Pediatr Nephrol (2012) 27:1059–1066
DOI 10.1007/s00467-011-1928-4
REVIEW
Glucocorticoid-induced hypertension
Julie E. Goodwin & David S. Geller
Received: 1 April 2011 / Revised: 12 May 2011 / Accepted: 13 May 2011 / Published online: 9 July 2011
# IPNA 2011
Abstract Glucocorticoid-induced hypertension is a common
clinical problem that is poorly understood, thus rendering
treatment strategies sub-optimal. This form of hypertension
has been commonly thought to be mediated by excess sodium
and water reabsorption by the renal mineralocorticoid
receptor. However, experimental and clinical data in both
humans and animal models suggest important roles for the
glucocorticoid receptor as well, in both the pathogenesis and
maintenance of this hypertension. The glucocorticoid receptor
is widely expressed in a number of organ systems relevant to
blood pressure regulation, including the kidney, the brain and
the vasculature. In vitro studies in isolated kidney tissues as
well as in vascular smooth muscle and vascular endothelial
cells have attempted to elucidate the molecular physiology of
glucocorticoid-induced hypertension, but have generally been
limited by the inability to study signaling pathways in an
intact organism. More recently, the power of mouse genetics
has been employed to examine the tissue-specific contribu-
tions of vascular and extra-vascular tissues to this form of
hypertension. Here we review recent developments in our
understanding of the pathogenesis of glucocorticoid-induced
hypertension.
J. E. Goodwin (*)
Section of Nephrology, Department of Pediatrics,
Yale University School of Medicine,
333 Cedar Street, PO Box 208064, New Haven, CT 06520, USA
e-mail: julie.goodwin@yale.edu
D. S. Geller
Section of Nephrology, Department of Medicine,
Yale University School of Medicine,
New Haven, CT 06520–8029, USA
D. S. Geller
Department of Medicine, Veterans Affairs Medical Center,
West Haven, CT 06516, USA
Keywords Hypertension . Glucocorticoid receptor . Mouse
model . Vascular smooth muscle . Endothelium . Nitric oxide
Introduction
Excess glucocorticoid, whether endogenous, as in Cushing's
syndrome, or exogenous, via pharmacological administration
of glucocorticoids, induces hypertension. Approximately
80% of patients with Cushing’s syndrome have hyperten-
sion, while 20% of patients receiving chronic pharmacolog-
ical treatment with glucocorticoids have hypertension [1]. In
the general population, hypertension increases the risk of
cardiovascular disease with a doubling in mortality from
ischemic heart disease and stroke for every 20 mm Hg
systolic or 10 mm Hg diastolic increase in blood pressure
[2]. This likely contributes to increased mortality; patients
with Cushing’s disease have a five-fold increased standard
mortality ratio for vascular disease [3].
Given the widespread usage of glucocorticoids in the
treatment of neoplastic, rheumatological, immunological
and other disease processes, the public health significance
of glucocorticoid-induced hypertension is clear. Despite
this, however, the mechanisms underlying this association
are unclear. This form of hypertension is commonly
believed to be mediated through promiscuous activation
of the mineralocorticoid receptor by excess glucocorticoid
[2, 4], and this certainly plays a role. However, increasing
evidence argues against this being the only, or perhaps even
the most significant, factor.
The hypertensive response to glucocorticoids in patients
suffering from Addisonian shock occurs much too rapidly
to be explained by renal mechanisms alone and suggests the
crucial role of vascular tissues in acute blood pressure
responses [5]. More significantly, however, many lines of
1060
evidence indicate that glucocorticoids are capable of
inducing sustained elevations of blood pressure in both
humans and in animal models via effects entirely indepen-
dent of the mineralocorticoid receptor. For example,
budesonide, a potent glucocorticoid with essentially no
activity at the mineralocorticoid receptor, produces sustained
hypertension in humans [6], while RU486, an anti-
glucocorticoid agent without anti-mineralocorticoid effects,
prevents hypertension in both humans with Cushing’s
syndrome [7–9] as well as in rat models of glucocorticoid-
induced hypertension [10, 11]. Similarly, spironolactone does
not inhibit glucocorticoid-mediated hypertension in humans
[12] or in rat models [13, 14], despite blocking salt and water
retention; excess renal sodium reabsorption does not appear
to be required for the development of hypertension in these
model systems either [15]. In fact, in vivo studies consis-
tently demonstrate that glucocorticoids acutely increase renal
sodium excretion in adrenalectomized rats [16–19] although
the sustained effects of glucocorticoids on renal sodium
handling are more challenging to assess.
These data argue that the effects of glucocorticoids,
other than their activity on the renal mineralocorticoid
receptor, must play a role in the causation of hyperten-
sion by glucocorticoids. Surprisingly, we have little
understanding of what these mechanisms are or where
they might be active. Glucocorticoids have been impli-
cated in the regulation of blood pressure via a wide
variety of extrarenal tissues, including the vascular
smooth muscle, vascular endothelium, CNS, and adipose
tissue, as shown in Fig. 1. Here, we will review what is
known about the glucocorticoid effects on blood pressure in
each of these systems.
Fig. 1 Schematic representation
of the proposed important path-
ways in glucocorticoid-induced
hypertension described in the
text
Pediatr Nephrol (2012) 27:1059–1066
The glucocorticoid receptor and the kidney
Is it possible that glucocorticoids may regulate renal
sodium reabsorption via effects on the renal glucocorticoid
receptor? The glucocorticoid receptor is widely expressed
in the kidney, and yet, its role there is poorly understood.
While glucocorticoid receptor mRNA has been identified in
most cells of the (rat and rabbit) nephron, it is most
abundant in the glomerulus, proximal tubule, and thick
ascending limb segments [20]. Conversely, immunoreactive
(human) glucocorticoid receptor has been demonstrated by
light microscopy primarily in the distal convoluted tubules
and collecting ducts, with moderate detection in the
glomerulus, and a faint presence in the proximal tubule.
Within the glomerulus, light microscopy and electron
microscopy identified the glucocorticoid receptor in all cell
types, including visceral epithelial cells, parietal epithelial
cells, mesangial cells, and endothelial cells [21].
Despite its wide expression within the kidney, the role of
glucocorticoids within any cells of the nephron is not clear,
as data on functional effects of glucocorticoids in the
kidney have been contradictory [20]. Glucocorticoids have
been ascribed a number of roles within the kidney via in
vitro studies, including a role in increasing glomerular
filtration rate [22], regulation of renal ammoniagenesis [23],
gluconeogenesis [24], sodium–hydrogen ion exchange [25,
26], and sodium–phosphate cotransport [25, 27].
Micropuncture studies suggest that dexamethasone
increases the rate of sodium transport in the loop of Henle
[28], as well as Na-K-ATPase activity in the medullary thick
ascending limb [29], but in situ microperfusion showed no
effect of glucocorticoid hormones on loop sodium transport
Pediatr Nephrol (2012) 27:1059–1066
[30]. In the distal nephron, there is increasing evidence that
glucocorticoids serve to regulate the sodium reabsorption
machinery.
Dexamethasone increases mRNA abundance of a number
of genes central to renal sodium reabsorption, including sgk-1,
α-ENaC, and GILZ [18]. RU28362, a pure glucocorticoid
agonist devoid of mineralocorticoid effects, induces
mineralocorticoid-like effects in cultured collecting duct
cells; this activity is blocked by glucocorticoid, but not
mineralocorticoid antagonists [31]. Finally, dexamethasone
induces a kidney-specific WNK1 isoform in cultured cells
[32] while decreasing expression of WNK4 as well [33];
elevated expression of WNK1 and decreased activity of
WNK4 have both been associated with a hereditary form of
human hypertension and hyperkalemia via upregulation of
thiazide-sensitive cotransporter activity [34–36].
It should be noted, of course, that this potential activation
of the distal nephron glucocorticoid receptor by glucocorti-
coids, as with activation of the mineralocorticoid receptor,
would require glucocorticoids to evade 11β-HSD2 machinery
metabolizing glucocorticoids, at least in aldosterone-sensitive
epithelia.
Although the sum of these in vitro observations would
seem to point to an anti-natriuretic role of glucocorticoids in
the distal nephron, studies performed in live animals have
consistently demonstrated that glucocorticoids induce
natriuresis in conjunction with a more prominent kaliuresis
[17, 18]. As such, the contribution of glucocorticoids to renal
sodium handling has remained difficult to comprehend. We
believe glucocorticoid infusion acutely increases blood
pressure in these rats via vascular mechanisms, as noted
above, thus increasing renal perfusion and triggering a
pressure natriuresis independent of any renal effects of
glucocorticoids. Furthermore, even in non-adrenalectomized
rats, dexamethasone induces a rapid rise in blood pressure
and hemodynamics that likely triggers a pressure natriuresis
by the kidney despite the induction of sodium-transporting
machinery.
We have investigated the role of the glucocorticoid
receptor in the distal nephron via a mouse model yielding a
tissue-specific deletion of the glucocorticoid receptor, using
the Ksp-cadherin Cre model. We initially predicted that the
mice lacking the glucocorticoid receptor in the distal
nephron would become acutely hypertensive, but would
be unable to sustain this elevated blood pressure chronical-
ly. However, in our studies, mice lacking the glucocorticoid
receptor in the distal nephron developed the same degree of
acute and chronic hypertension as controls when treated
with dexamethasone [37]. These mice also demonstrated a
similar nephron number and aldosterone levels as controls,
although they had a small but significant elevation in mean
blood pressure (7 mmHg) at baseline, the etiology of which
is as yet undetermined [37]. Since the excision of the
1061
glucocorticoid receptor using the Cre-lox system is not
100% efficient the authors could not exclude the possibility
that only a small percentage of existing glucocorticoid
receptor need be present to perpetuate steroid-mediated
hypertension, nor could they rule out the possibility that
proximal upregulation of the glucocorticoid receptor was
playing a role.
Glucocorticoids and vascular tissues
The rapidity with which glucocorticoids induce a rise in
blood pressure is inconsistent with glucocorticoids inducing
hypertension via augmentation of renal sodium reabsorp-
tion and suggests, perhaps, a profound effect of glucocorti-
coids on vascular tone. Perhaps the most concentrated
efforts to date have been focused on trying to understand
the vascular effects of glucocorticoids and how they may
contribute to clinically observed hypertension. There is
evidence that the glucocorticoid receptor is present both in
vascular smooth muscle [38–40] and in the vascular
endothelium [39, 41, 42]. The majority of studies that have
investigated glucocorticoid activity at either of these sites
have employed in vitro models.
Studies in smooth muscle cell culture have observed an
upregulation in angiotensin II type I (AT I) receptors
induced by glucocorticoids, which are hypothesized to
result in alterations in blood pressure [43, 44]. Other in
vitro studies using vascular smooth muscle cells have
indicated that the glucocorticoid receptor as well as the
mineralocorticoid receptor may mediate the effect of
glucocorticoids on the influx of Na+ and/or Ca2+ into cells
[39, 45].
Molnar et al. previously demonstrated that corticosterone-
induced signaling pathways in rat aortic vascular smooth
muscle cells involved phosphorylation of the mitogen-
activated protein kinases, Src and Akt which is believed
to be mediated through the classical mineralocorticoid
receptor. In the same study, the authors showed that
corticosterone enhanced phenylephrine-induced vasocon-
striction in isolated aortic rings in a dose-dependent
manner, and that this effect was blocked by pre-treatment
of the rings with L-NAME or indomethacin, suggesting
that the effect of corticosterone is endothelial-dependent.
Pre-incubation with RU486, a glucocorticoid receptor
blocker lessened the observed corticosterone-dependent
effects, while pre-incubation with spironolactone, a
mineralocorticoid blocker, did not. Ultimately, the authors
suggest that glucocorticoids may activate signaling of the
mineralocorticoid receptor in non-epithelial tissues,
resulting in the formation of a protein complex that
may also include the glucocorticoid receptor, which then
transmits the signal [46].
1062
A recent study in rats by Ong et al. is one of the only
attempts in vivo to try to dissect the underlying mechanism
of hypertension by examining regional blood flow [47]. In
this study, central and regional blood flows of
dexamethasone-treated rats were compared with those of
rats treated with minoxidil and dexamethasone, saline
alone, and minoxidil alone. The authors were able to
measure cardiac output and regional blood flow directly by
placing a perivascular probe around the aorta, renal artery,
superior mesenteric artery and common iliac artery of
anesthetized animals.
Dexamethasone increased blood pressure in association
with an increase in total peripheral resistance. Interestingly,
there was no detectable increase in the peripheral resistance
in any of the regional vascular beds assessed. In the group
treated with both minoxidil and dexamethasone, the authors
show that these rats have significantly lower total peripheral
resistance and significantly higher cardiac output than the
rats treated with dexamethasone alone, although there is no
significant decrease in mean arterial pressure. Since the
increase in total peripheral resistance was prevented, while
the increase in blood pressure was not, the authors suggest
that increased total peripheral resistance is not necessary for
the development of glucocorticoid-induced hypertension.
They speculate that changes in cardiac output and specifically
stroke volume and resulting plasma expansion may have
offset the vasodilator effects of minoxidil, even though there
were no observed differences in hematocrit between the
dexamethasone-only-treated rats and the minoxidil- and
dexamethasone-treated rats in this study [47].
Vascular glucocorticoid effects and nitric oxide
There is evidence to confirm the presence of the glucocor-
ticoid receptor in vascular smooth muscle cells [48, 49] and
in the vascular endothelium [49–51], but little is known
about its role at these sites. In vitro experiments with
endothelial cell culture models have suggested that gluco-
corticoids regulate vascular reactivity via suppression of the
production of vasodilators, such as prostacyclin and nitric
oxide, but conflicting evidence exists in this regard.
Provencher et al. demonstrated an increase in angiotensin
II receptor levels, yet a decrease in endothelin-1 levels in
response to synthetic glucocorticoids in a cell culture model
of vascular smooth muscle cells [38]. Endothelin-1,
secreted only by the endothelium, is the strongest vasocon-
strictor known. These contradictory results led the authors
to speculate that glucocorticoids function as modulators of
vascular inflammation and not solely as vasoconstrictive
agents.
Experiments performed using vascular endothelial models
have generally employed vessels in which the endothelium
Pediatr Nephrol (2012) 27:1059–1066
has been mechanically stripped, and hence is devoid of all
endothelial function. Wallerath et al. suggest that it is the
ability of glucocorticoids to destabilize endothelial nitric
oxide synthase (eNOS) mRNA and reduce eNOS protein
expression that is responsible for the ensuing hypertension
observed in rats treated with dexamethasone [52]. More
recent studies in isolated rat aortas showed that, through the
glucocorticoid receptor, glucocorticoids could decrease
expression of guanosine triphosphate cyclohydrolase 1
(GTPCH1) mRNA, the rate-limiting enzyme in the
production of tetrahydrobiopterin (BH4), a cofactor for
nitric oxide synthase [53]. However, in this series, eNOS
mRNA levels were not significantly different in control
vessels than in those treated with dexamethasone.
Studies in smooth muscle cell culture have postulated
that the observed glucocorticoid-induced upregulation of
AT1 receptors may alter blood pressure [43]. To date, there
has not been a reliable way to assess the role of vascular
endothelial glucocorticoid receptor in vivo. In addition,
there is increasing focus on the purported non-genomic
effects of glucocorticoids that would allow very rapid
signaling responses as opposed to the traditional notion of
nuclear translocation and transcription, which theoretically
take much longer. The mystery as to how a receptor with
only one known gene can effect such a vast array of
physiological and pharmacological consequences suggests
that there must be multiple promoters, mRNAs, transla-
tional isoforms and/or post-translational modifications to
account for such diversity. The discovery of profound
species diversity in glucocorticoid sensitivity also suggests
that there may be specific environmental or epigenetic
influences that have an impact on cellular responses to
glucocorticoids. Given all of these variables, it is
conceivable that a dozen or more glucocorticoid receptor
isoforms may be able to be generated in a single cell
[54]. Therefore, it is not particularly surprising that there is
much that is poorly understood about vascular responses
to glucocorticoids.
To answer these questions, we have used advances in
mouse genetics to enable a more targeted in vivo approach.
We recently characterized a mouse model in which we were
able to selectively remove the glucocorticoid receptor
specifically from vascular smooth muscle tissues via the
use of SM22-Cre. We showed that, while knockout and
control mice had similar baseline blood pressures with
normal diurnal variation, knockout animals demonstrated a
statistically significant attenuation of the acute hypertensive
response to exogenous dexamethasone [55]. This persisted
through 1 week of dexamethasone administration, but the
difference in blood pressure was not statistically significant
after 2 weeks. Interestingly, in this study, the acute
natriuretic response to dexamethasone was preserved in
the knockout animals even though the acute hypertensive
Pediatr Nephrol (2012) 27:1059–1066
response was not. This finding raises the possibility that the
preserved “pressure natriuresis” is responsible for the
absent hypertensive response and that the glucocorticoid
receptor’s presence in the vascular smooth muscle serves as
an obstacle to pressure natriuresis. This proposal is
speculative, but it seems clear that the preserved “pressure
natriuresis” in the absence of elevated blood pressure
suggests a complex relationship between glucocorticoids
and the systemic and renal vasculature, which will require
further investigation.
In a second mouse model used to investigate tissue-
specific contributions of the glucocorticoid receptor, we
removed the glucocorticoid receptor from the vascular
endothelium by using Tie-1 Cre. Interestingly, these
knockout animals had a small but statistically significant
increase in their baseline blood pressure, the source of
which could not be entirely explained. In addition, the
knockout animals were almost completely resistant to
glucocorticoid-induced hypertension and conspicuously
lacked the pressure natriuresis observed in the vascular
smooth muscle glucocorticoid receptor knockout model.
Intravital microscopy studies done in real-time on resis-
tance vessels from these knockout animals revealed a
statistically significant decrease in vessel contractility to
the glucocorticoid receptor-specific ligand dexamethasone
compared with wild-type animals. The contractility to
phenylephrine was similar between the two groups suggest-
ing that loss of the endothelial glucocorticoid receptor
confers a specific contractile defect in these animals,
presumably preventing them from mounting a hypertensive
response to systemic dexamethasone. In this study whole
blood nitric oxide levels were not different between the two
groups, although we cannot rule out the possibility of
differences in nitric oxide in local vascular beds [56].
Other laboratories have examined nitric oxide derange-
ments via ex vivo investigations in rats. In 2009, Aras-
Lopez et al. evaluated electrical-field stimulation-induced
neuronal nitric oxide release in mesenteric arteries of
Wistar–Kyoto (WKY) rats and spontaneously hypertensive
rats (SHRs) and the role of protein kinase C (PKC) in these
responses [57]. Through a series of manipulations involv-
ing various PKC inhibitors, the authors demonstrated that
dexamethasone was able to reduce neuronal nitric oxide
release in arteries from SHRs but not WKY rats, and that
this effect was mediated though activation of glucocorti-
coid receptors. This is the first study to address the
possibility that glucocorticoids exert their hypertensive
effects, at least in part, by altering the neuronal nitric oxide
release of the perivascular innervation of these tissues
[57]. This study raises important questions with regard to
differential effects of glucocorticoids on the various nitric
oxide isoforms, which appear to be affected by the overall
milieu.
1063
Glucocorticoids and the metabolic syndrome
The metabolic syndrome, comprising obesity, hypertension,
dyslipidemia, and insulin resistance, is an increasingly
common diagnosis in the industrialized world. The pheno-
type shares many characteristics with Cushing’s syndrome,
caused by excess systemic glucocorticoids, raising the
question of whether glucocorticoid effects might play a
role in the development of the metabolic syndrome. While
systemic elevations of glucocorticoid levels are rare in the
metabolic syndrome, local glucocorticoid effects could
account for some of the findings.
In this vein, Rask et al. found increased expression of
11β-HSD1 in the adipose tissue of obese patients [58]. As
11β-HSD1 functions in the local regeneration of inactive
corticosteroids (converting cortisone to the active cortisol in
humans and 11-dehydrocorticosterone to the active cortico-
sterone in rodents), this led to the question of whether its
presence could be related to the development of the
metabolic syndrome in these individuals.
This question was elegantly answered by Masuzaki and
colleagues who generated a transgenic mouse overexpress-
ing 11β-HSD1 specifically in visceral adipose tissue [59].
These mice essentially exhibited the metabolic syndrome,
with visceral obesity, insulin resistance, dyslipidemias, and
intriguingly, hypertension. Importantly, systemic glucocor-
ticoid levels were identical to those in control mice,
suggesting that the hypertension could not be readily
explained by systemic glucocorticoid excess. On the other
hand, glucocorticoid levels were found to be elevated in the
portal circulation, suggesting that downstream effects of
glucocorticoids, particularly in the liver, could be playing a
role in some of the observed metabolic derangements.
To further investigate this question, Paterson et al. made
a second transgenic mouse, this time overexpressing 11β-
HSD2 in hepatic tissue. They identified insulin resistance,
dyslipidemia, and hypertension in these mice as well,
suggesting that at least some of the metabolic derangements
present in the adipose model described above, including the
hypertension, could be due to downstream portal flow of
newly generated corticosteroids. Of note, however, there
was low level expression of 11β-HSD1 in the kidney of
these mice that the authors did not further characterize—if
this expression were localized to the distal nephron, this
could contribute to the observed hypertension. Furthermore,
systemic effects of downstream glucocorticoid release
could not be definitively ruled out [60].
To further address these questions, we have recently
evaluated a novel model of tissue-specific excess glucocor-
ticoid effect. We created a mouse, permitting tissue-specific
expression, but not overexpression, of a novel gain-of-
function glucocorticoid receptor characterized in our labo-
ratory [61]. As this system relies on a receptor with
1064
increased glucocorticoid sensitivity as opposed to newly
synthesized glucocorticoids, there is no possibility of a
“downstream” glucocorticoid effect. Intriguingly, expres-
sion of this overactive receptor in either adipose or
hepatic tissue is sufficient to cause hypertension in our
mice (Zhang et al., unpublished results). The mechanism
by which excess glucocorticoid effect in these tissues
leads to hypertension is not clear, although it is
interesting to note that adipose tissue has been reported
to secrete a factor that stimulates adrenal aldosterone
release in vitro [62].
Conclusions
In summary, despite an enormous body of basic science
research as well as robust clinical experience, the mecha-
nism by which steroids induce hypertension remains
unclear. It appears that there may be multiple interactions
with glucocorticoids and the glucocorticoid receptor in
multiple different tissues that result in an acute induction
phase, mainly mediated through vascular effects, and a
chronic maintenance phase, which requires the active
participation of the kidney. As shown in Fig. 1, any or all
of these mechanisms may be acting simultaneously. The
most recent studies suggest a paracrine and/or autocrine
role of glucocorticoids, which is specific to the local tissues
and milieu. Speculation about the complicated sequence of
events set in motion by glucocorticoid administration and
leading to hypertension suggests that the effects of these
ubiquitously used agents may be more far-reaching than
ever imagined.
These observations beg the question of which anti-
hypertensive agents should be employed in cases of
glucocorticoid-induced hypertension. The optimal regimen
is certainly not clear given the potential impact of
glucocorticoids on several hypertensive pathways, includ-
ing increased vascular tone, increased sodium reabsorption,
and centrally mediated mechanisms. We propose using
calcium channel blockers or other vascular relaxants if
hypertension is manifest within the first few days of
glucocorticoid administration with the eventual addition of
a diuretic if the hypertension persists or worsens. There is
potentially a role for centrally acting agents such as
clonidine, either in addition to other pharmacotherapy or
independently, although this is less clear. As for
glucocorticoid-mediated hypertension accompanied by the
stigmata of the metabolic syndrome, there is no specific
agent currently available to target overproduction of
glucocorticoids in the liver and/or adipose tissue. As
research continues in this area we speculate that the
eventual development of a clinically-approved 11β-HSD1
antagonist may prove effective.
Pediatr Nephrol (2012) 27:1059–1066
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