Download Nuclear Hormone Receptors as Regulators of the

Nuclear Hormone Receptors as Regulators of the
Renin-Angiotensin-Aldosterone System
Irma Kuipers, Pim van der Harst, Gerjan Navis, Linda van Genne, Fulvio Morello, Wiek H. van Gilst,
Dirk J. van Veldhuisen, Rudolf A. de Boer
T
Downloaded from http://hyper.ahajournals.org/ by guest on May 6, 2017
he renin-angiotensin-aldosterone system (RAAS) has
been identified as the main system involved in blood
pressure regulation, renal hemodynamics, and sodiumvolume homeostasis. Furthermore, the RAAS directly affects
vascular and cardiac remodeling through proliferative and
inflammatory signaling. Pharmacological targeting of the
RAAS is a consolidated and evidence-based approach in the
treatment of various aspects of cardiovascular disease. An
exploding number of recent studies have provided novel
insights into nuclear receptor biology in relation to cardiovascular (patho)physiology. In particular, members of the
nuclear hormone receptor (NHR) superfamily have been
identified as key molecules in various relevant cellular
processes. As such, NHRs have been proposed as amenable
targets for therapy, and their role in cardiovascular disease is
currently explored.
This review focuses on the potential effects of NHRs on the
RAAS, summarizing the extensive body of evidence from
experimental, animal, and clinical studies, suggesting that
NHRs and the RAAS are closely intertwined. We discuss
how these findings might translate into the clinical setting and
discuss the (older) trials that evaluated NHR agonists in
humans. We postulate that therapies targeting NHRs will
cause ancillary effects (ie, modulating the RAAS) that need to
be considered.
indicated as “orphan” receptors, because their ligands are as
yet unknown. After activation by their ligands, NHRs bind to
DNA-responsive elements located within target gene promoters or have cross-talk with other signaling pathways. Effects
are often modified by nuclear coregulators (coactivators and
corepressors).
However, if and how different NHRs may affect the RAAS
remain largely unknown. Angiotensin II (Ang II) is the main
effector peptide of the RAAS. Other end products are
generated as well, such as angiotensin IV, angiotensin (1-7),
and others (detailed in Figure S1). In this review, we focus
mainly on the effects of NHRs on renin, angiotensinogen, and
angiotensin receptors.
NHRs and Renin
Renin is (almost) exclusively secreted from specialized juxtaglomerular (JG) cells, located in the afferent arterioles of
the kidney. Renin transcription is tightly regulated.3 It has
become clear that several NHRs regulate renin transcription
through interaction with specific responsive elements in the
renin promoter (Figure 1). Through specific responsive elements, NHRs can act as either positive or negative regulators
of renin transcription (Table).
Liver X Receptors
Liver X receptor (LXR)-␣ and the highly homologous
LXR-␤ are important modulators of lipid and glucose metabolism, inflammation, and innate immunity.4 LXR-␣ is expressed predominantly in liver, gut, heart, kidney, and adrenals, whereas LXR-␤ is ubiquitously expressed. Tamura et al5
provided evidence that LXRs play an important role in renin
regulation. Previously, they described a specific responsive
element in the mouse renin promoter, called cAMP-negative
response element (CNRE; Figure 1). LXR-␣ was identified as
a CNRE-binding protein that regulates renin mRNA expression. This finding was confirmed recently using a mouse in
vivo model.6 Both LXR-␣ and LXR-␤ were shown to be
regulators of renin transcription. Renal expression of LXR-␣
was found confined to JG cells (Figure 2). Interestingly,
LXR-␣ and LXR-␤ markedly differ in their control of renin
NHRs and the RAAS
NHRs constitute a superfamily of ligand-activated transcription factors involved in multiple cellular functions, acting as
monomers, homodimers, or heterodimers (usually with the
retinoid X receptors). The NHR superfamily is divided into 6
subfamilies (Table S1, available in the data supplement
online at http://hyper.ahajournals.org).1 Cloning of the NHRs
revealed that many of the NHRs share close homology. The
fourth, fifth, and sixth classes (not mentioned in Table S1)
include various NHRs that are less well described. NHR
ligands include hormones, xenobiotics, prostaglandins, fatty
acids, and cholesterol derivatives. An overwhelming amount
of evidence exists for the role of NHR in cholesterol, lipid,
and glucose metabolism.2 Several NHRs are provisionally
Received December 19, 2007; first decision January 9, 2008; revision accepted March 17, 2008.
From the Departments of Cardiology (I.K., P.v.d.H., L.v.G., W.H.v.G., D.J.v.V., R.A.d.B.) and Nephrology (G.N.), University Medical Center
Groningen, University of Groningen, Groningen, The Netherlands; and the IVth Division of Internal Medicine (F.M.), San Vito Hospital, Torino, Italy.
Correspondence to Rudolf A. de Boer, Department of Cardiology, University Medical Center Groningen, University of Groningen, PO Box 30.001,
9700 RB, Groningen, The Netherlands. E-mail [email protected]
(Hypertension. 2008;51:1442-1448.)
© 2008 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.107.108530
1442
Kuipers et al
vitamin D
retinoic acid
RXR
VDR
Ear2
thyroxine
NHRs as Regulators of the RAAS
FA, fibrates, TZDs
1443
cAMP, oxysterols
RAR
P
competition
TR
PPAR RXR
LXR
TGACCT (N)10 TGACCT
AGGTCA caa tGTTCCT
AGGTCA (N)1,2 AGGTCA
TC(C/T)CA(C/G)AG
-2633 to -2615
-1061 to -1046
??
-607 to -600
T3R/RARE
TRHE
PPRE
CNRE
Enhancer elements Eb and Ec
Figure 1. Schematic overview of NHR responsive elements in the renin promoter and topographical position in the renin promoter.
Ligands are listed above NHRs. NHRs acting as positive regulators are displayed in green boxes; negative regulators are in red boxes.
Liganded NHRs have a small triangle on top. P indicates phosphorylated; THRE, thyroid hormone response element.
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transcription, because the latter constitutively upregulates
renin mRNA expression, whereas LXR-␣ increases renin
mRNA only in a cAMP-dependent manner. Importantly,
high-renin status models were associated with prominent
LXR-␣ binding activity to the CNRE. Experiments in LXRdeficient mice confirmed that LXR-␣ is necessary for the
cAMP-dependent response of JG cells, whereas LXR-␤
confers a basal constitutive effect on renin transcription and
seems not strictly required for the functional responses of the
JG apparatus.
LXR agonists are currently explored as a novel therapy
aimed at enhancing reverse cholesterol transport, thereby
inhibiting the progression of atherosclerosis. To our knowledge, no LXR-specific interventions have been put to test in
humans yet. The observation that LXRs function as renin
regulators may warrant the development of selective modulators of LXR function that circumvent renin activation while
retaining the advantageous effects on lipid metabolism.
Vitamin D Receptors
Li et al7 reported direct evidence that the vitamin D receptor
(VDR) acts as a negative regulatory factor of renin transcription. VDR-transfected As4.1 cells treated with calcitriol
Table.
exhibited an almost complete abolishment of renin expression. Treatment of wild-type mice with vitamin D also
suppressed renin expression, whereas in VDR-deficient mice,
renin expression was elevated several-fold. So, vitamin D
yields a direct negative regulatory effect on renin expression
through a VDR-mediated mechanism. These findings are in
agreement with the well-known inverse correlation between
plasma vitamin D and blood pressure related to decreased
plasma renin activity in humans.8
Thyroid Hormone Receptors
Thyroid hormone receptor (TR) expression is ubiquitous,
including in the kidney. Ichihara et al9 showed that, in
cultured rat JG cells, treatment with thyroid hormones induces renin transcription/secretion in a dose-dependent fashion. The same group described 3 candidate thyroid hormone
response elements (Figure 1) located in the human renin gene
and showed that, in CaLu-6 cells, thyroid hormones stimulate
the transcription of the human renin gene.10 In vivo, plasma
renin activity and renal renin expression are significantly
reduced in hypothyroid rats and elevated in hyperthyroid
rats.11 Hyperthyroidism-induced cardiac hypertrophy is accompanied by activation of the cardiac RAAS with a signif-
Summary of NHRs Acting as Regulators of Renin Transcription
NHR
LXR-␣
LXR-␤
Activator Tested
Positive/Negative Regulator
Heterodimer/Monomer
Binding Sequence
References
cAMP
Positive
Monomer
CNRE
5, 6
Unliganded
Positive
Monomer
CNRE
6
TR
Thyroid hormone
(T3)
Positive
Monomer
TRHE
9, 10, 12
VDR
1–25(OH)2 vitamin
D3
Negative
Both?
Ec/Eb/DR3
7
Fibrates
Positive
Unknown
Unknown
16, 21
PPAR-␣
PPAR-␥
Fatty acid, TZDs
Positive
Unknown
Unknown
25
9-Cis-retinoic acid,
retinoic acid
Positive
(Hetero/homo) dimer
DR2/DR3/DR4/DR5
59
Ear2
Unknown
Negative
Unknown
RARE
60
MR
Aldosterone
Positive
Both
Unknown
61
RXR-␣/RAR-␣
THRE indicates thyroid hormone response element; TZD, thiazolidinedione; RXR, retinoid X receptor; RAR, retinoic acid receptor; RARE, rapid
acquisition with relaxation enhancement; MR, mineralcorticoid receptor.
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Hypertension
June 2008
itant blood pressure reduction or other ancillary effects of
PPAR agonists (eg, antiinflammatory and antiproliferative
effects on the vasculature or increased sympathetic activity).
Activation of PPAR-␥ signaling has been consistently
shown to lower blood pressure in various animal models and
in human studies, at least in part through direct vascular
effects.20 –23 However, controversy remains concerning the
mechanism of how PPAR-␥ influences blood pressure regulation. In an in vitro study using CaLu-6 cells, it was shown
that activation of PPAR-␥, both by endogenous and pharmacological agonists, causes a significant increase in renin
transcription.24 In a small clinical study, however, the
PPAR-␥ agonist pioglitazone reduced plasma renin levels in
humans.25 Overall, there is scarce evidence suggesting that
PPAR-␥ is a candidate regulator of JG cell function; further
studies should specifically address this issue.
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Figure 2. LXR-␣ is coexpressed with renin in JG cells in the
murine kidney. Strict colocalization is observed with dual in situ
hybridization. Both signals colocalized in JG cells (middle panel).
Reprinted with permission from Morello et al.6
icant upregulation of renin mRNA in the kidney.12 Taken
together, several lines of evidence suggest that TRs function
as positive regulators of renin transcription.
Peroxisome Proliferator-Activated Receptors
Pharmacological targeting of peroxisome proliferator-activated receptors (PPARs; fibrates and thiazolidinediones) has
been tested in the treatment of dyslipidemia, diabetes, and
established cardiovascular diseases, such as heart failure and
myocardial infarction. The 2 isoforms of PPAR are discussed
in detail below.
Several animal studies have suggested a role for PPAR-␣
in the control of renin expression. PPAR-␣– deficient mice
put on a high-fat diet are protected from the development of
hypertension.13 Mice deficient for both the low-density lipoprotein receptor and PPAR-␣ have been used to elucidate
the role of PPAR-␣ in the development of glucocorticoidrelated insulin resistance.14 In the absence of PPAR-␣, mice
were normotensive and euglycemic, despite dexamethasone
treatment. When hepatic PPAR-␣ expression was restored by
gene transfer, it not only reinduced hyperglycemia, but also
increased plasma renin activity, blood pressure, sympathetic
nervous activity, and renal sodium retention. Similar results
were obtained in PPAR-␣– deficient Tsukuba hypertensive
mice.15 Tsukuba hypertensive mice carry the human renin and
angiotensinogen genes and serve as a model of Ang IImediated hypertension. PPAR-␣ deficiency in Tsukuba hypertensive mice decreases plasma renin concentration by
⬇50% and prevents hypertension and myocardial hypertrophy. These observations are supported by observations made
in spontaneously hypertensive rats16 and healthy, human
volunteers.17 The exact role of PPAR-␣ in the regulation of
blood pressure remains unclear, because several other studies
conducted in various rat models of hypertension have provided inconsistent results.18,19 It is currently not known
whether renin activation associated with PPAR-␣ activation
is a direct transcriptional effect of PPAR-␣ or if it should be
regarded as a secondary phenomenon, attributable to concom-
Steroid Hormone Receptors
So far, the specific role of the estrogen receptors and
progesterone receptors in renin expression has not been
addressed directly. Renin levels fluctuate with the menstrual
cycle, suggesting that estrogen and progesterone are regulators of renin transcription. In cultured human chorion cells,
progesterone, estradiol, testosterone, and aldosterone all affect renin expression levels.26 Estradiol and progesterone
seem to synergistically increase renin expression, because the
combined treatment with both completely restores renin
expression in ovariectomized rats.27 Prorenin and renin are
released from placental cytotrophoblastic tissue.28 This release occurs in parallel with other placental hormones but
does not appear to be regulated by steroid receptors, human
chorionic gonadotrophin, intracellular calcium, or cAMP.
Therefore, (pro)renin release from placenta may in fact be
regulated in a different fashion from renal renin release, eg,
by local factors, such as estrogen and progesterone.
Renin Receptor
In 2002, a human renin/prorenin receptor was been cloned,
which specifically binds renin and prorenin.29 Binding of
renin to its receptor increases the catalytic activity of renin,
and binding of prorenin renders prorenin enzymatically active, comparable to renin. Although studies revealing transcription mechanisms of the renin receptor are currently
underway,30 thus far no “classical” NHRs have been identified as transcription factors for the renin/prorenin receptor.
NHRs and Angiotensinogen
Presently, only TRs, PPARs, and estrogen receptors have
been implicated in angiotensinogen transcriptional activation
and will be discussed below.
Thyroid Hormone Receptors
The thyroid hormone is a positive regulator of angiotensinogen. Hyperthyroidism, induced by treatment with thyroid
hormone (T3), causes an increase of plasma angiotensinogen
by 85% in rats.31 In parallel, hypothyroidism results in a 71%
decrease of plasma angiotensinogen levels. Similar results
were found in vitro.32 T3 treatment causes upregulation of
angiotensinogen transcription in the human hepatic cell line
Kuipers et al
HepG2. We speculate that the well-described effects of
thyroid hormones on blood pressure can partially be explained through regulation of angiotensinogen expression and
consequent activation of the RAAS.
Peroxisome Proliferator-Activated Receptors
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PPAR-␣ acts as a positive regulator of angiotensinogen
transcription. In contrast to HepG2 cells, HeLa cells treated
with the PPAR-␣ agonist bezafibrate displayed activation of
the angiotensinogen promoter.33 This difference between
HepG2 and HeLa cells might be explained by the presence of
hepatocyte nuclear factor-4 in HepG2. Hepatocyte nuclear
factor-4 binds to the same responsive region of the angiotensinogen promoter as PPAR-␣. Hepatocyte nuclear factor-4 is
not present in the cervical cell line HeLa, and cotransfaction
of hepatocyte nuclear factor-4 expression in HeLa cells
attenuated the activation of the angiotensinogen promoter by
bezafibrate.
A dominant-negative form of the PPAR-␥ gene was cloned
to create a transgenic mouse strain.34 The used mutation was
equivalent to the P467L mutation in humans causing severe
insulin resistance and hypertension. The mouse strain did not
develop high blood pressure nor increased kidney renin
mRNA content. However, upregulations of angiotensinogen
and the angiotensin type 1 receptor (AT1R) were reported.
Further research in these mice revealed an increased expression of angiotensinogen in their subcutaneous adipose tissue,
suggesting a role for PPAR-␥ in blood pressure regulation,
via the RAAS, by modulating angiotensinogen expression in
fatty tissue.
Steroid Hormone Receptors
Early studies demonstrated that estrogens and glucocorticoids
can regulate hepatic angiotensinogen production.35 Estrogen
treatment results in a prompt and significant upregulation of
angiotensinogen mRNA in rodent liver cells.36 Similar findings have been reported in humans, where women receiving
oral contraceptives or estrogen replacement therapy develop
increased circulating angiotensinogen and Ang II levels.37
Overall, the effects of estrogen receptor on angiotensinogen are potentially important in the pathophysiology
of hypertension in susceptible women and should be considered when contraceptive or hormone replacement regimens
are prescribed.
NHRs and Angiotensin Receptors
The effects of Ang II are mainly mediated via 2 plasma
membrane receptors, AT1R and angiotensin type 2 receptor
(AT2R). Most effects of Ang II are mediated by the AT1R,
including an increase of arterial blood pressure, aldosterone
secretion, and adverse cardiac and renal remodeling. Rodents
express 2 subtypes of the AT1R (A and B), whereas humans
express only 1 subtype. AT2R is expressed at high levels in
fetal tissues and decreases rapidly after birth. Although the
exact function of AT2Rs is less well understood than that of
the AT1R, it seems that AT2Rs antagonize AT1R-mediated
effects. We discuss the influence of PPARs and steroid
hormone receptors on AT1Rs and AT2Rs below.
NHRs as Regulators of the RAAS
1445
Peroxisome Proliferator-Activated Receptors
The role of PPARs in AT1R expression is well established. It
has been convincingly shown that the expression of AT1Rs is
decreased by PPAR-␥ agonists in rat vascular smooth muscle
cells,38 leading to functional inhibition of Ang II-induced cell
proliferation via AT1Rs. Functionally, Diep et al39 showed
that treatment with the PPAR-␥ activators rosiglitazone and
pioglitazone attenuated the detrimental effects of Ang II
infusion in rats. Development of hypertension, small resistance artery remodeling, endothelial dysfunction, proinflammatory mediators, and upregulation of AT1Rs, all of which
are increased by Ang II infusion, were blunted in blood
vessels of rats treated with rosiglitazone or pioglitazone. Diep
et al,39 furthermore, showed that PPAR-␥ ligands are capable
of increasing AT2R expression on a protein level. These
findings are consistent with the significant increase in myocardial AT2R mRNA found in rosiglitazone-fed rats subjected to an ischemia-reperfusion model.40 Whereas in this
model AT1R mRNA expression was reduced after rosiglitazone treatment, AT2R mRNA expression was increased by
⬎100-fold.
Cross-talk between angiotensin receptors and PPAR-␥ is,
thus, relevant. This is further underscored by the observation
that some angiotensin receptor blockers, such as telmisartan
and irbesartan are in fact partial PPAR-␥ agonists.41 The
influence of PPAR-␣ activator docosahexaenoic acid (DHA)
has also been investigated in Ang II-infused rats.42 Like
activation of PPAR-␥, activation of PPAR-␣ also attenuated
the damaging effects of Ang II infusion in rats, resulting in
reduction of Ang II-induced oxidative stress, expression of
inflammatory mediators, blood pressure, endothelial dysfunction, and remodeling of small resistance arteries. The potential clinical implications of the interaction between PPARs
and the AT1R is discussed in detail below.
Steroid Hormone Receptors
Sex hormones, especially estrogens, modulate the expression
of angiotensin receptors. Estrogen attenuates AT1R mRNA,
but increases AT2R gene expression in rat cardiac fibroblasts.43 In line with this, increased AT1R expression was
found in estrogen treated ovariectomized rats and cell cultures of rat smooth muscle cells.44 Later, this group showed
that progesterone addition to smooth muscle cell cultures
upregulated AT1R expression.45 It may be speculated that the
contrary effects of female sex hormones on angiotensin
receptor expression could be involved in the changes in
arterial pressure during the menstrual cycle and perhaps also
postmenopausal.
Potential Clinical Implications
The discussed data suggest that modulation of NHR activity
comodulates RAAS activity. Large-scale clinical studies with
NHR agonists have been conducted or are underway, with
potential clues on the role of NHRs in cardiovascular disease.
Specific agonists of PPAR-␣, PPAR-␥, VDR, and steroid
hormone receptors have been put to trial, whereas other
agonists are yet to enter the clinical arena. Unfortunately,
most clinical trials did not include end-points directly linked
to the RAAS, such as plasma renin activity or angiotensin-
1446
Hypertension
June 2008
converting enzyme activity. We will discuss the limited data
available.
Vitamin D Receptors
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Vitamin D acts as a negative regulator of renin and might
consequently reduce cardiovascular morbidity and mortality.
Currently, no large-scale mortality trials have tested the
efficacy of vitamin D in reducing events in patients with
established cardiovascular disease. Some clues are available
from trials in patients with end-stage renal disease (ESRD),
when vitamin D is primarily prescribed to treat secondary
hyperparathyroidism.
In a small study, analyzing 242 chronic hemodialysis
patients, patients treated with alfacalcidol (a vitamin D
analogue) had a significantly lower risk of cardiovascular
mortality than patients with no vitamin D treatment.46 In fact,
several observational studies indicate that there may be a
protective effect of vitamin D treatment against cardiovascular disease. This claim is hitherto restricted to hemodialysis
patients with ESRD whose main cause of death is cardiovascular. We postulate that in patients with low serum vitamin D
levels, and who are at risk for cardiovascular disease, the use
of oral vitamin D substitutes may reduce the risk for future
cardiovascular events.
Peroxisome Proliferator-Activated Receptors
PPAR-␣ agonists have been primarily tested in patients with
hypertriglyceridemia and end-points in such studies typically
were coronary events and death. The clinical use of fibrates
preceded the identification of PPAR-␣ as a nuclear receptor,
harboring potential ancillary effects beyond lipid lowering.
As such, clinical trials with PPAR-␣ agonists could be
revisited for clues regarding the impact of presumable
PPAR-␣ activation on RAAS activity. There are observations
that support the notion that other effects than lipid-lowering
effect alone play an important role. For instance, in the
Helsinki study, a paradoxical increase in noncoronary death
was observed.47 However, to our knowledge, in large scale
trials with PPAR-␣ agonist, such as the Helsinki Heart
Study, the Veteran’s Administration-HDL Intervention Trial
(VA-HIT),48 and the FIELD,49 no analyses were conducted
with regard to RAAS activity.
PPAR-␥ agonists (thiazolidinediones) exert beneficial effects on the vasculature, including decreased carotid artery
intima-medial thickness,50 improved endothelial function,
and decreased inflammation.51 Because the RAAS is a
dominant player in vascular remodeling, we speculate on
some effects to be conferred via the RAAS. In previous
sections, we discussed experimental data that show the
interaction between PPAR-␥ and the RAAS. This interaction
is predominantly at the level of the AT1R. Some angiotensin
receptor blockers are partial PPAR-␥ agonists, whereas treatment with glitazones can block Ang II-mediated effects.52
Some metabolic effects of angiotensin-converting enzyme
inhibitors and angiotensin receptor blockers, including a
reduction of new-onset diabetes, as seen in the Heart Outcomes Prevention Evaluation53 and the Losartan Intervention
for Endpoint Reduction in Hypertension,54 are suggestive for
the existence of PPAR-␥–like effects of RAAS inhibition.
Several large-scale randomized, controlled trials with
PPAR-␥ agonists have been completed recently. The Prospective Pioglitazone Clinical Trial in Macrovascular
Events55 showed rather favorable outcomes, such as a decrease in recurrent myocardial infarction and a decrease in
recurrent stroke. The Diabetes Reduction Approaches With
Ramipril and Rosiglitazone Medications Study established a
decrease in progression to diabetes in prediabetic patients
(with impaired glucose tolerance and/or impaired fasting
glucose) in rosiglitazone-treated patients.56 Unfortunately,
none of these trials reported any parameters of RAAS
activity.
These outcomes may suggest that PPAR-␥ agonists decrease cardiovascular events over time; however, this remains
speculative. Recently, PPAR-␥ agonists have come under fire
because of claims that they may increase rather than decrease
the risk of myocardial infarction.57 Although the limitations
of this meta-analysis have been pointed out by its authors and
by others,58 controversy remains concerning the safety of
thiazolidinedione treatment.
From the trials with PPAR agonists, it becomes clear that
the theoretical working profile is not paralleled with a (solely)
beneficial clinical efficacy. Likely, the effects that PPARs
exert are more global that we currently understand: the
beneficial effects may not outweigh adverse effects. We
suggest putting combinatorial therapies with RAAS-inhibitors and PPAR-␥ agonists to test in future studies, because
from the theory this might be more efficacious than either
therapy alone.
Perspectives
NHRs have emerged as a class of receptors with a wide array
of physiological effects pertaining to fatty acid, lipid, and
carbohydrate metabolism but also to other pathways, such as
inflammation, cellular proliferation, and vascular remodeling.
These processes are pivotal in cardiovascular disease, and
pharmacological targeting of NHRs might provide a novel
and promising treatment approach. Some agonists of NHRs
have entered the clinical arena, showing a promising efficacy
and safety profile. Because the RAAS is a main player in
cardiovascular homeostasis, any effects of NHRs on RAAS
activity may likely affect its working and safety profile.
In this review, we discussed the levels of interaction
between some NHRs and the RAAS. Experimental studies
have partially elucidated the molecular mechanisms of the
regulation of the RAAS by NHRs. It is speculated that, by
exploring the clinical value of NHRs, the effect on RAAS
activation may have important repercussions for their efficacy and safety. We, therefore, recommend that future clinical studies include analyses of RAAS activation.
Source of Funding
This work was supported by the Netherlands Heart Foundation (grant
2004T004).
Disclosures
None.
Kuipers et al
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Nuclear Hormone Receptors as Regulators of the Renin-Angiotensin-Aldosterone System
Irma Kuipers, Pim van der Harst, Gerjan Navis, Linda van Genne, Fulvio Morello, Wiek H. van
Gilst, Dirk J. van Veldhuisen and Rudolf A. de Boer
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Hypertension. 2008;51:1442-1448; originally published online April 14, 2008;
doi: 10.1161/HYPERTENSIONAHA.107.108530
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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Correction
In the Hypertension article by Kuipers et al (Kuipers I, van der Harst P, Navis G, van Genne L,
Morello F, van Gilst WH, van Veldhuisen DJ, de Boer RA. Nuclear hormone receptors as
regulators of the renin-angiotensin-aldosterone system. Hypertension. 2008;51:1442–1448) there
is an incorrect statement in the upper right paragraph on page 1444. The statement “In a small
clinical study, however, the PPAR-␥ agonist pioglitazone reduced plasma renin levels in humans.”
should read “In a small clinical study, the PPAR-␥ agonist pioglitazone increased plasma renin
levels in humans.”
The authors regret the error.
(Hypertension. 2008;52:e30.)
© 2008 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.108.000074
e30
NUCLEAR HORMONE RECEPTORS AS REGULATORS OF THE RENIN-ANGIOTENSINALDOSTERONE SYSTEM
Irma Kuipersa MSc; Pim van der Harsta MD; Gerjan Navisb MD; Linda van Gennea BSc; Fulvio
Morelloc MD; Wiek H. van Gilsta PhD; Dirk J. van Veldhuisena MD; Rudolf A. de Boera MD
From the Departments of Cardiologya and Nephrologyb from the University Medical Center
Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, The Netherlands and from
the IVth Division of Internal Medicinec, San Vito Hospital, Strada San Vito 34, 10134 Torino, Italy.
Short title: NHRs as regulators of the RAAS
Word count total manuscript: 5991 words
Word count abstract: 136 words
Number of figures: 2 figures
Please address correspondence to:
Rudolf A. de Boer, MD
Department of Cardiology, University Medical Center Groningen, University of Groningen, PO Box
30.001, 9700 RB, Groningen, The Netherlands.
Phone: +31503612355 / Fax: +31503614391 / E-mail address: [email protected]
Table S1: Subfamilies of mammalian nuclear receptors (adapted and modified from2).
Class
Receptor
Subtype
Denomination
Ligand
I
LXR
,
Liver X receptor
Oxysterols, bile acids, T090317
Vitamin D receptor
1-25(OH)2 vitamin D3
VDR
II
III
TR
,
Thyroid hormone receptor
Thyroid hormone (T3)
PPAR
, / ,
Peroxisome proliferators-activated
receptor
Eicosanoids; thiazolidinediones (TZD’s); 15-deoxy-12,41prostaglandin J2; polyunsaturated fatty acids
RAR
, ,
Retinoic acid receptor
Retinoic acid
RXR
, ,
Retinoid X receptor
9-Cis-retinoic acid
COUP-TF
, ,
Chicken ovalbumin upstream promoter
transcription factor
Unknown
HNF-4
, ,
Hepatocyte nuclear factor 4
Fatty acyl-CoA thioesters
MR
Mineralocorticoid receptor
Aldosterone
GR
Glucocorticoid receptor
Glucocorticoids
Estrogen receptor
Estradiol
PR
Progesterone receptor
Progestins
AR
Androgen receptor
Androgens
ER
,
Figure S1: Schematic overview of the RAAS. Renin is the primum movens of the RAAS and cleaves angiotensinogen into angiotensin I.
Subsequently, angiotensin I is converted into angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin II mediates its effects via the
angiotensin type 1 receptor (AT1R) and type 2 receptor (AT2R).