect local tissue effects of aldosterone from systemic
effects of sodium retention. This point is highlighted by
the observation that MR-deficient mice die from sodium
wasting and dehydration [59]. In addition, studies in
genetically modified mice provide conflicting data as
to whether aldosterone or MR activation is the critical
step in initiating fibrosis and whether aldosterone acts
exclusively through MR-dependent pathways. On the
one hand, local aldosterone expression causes coronary
endothelial dysfunction, not fibrosis, suggesting that
MR activation is critical [60]. On the other hand,
cardiac-specific overexpression of the MR does not cause
fibrosis [61]. On the contrary, conditional knockdown
of the cardiac MR using antisense mRNA results in the
development of cardiac fibrosis and heart failure [62].
Although this has been attributed to an artifact related
to overexpression of a foreign protein in myocytes, the
finding that spironolactone, which increases circulating
aldosterone concentrations, enhanced fibrosis in this
model raises the possibility that knockdown of the cardiac
MR unmasked an MR-independent effect of aldosterone
[62].
The availability of pharmacological aldosterone synthase inhibitors [40] and aldosterone-synthase-deficient
mice [63] should contribute to our understanding of the
relative importance of aldosterone compared with MR
activation, if not to our understanding of local compared
with systemic effects.
POSSIBLE MECHANISMS OF
ALDOSTERONE-INDUCED FIBROSIS
Although many studies have focused on the role of oxidative stress and inflammation in the initiation of aldo-
sterone-mediated end-organ damage, much remains to be
learned about the pathways involved in progression from
inflammation to remodelling and fibrosis. Aldosterone
stimulates the expression of several profibrotic molecules
that may contribute to the pathogenesis of cardiac
remodelling. For example, aldosterone increases the
activity of TGF-β 1 (transforming growth factorβ 1 ) in cultured cardiomyocytes [64]. Aldosterone/salt
treatment increases and MR antagonism decreases
myocardial TGF-β 1 expression in some studies [44,65],
although not all [66]. Aldosterone increases renal TGFβ 1 mRNA expression and signalling [67,68], and causes
a rapid increase in urinary excretion of TGF-β 1 through
an MR-dependent post-transcriptional mechanism [69].
TGF-β 1 promotes fibrosis and tissue remodelling by
stimulating cellular transformation to fibroblasts [70],
increasing the synthesis of matrix proteins and integrins
and decreasing the production of MMPs (matrix
metalloproteinases) [71].
In addition, TGF-β 1 increases the expression of PAI-1
(plasminogen activator inhibitor-1) (Figure 3) [72].
Aldosterone also increases PAI-1 expression in endothelial cells, VSMCs, cardiomyocytes and monocytes
[25,73–75]. PAI-1, a member of the serpin (serine protease inhibitor) superfamily and the major physiological
inhibitor of t-PA (tissue-type plasminogen activator) and
uPA (urokinase plasminogen activator) in vivo, can, in
turn, accelerate fibrosis by decreasing both direct and
indirect effects of plasmin on ECM (extracellular matrix)
[76]. Treatment of mice or rats with aldosterone increases
cardiac PAI-1 expression, whereas MR antagonism
reduces cardiac PAI-1 expression [44,77]. Similarly, MR
antagonism decreases renal injury and PAI-1 expression
in a radiation model of glomerular injury and in
streptozotocin-induced diabetes [51,67]. Importantly,
treatment with spironolactone can reverse pre-existing
glomerular injury and associated PAI-1 expression [78].
On the basis of these findings, one might predict that
PAI-1 deficiency would decrease aldosterone-induced
cardiac fibrosis and renal injury. Indeed, genetic PAI-1
deficiency protects against AngII-stimulated aortic
remodelling and aldosterone-mediated glomerular injury
[79,80]. However, paradoxically, genetic PAI-1 deficiency
increases cardiac fibrosis, as well as the expression of proinflammatory genes, in AngII- and aldosterone-treated
rodents [79,80]. These findings highlight the complex
role of the plasmin/protease system in the regulation of
ECM degradation and cell migration. PAI-1 promotes
fibrosis and remodelling by inhibiting plasmin-mediated
MMP activation and ECM degradation, but PAI-1 may
also prevent fibrosis by retarding cellular infiltration and
inflammation or by impeding uPA- or plasmin-mediated
activation or release of latent growth factors, such as
FGF (fibroblast growth factor) and VEGF (vascular
endothelial growth factor) [81,82]. In support of a role
for PAI-1 in modulating uPA-dependent cell infiltration,
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Figure 3 Effect of aldosterone on the expression of profibrotic factors
AngII and aldosterone increase ET-1, TGF-β and PAI-1 mRNA expression through MR-dependent mechanisms. Aldosterone also stimulates PAI-1 expression in
cardiomyocytes through a non-genomic pathway. TGF-β stimulates collagen expression, as well as PAI-1 expression. PAI-1 inhibits the formation of plasmin from
plasminogen. This decreases ECM degradation by decreasing plasmin-mediated activation of MMPs; however, increased PAI-1 can also prevent plasmin-mediated activation
of latent TGF-β and affect cell migration through complex mechanisms involving the interaction of u-PA with urokinase receptor (uPAR), lipoprotein-receptor-related
peptide (LRP) and cell-surface integrins. HRE, hormone-responsive element.
Dichek and co-workers [83] have reported that PAI-1deficient mice and transgenic mice overexpressing macrophage uPA develop cardiac fibrosis through a TGF-βindependent mechanism.
Increased expression of (prepro) ET (endothelin)-1
also contributes to aldosterone-mediated cardiac and
vascular fibrosis and hypertrophy. Aldosterone/salt
treatment increases ET expression in the heart, vasculature and kidney [84,85]. ET stimulates cardiomyocyte
hypertrophy and increases collagen synthesis by cardiac
fibroblasts, in part, through effects of TGF-β 1 [86,87].
Importantly, ETA (ET type A receptor) antagonism
prevents small artery remodelling and cardiac and aortic fibrosis and hypertrophy in aldosterone- and aldosterone/salt-treated rats respectively [84,88].
CLINICAL TRIALS OF MR ANTAGONISTS
IN CHF
Increased plasma aldosterone concentrations portend a
poor prognosis in CHF. The observation that aldosterone
concentrations ‘escape’ during chronic ACE inhibition
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spurred clinical trials examining the effect of combined
MR antagonism and ACE inhibition in patients with
CHF. In RALES (Randomized Aldactone Evaluation
Study), the addition of 25 mg of spironolactone to
patients with NYHA (New York Heart Association)
Class III or IV heart failure, who were already treated
with an ACE inhibitor, diuretics and digoxin, reduced
mortality by 30 % [89]. The EPHESUS (Eplerenone
Neurohormonal Efficacy and Survival) trial studied the
effect of the addition of 25–50 mg of eplerenone/day
to standard therapy with ACE inhibitors, AT1 receptor
antagonists, β-blockers, digoxin and diuretics in patients
with LV (left ventricular) dysfunction following a recent
myocardial infarction [90]. The addition of eplerenone
reduced all-cause and cardiovascular mortality.
MR antagonism reduces the incidence of fatal arrhythmias in patients with CHF [91]. This could result
from classical effects of MR antagonism on sodium and
potassium homoeostasis and decreased relative hypokalaemia or from alterations in noradrenaline (norepinephrine) re-uptake. CHF is characterized by activation
of the sympathetic nervous system; impaired cardiac
re-uptake of noradrenaline is associated with a poor
Aldosterone and end-organ damage
prognosis in CHF patients [92]. Studies in the Dahl
salt-sensitive rat indicate that aldosterone also inhibits
NET (noradrenaline transporter) via an ETA -dependent
mechanism, whereas MR antagonism restores NET
function [93]. Alternatively, MR antagonism could also
reduce mortality by decreasing fibrosis and remodelling
and, in turn, affecting the substrate for the generation
of arrhythmias. In this regard, it is notable that the
reduction in markers of ECM turnover, such as PIIINP
(procollagen type III N-terminal peptide), predicted the
reduction of mortality in RALES [94].
RALES and the EPHESUS trial were conducted in
patients with systolic dysfunction. Heart failure due to
LV hypertrophy and diastolic dysfunction causes considerable morbidity and mortality in patients with longstanding hypertension. The 4E-LV Hypertrophy Study
compared the effects of the ACE inhibitor enalapril
(40 mg/day), eplerenone (200 mg/day) or a combination
of enalapril (10 mg/day) and eplerenone (200 mg/day)
[95]. Both enalapril and eplerenone decreased LV mass
as measured by MRI (magnetic resonance imaging), but
the combination of enalapril + eplerenone decreased LV
mass to a greater degree than the MR antagonist alone.
Unfortunately, interpretation of this study is confounded
by the fact that systolic BP was also reduced to a greater
degree in the combination arm compared with the MRantagonist-treatment arm.
INAPPROPRIATELY HIGH ALDOSTERONE
CONCENTRATIONS IN RESISTANT
HYPERTENSION
In 1955, Dr Jerome Conn [96] first described a patient
with severe hypertension, hypokalaemia and an aldosterone-secreting adenoma. Although aldosteronesecreting adenomas are relatively uncommon among
patients with hypertension, the work of Calhoun et al.
[97,98] and others suggests that aldosterone concentrations are inappropriately high relative to salt intake in a
substantial proportion of individuals with hypertension,
particularly among those who are overweight or have
sleep apnoea. Whether the apparent increase in the
prevalence of primary hyperaldosteronism results from
the increased use of the ARR (aldosterone/renin ratio)
in screening or due to a true increase in the prevalence,
perhaps related to the epidemic of obesity (see below), is
a topic of debate. Although elevated plasma aldosterone
concentrations provide a useful screening tool, increased
plasma renin activity due to antihypertensive treatment
can falsely decrease the ARR; therefore the salinesuppression test and measurement of urinary aldosterone
excretion during sodium loading remain the screening
tests of choice for primary hyperaldosteronism [99].
Nevertheless, studies demonstrating the effectiveness
of MR antagonism in patients with resistant hypertension
support a high prevalence of hyperaldosteronism among
this population. For example, among patients requiring
treatment with adequate doses of three or more
antihypertensive medication, 20 % have elevated urinary
aldosterone concentrations and suppressed plasma renin
activity. Treatment with an MR antagonist dramatically
lowered BP in these patients [97]. In the ASCOT
(Anglo–Scandinavian Cardiac Outcomes Trial)-BloodPressure-Lowering Arm, the non-randomized addition
of spironolactone as a fourth-line antihypertensive agent
reduced BP by 21.9/9.5 mmHg in participants who
were already taking an average of 2.9 antihypertensive
medications [100]. As in animal models, MR antagonism
reduces circulating biomarkers of inflammation, such as
PAI-1, in individuals with hypertension [101].
CLINICAL STUDIES OF THE EFFECT OF MR
ANTAGONISM IN RENAL DISEASE
Although ACE inhibitors and AT1 receptor antagonists
slow the progression of diabetic and non-diabetic nephropathy, albuminuria can return to baseline levels with
chronic therapy [102]. Escape from the renoprotective
effects of ACE inhibitors has also been associated with
aldosterone escape in patients with Type 2 diabetes
mellitus [103].
Several studies have examined the effect of MR antagonism on microalbuminuria in individuals with essential
hypertension. In addition to predicting progression to
renal insufficiency, urinary albumin excretion has been
associated with an increased risk of cardiovascular events
[104]. In the 4E-LV Hypertrophy Study, combination
treatment with the ACE inhibitor enalapril and
eplerenone reduced the urine albumin/creatinine ratio to
a greater degree than did either eplerenone or enalapril
alone [95]. Again, it is not possible to conclude whether
this renoprotective effect of a combination of ACE
inhibition/MR antagonism resulted from interruption
of the RAAS or superior BP reduction in this study.
However, in a study of patients with mild-to-moderate
hypertension, 50–200 mg of eplerenone/day reduced
urine albumin excretion to a significantly greater extent
than did 10–40 mg of enalapril, despite equivalent effects
of the two drugs on BP [105]. Similarly, in older patients
with systolic hypertension, eplerenone reduced urine
albumin to a greater extent than did amlodipine at
comparable hypotensive doses [106].
MR antagonism also reduces microalbuminuria in
patients with mild diabetic nephropathy. For example,
addition of 25 mg of spironolactone/day to patients with
Type 2 diabetes with aldosterone escape significantly
reduced urinary albumin excretion without affecting BP
[103]. Rachmani et al. [107] reported the effect of randomized treatment with either spironolactone (100 mg/day)
or the ACE inhibitor cilazapril (5 mg/day) on a
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background of atenolol and hydrochlorothiazide in a
group of hypertensive post-menopausal female diabetic
patients. Despite equivalent effects on BP and HbA1c
(glycated haemoglobin), spironolactone reduced urinary
albumin excretion to a greater extent than did cilazapril.
Addition of spironolactone enhanced the effect of
cilazapril on urine albumin excretion when both groups
were crossed over to combination therapy with spironolactone and cilazapril at the end of the study. In patients
with Type 2 diabetes, 50–200 mg of eplerenone/day
reduced urinary albumin/creatinine ratio to a greater
extent than treatment with 10–40 mg of enalapril/day
and the combination of eplerenone + enalapril was more
effective than either agent alone [108].
Studies have also examined the effect of adjuvant MR
antagonism on renal function in patients with overt
proteinuria or renal insufficiency. For example, in patients
with residual proteinuria despite ACE inhibition and
BP control, the addition of 25 mg of spironolactone/day
significantly reduced proteinuria and urinary excretion
of Type IV collagen, a potential marker of renal collagen
turnover, without affecting BP [109]. In patients with depressed glomerular function treated with ACE inhibitors
and/or AT1 receptor antagonists, the addition of 25 mg of
spironolactone/day significantly reduced urinary protein
excretion through a BP-independent mechanism [110].
These clinical studies suggest that MR antagonism
reduces urine albumin excretion in hypertension, mild
diabetic nephropathy and mild-to-moderate chronic
renal disease; however, whereas ACE inhibition and AT1
receptor antagonism have been demonstrated to improve
outcomes in patients with renal disease, the effect of MR
antagonism on progression to end-stage renal disease and
mortality has yet to be determined.
ALDOSTERONE, THE METABOLIC
SYNDROME AND DIABETES
Elevated aldosterone concentrations are associated not
only with difficult-to-control hypertension, but also
with obesity and the metabolic syndrome [111,112].
Aldosterone concentrations correlate with BMI (body
mass index), particularly in women [113,114]. The
stimulation of aldosterone synthesis by oxidized fatty
acids such as 12,13-epoxy-9-keto-10(trans)-octadecenoic acid may contribute to this association [115].
However, results from clinical trials indicating that
interruption of the RAAS by ACE inhibition or
AT1 receptor antagonism decreases the incidence of
Type 2 diabetes mellitus [116] suggests the alternative
possibility that aldosterone concentrations influence the
development of the metabolic syndrome and diabetes.
Aldosterone decreases glucose-stimulated insulin
release [117] and may affect insulin release indirectly by
lowering potassium [118]. Aldosterone can also decrease
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insulin receptor expression in adipocytes and monocytes
via an MR-dependent mechanism [119]. MR activation
attenuates the effect of insulin on hepatic gluconeogenesis
[120]. These effects do not appear to be mediated by expression of sgk-1, as sgk-1 up-regulates GLUT-1
(glucose transporter-1) activity and expression, and
sgk-1-deficient mice exhibit decreased glucose uptake
and increased circulating glucose concentrations after a
glucose load [121].
Most studies on the effect of aldosterone on insulin
sensitivity and glucose homoeostasis in humans have
focused on patients with primary hyperaldosteronism.
Conn [122] reported the association of hypokalaemia
with impaired carbohydrate tolerance over 40 years ago.
Surgical resection of aldosterone-secreting adenomas
improves glucose concentrations and has been reported
to improve or to have no effect on HOMA-IR (homoeostasis model assessment-insulin resistance), an indirect
measure of insulin sensitivity [123,124]. Hyperinsulinaemic euglycaemic clamp studies indicate that surgical
resection of aldosterone-secreting adenomas improves
insulin sensitivity, whereas MR antagonism in patients
with idiopathic hyperaldosteronism does not [125].
On the contrary, spironolactone has been reported
to increase HbA1c concentrations in patients with
Type 2 diabetes [126,127]. Given that circulating aldosterone concentrations are often increased during MR
antagonism, this suggests that aldosterone affects glucose
metabolism and/or insulin sensitivity through an MRindependent effect, a possibility that merits further
investigation.
CONCLUSIONS
Aldosterone contributes to cardiac and vascular
hypertrophy by acting on MR-dependent pathways
in the kidney to foster systemic sodium retention and
hypertension. During high-salt intake, inappropriately
high aldosterone concentrations also promote cardiovascular remodelling and renal injury by stimulating oxidative stress, endothelial dysfunction, inflammation and
fibrosis. Induction of oxidative stress, inflammation
and fibrosis involves complex interactions between the
MR and the AT1 receptor, as well as EGFR, and may
involve both genomic and non-genomic mechanisms.
Continuing research in vitro and in vivo in animal
models is required to discern the ligand specificity of MR
activation, the role for MR-dependent compared with
-independent effects, and the importance of genomic
compared with non-genomic pathways. Likewise,
further studies are needed to elucidate the mechanism
through which salt facilitates the profibrotic effects of
aldosterone or MR activation, and to identify tissuespecific pathways involved in the progression from
inflammation to fibrosis.
Aldosterone and end-organ damage
At the same time, clinical studies provide unequivocal
evidence of a beneficial effect of MR antagonism in
patients with CHF, who are screened and monitored to
reduce the risk of hyperkalaemia. MR antagonism shows
promise in the treatment of resistant hypertension and
diabetic and hypertensive nephropathy, but large trials
with morbidity and mortality outcomes are needed.
ACKNOWLEDGMENTS
This work was supported by NIH (National Institutes of
Health) grants HL067308, HL060906 and HL 077389.
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Received 4 April 2007/9 May 2007; accepted 16 May 2007
Published on the Internet 13 August 2007, doi:10.1042/CS20070123
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