r e v i e w

F o c u s o n Va s c u l a r D i s e a s e

Under pressure: the search for the

essential mechanisms of hypertension
2011 Nature America, Inc. All rights reserved.

Thomas M Coffman1,2
High blood pressure, or hypertension, is a very common disorder with a substantial impact on public health
because of its associated complications. Despite the high prevalence of essential hypertension and years of
research, the basic causes remain obscure. Here I review recent advances in understanding the pathophysiology
of hypertension. I present a general overview of the field and, by necessity, use broad strokes to portray recent
progress and place it in context. For this purpose, I use illustrative examples from the large number of important
developments in hypertension research over the last five years. The intent of this review is to provide a sense of
where the field is progressing, with an emphasis on work that sheds light on pathogenic mechanisms and that is
therefore likely to inform new translational advances.
Hypertension is one of the most common chronic diseases in the
human population, affecting more than 1 billion people worldwide1.
Its complications, including stroke, heart failure and kidney disease,
are major sources of morbidity and mortality. Reducing blood pressure in individuals with hypertension prevents or attenuates these
complications2. However, despite the high prevalence of hypertension
and increasing public awareness of this disorder and its risks, control
rates remain unsatisfactory, and a substantial proportion of people
with hypertension under treatment do not achieve the target levels
of blood pressure control recommended by current guidelines3. The
reasons for these poor outcomes are complex. Health service issues
regarding access to care, diagnosis and optimal implementation of
existing therapies have a role. However, persistent gaps in understanding the pathogenesis of hypertension as well as the availability
of only a relatively small repertoire of antihypertensive therapies also
contribute to disappointing clinical results.
The etiology of elevated blood pressure cannot be determined in
the vast majority of individuals with essential hypertension. Thus, it
has proved difficult to develop precise profiles for individual patients
for the purposes of identifying optimal therapies and predicting prognosis. Consequently, choices of antihypertensive therapy are typically
empirical and are based on broad epidemiological categories such as
age, race and the presence of coexisting disorders such as diabetes or
heart disease. Accordingly, developing a more precise understanding of the molecular pathogenesis of hypertension remains a pressing
priority for both basic and translational researchers in the field.
1Division of Nephrology, Department of Medicine, Cardiovascular Research Center,
Duke University and Durham Veterans Affairs Medical Centers, Durham, North
Carolina, USA. 2Cardiovascular and Metabolic Disorders Research Program,
Duke-National University of Singapore Graduate Medical School, Singapore.
Correspondence should be addressed to T.M.C. (tcoffman@duke.edu).

Published online 7 November 2011; doi:10.1038/nm.2541

1402

In the simplest sense, determinants of blood pressure are approximated by Ohms law modified for fluid dynamics (pressure = flow
resistance). Blood flow depends on cardiac output and blood volume,
whereas resistance is primarily determined by the contractile state of
small arteries and arterioles throughout the body. These components
of blood pressure are subject to a range of regulatory influences. Thus,
unraveling the root causes of hypertension requires consideration of
the many systems contributing to blood pressure homeostasis, including the vasculature, the central and sympathetic nervous systems and
the kidney, along with their various hormonal regulators. Although
the interactions of these systems in the regulation of blood pressure
have been intensely scrutinized for decades, their specific roles in
hypertension have not been resolved, and this remains an area of
vigorous debate among hypertension researchers.
Studies of hypertension causality are particularly challenging in
clinical settings, where opportunities for invasive study are limited
and where primary pathophysiological mechanisms may be masked
by compensatory pathways and the confounding effects of diet and
medications. To facilitate mechanistic studies, several widely used
genetic models of hypertension in rats have been generated through
selective breeding for the traits of increased blood pressure, salt
sensitivity or both. Hypertension can also be induced in animals by
pharmacological or transgenic modulation of key neurohormonal
regulators. Although these models do not fully recapitulate all of the
features of human hypertension, they have nevertheless provided
useful insights that have proved relevant to the human disorder.
Accordingly, in this review, I cite and discuss work using these
models as well as studies in humans to illustrate recent progress in
understanding the mechanisms of hypertension pathogenesis.
A key role for the kidney?
More than 30 years ago, Arthur Guyton and his associates argued
that the kidney has a central role in blood pressure control4. They

VOLUME 17 | NUMBER 11 | NOVEMBER 2011 nature medicine

review
Epidermis
Dermis
Na+

Subdermal
compartment

Na+

nature medicine VOLUME 17 | NUMBER 11 | NOVEMBER 2011

2011 Nature America, Inc. All rights reserved.

Macrophage

Intravascular
compartment
Na+

Arteriole

Lymphatic
vessels

Na+

Na+

VEGF-C

Na+

H 2O
Na+

H2O

Venule

Na+

Capillary
H 2O

suggested that the capacity of the kidney to rapidly increase urinary

sodium excretion in response to elevations in blood pressure, socalled pressure natriuresis, provides an important pathway for reducing body fluid volumes and returning systemic pressures to normal
regardless of the initiating cause4. As a corollary, defects in the excretory functions of the kidney would be a permissive requirement for
sustaining chronic increases in intra-arterial pressure. In addition, the
association between dietary sodium intake and risk for hypertension
is cited as supporting a key contribution of the kidney in hypertension
pathogenesis5. Moreover, diuretic agents, which inhibit reabsorption
of sodium by transporters along the nephron, are a cornerstone of
current antihypertensive therapy. In this regard, thiazide diuretics that
block the sodium-chloride cotransporter in the renal distal convoluted tubule are especially effective6. Although the validity of Guytons
hypothesis has been questioned and debated over the past 30 years,
there is substantial evidence supporting a crucial role for sodium
excretory pathways in the control of blood pressure.
A kidney-centric view of hypertension is also supported by kidney
cross-transplantation studies in strains of hypertensive rats where
blood pressure followed the kidney donor. In these studies, transplanting a donor kidney from a hypertensive strain caused hypertension in recipient controls and, conversely, a kidney from a normal rat
transplanted into a hypertensive recipient normalized the recipients
blood pressure (reviewed in ref. 7). In a more modern version of this
experiment, a research group that I was a part of carried out kidney
cross-transplantation studies between mice lacking the major AT 1
receptor for angiotensin II and wild-type controls8,9. Because of the
major influence of the renin-angiotensin system (RAS) on blood
pressure, our premise was that key cellular targets of angiotensin II
with a strong effect on blood pressure would probably reflect crucial
archetypal pathways for blood pressure homeostasis. AT1 receptors
mediate the predominant actions of angiotensin II on blood pressure. These receptors are also the targets of a widely used class of
antihypertensive drugs: the angiotensin receptor blockers. We found
that the development of hypertension depended on whether or not
the kidney expressed AT1 angiotensin receptors8. The presence
of these receptors in the kidney was sufficient to generate the full
phenotype of hypertension, whereas their absence conferred protection against hypertension despite the normal expression of AT1
receptors in all other tissues. In more recent studies, we found that
specific elimination of AT 1A receptors from the kidney proximaltubule epithelium using Cre-loxP technology attenuated hypertension despite fully preserving angiotensin-dependent vasoconstrictor
responses10. Protection against hypertension was associated with
facilitated excretion of sodium, indicating a role for proximal-tubule
AT1A receptors in regulating the pressure-natriuresis response.

Na+

Salt

Na+

Na+
Na+

H2O

Interstitial
compartment

Katie Vicari

Figure 1 The proposed three-compartment model for the disposition of

sodium. The Guytonian model4 presumes that the volumes of the two
major compartments of extracellular fluid within the intravascular and
interstitial spaces are in equilibrium. As sodium is the major cation in the
extracellular fluid, impaired sodium excretion would lead directly to an
expansion of the extracellular fluid volume, thereby promoting increased
pressure. Recent studies by Titze and his colleagues13 suggest that
the interstitium of the skin is a distinct third compartment for sodium
distribution, acting as a dynamic reservoir that buffers the impact of
sodium accumulation on intravascular volume and blood pressure.
With high salt intake, sodium accumulates in the subdermal interstitium
at hypertonic concentrations through interactions with proteoglycans.
Macrophages respond to this hypertonicity by secreting VEGF-C to
promote the expansion of lymphatic vessels, which provides a buffer
against increased blood pressure.

Recent studies by Sigmund and his colleagues confirmed the effects

on baseline blood pressure of cell-specific deletion of AT 1 receptors
from the proximal tubule; they also found that overexpression of
receptors in the same epithelial cell lineage raised blood pressure11.
Together, these studies suggest that effective inhibition of sodium
reabsorption in the renal proximal tubule could be a useful therapeutic strategy in hypertension, supplementing the range of diuretic agents currently used to target sodium reabsorption in distal
nephron segments. Finally, these findings are consistent with the
body of work by Navar et al.12 indicating that the proximal tubule
is a key component of an independently regulated intrarenal RAS.
These findings suggest that the proximal tubule is a source of angiotensinogen and angiotensin II for the glomerular ultrafiltrate and
may therefore have broad influences on nephron function and blood
pressure control12.
Another skin in the game of salt handling
A substantial subset of the population has exaggerated changes in
blood pressure in response to alterations in dietary salt intake known
as salt sensitivity5. These individuals have an enhanced propensity to
develop hypertension, but it has been difficult to precisely define the
mechanisms of their salt-sensitive hypertension. As sodium is the
major cation in the extracellular fluid, the Guytonian model4 would
suggest that impaired sodium excretion by the kidney leads directly
to an expansion of extracellular fluid volume, promoting increased
blood pressure. This model presumes that the two major components of extracellular volume within the intravascular and interstitial spaces are in equilibrium (Fig. 1). In this construct, retention of
sodium would be accompanied by commensurate retention of water
to maintain iso-osmolality and would thereby proportionally expand
the intravascular volume.
However, studies by Titze and his colleagues13 suggest that sodium
handling during periods of increased dietary intake is more complex than that suggested by this classical two-compartment model
(Fig.1). Moreover, their work highlights the dynamic role of the interstitium of the skin as a reservoir that can buffer the impact of sodium
accumulation on intravascular volume and blood pressure. During
high-salt feeding, Titze and his colleagues showed that sodium accumulates in the subdermal interstitium at hypertonic concentrations
and that this storage of sodium is mediated through its interactions
with proteoglycans13. Macrophages infiltrating the interstitial space

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review

Angiotensin II

Ligand
VSMC membrane

AT1 receptor

Gq-G11

PLC

Rho
GTPase
(active)

IP3

Rho
GTPase
(inactive)

G12-G13

ROCK

Ca2+

Arhgef1
JAK2

CAM

MLCK

MLC
MLCP
MLC

2011 Nature America, Inc. All rights reserved.

Vasoconstriction

sense the hypertonicity caused by the deposition of sodium in excess

of water and trigger expression of tonicity-responsive enhancer binding protein (TonEBP). TonEBP is a transcription factor regulating the
expression of osmoprotective genes in response to osmotic stress. One
of the genes induced by TonEBP is that encoding vascular endothelial
growth factor C (VEGF-C), a potent inducer of lymphatics. Indeed,
in response to high-salt feeding, they found robust lymphatic vessel
hyperplasia in the dermal interstitium13. Macrophage depletion or
specific blockade of VEGF-C both prevented hyperplasia of lymphatic
vessels and enhanced the level of sodium-dependent hypertension,
showing that this pathway has a key role in the extrarenal control of
sodium and fluid volumes.
The findings of Titze and his colleagues13 also raise a number
of questions for future study. With regard to the molecular events
defining this pathway, the nature and regulation of proteoglycans that
mediate hypertonic storage of sodium in the skin, as well as mechanisms for the control of macrophage gene expression by hypertonicity,
remain unclear. Are there discrete abnormalities in this pathway that
contribute to sodium sensitivity and hypertension in humans and, if
so, could they be positively affected by therapeutic interventions? In
this regard, Titze and his colleagues found elevated plasma levels of
VEGF-C in individuals with refractory hypertension, indicating that
their findings might be potentially relevant to the human condition13.
It will also be interesting to determine whether there is crossregulation between this third compartment of sodium-volume regulation
and other control systems in the kidney, central nervous system and
vasculature. Finally, as discussed further below, recent work indicates an important role for the immune system in the development of
hypertension14, raising the possibility that a pathway exists for blood
pressure control in subcutaneous tissues that involves the immune
modulation of macrophage functions.
The vascular counterpoint
Along with changes in body-fluid volumes, peripheral vascular resistance is also an important determinant of blood pressure. Moreover,
despite the evidence that the kidney is crucial in the pathogenesis of
hypertension, elevated total peripheral resistance is a typical feature of
individuals with hypertension15. Vascular tone is regulated by a number
of hormonal mediators, many of which act through G proteincoupled
receptors and their associated signaling pathways (Fig.2). Studies
by Wirth et al.16 have recently defined key pathways for G protein
signaling in the vasculature with important consequences for control of
blood pressure both at baseline and in hypertension. Usingcell-specific

1404

GPCR

LARG

Hypertension
salt sensitivity

Katie Vicari

Figure 2 Key vascular signaling pathways in hypertension. Vascular tone is

regulated by a number of hormonal mediators, many of which act through
G proteincoupled receptors (GPCRs) and their associated signaling pathways.
Recent studies have defined new pathways for G protein signaling in the
vasculature linked to Rho GTPases with important consequences for the
control of blood pressure16,17. These include distinct pathways involving
G12-G13 proteins and the AT1 receptor for angiotensin II. In the former
pathway, the RhoGEF protein LARG activates ROCK in vascular smooth
muscle cells (VSMCs), which affects vascular tone by controlling myosin light
chain phosphorylation16. The AT1 angiotensin receptor also activates ROCK17
through a different pathway involving the guanine nucleotide exchange factor
Arhgef1, which is phosphorylated by JAK2, activating the monomeric
G protein RhoA. These studies reinforce the importance of vascular pathways
in the pathogenesis of hypertension, identifying their crucial but previously
unsuspected role in sodium-dependent hypertension. Intermediates in these
pathways are attractive potential targets for treatment of hypertension.
PLC, phospholipase C; CAM, calmodulin; IP3, inositol triphosphate; MLCK,
myosin light chain kinase; MLCP, myosin light chain phosphatase.

gene targeting, they showed that abrogation of Gq-G11 proteinlinked

pathways specifically in smooth muscle lowered baseline blood pressure and inhibited the development of deoxycorticosterone acetate
(DOCA) salt hypertension, which is a model of mineralocorticoidexcess and sodium-dependent hypertension. Elimination of G12-G13
proteins in smooth muscle also attenuated DOCA salt hypertension but did not affect baseline blood pressure. G12-G13 proteins can
activate the Rho-associated protein kinase (ROCK) signaling pathway, which affects vascular tone by controlling myosin light chain
phosphorylation. ROCK activation by G12-G13 is mediated through
direct interactions between the subunits of G12-G13 and various
Rho-guanine nuclear exchange factor (RhoGEF) domain proteins,
including leukemia-associated Rho-GEF (LARG), which is expressed
in blood vessels16. In this regard, Wirth et al.16 found that the blood
pressure responses in LARG-deficient mice mirrored those of the
G12-G13 smooth muscleknockout mice. As a number of vasoconstrictor agonists act by triggering Gq-G11 or G12-G13, this seems to be
an important common pathway that could be productively targeted
for treatment of hypertension. Because eliminating G12-G13 or LARG
prevented hypertension without affecting baseline blood pressure,
these studies further suggest that specific blockade of these pathways
might lower elevated blood pressure without inducing hypotension,
a problematic side effect of many antihypertensive drugs.
Guilluy et al.17 recently documented another previously unknown
signaling pathway linked to activation of ROCK that has a crucial role
in vascular responses in hypertension. They identified Arhgef1 as the
guanine nucleotide exchange factor that specifically mediates angio
tensin IIdependent activation of the monomeric G protein RhoA in
vascular smooth muscle cells (Fig. 2). They showed that Arhgef1 activation by the AT1 angiotensin receptor is mediated by a noncanonical
pathway involving phosphorylation of Arhgef1 by JAK2. JAK2 was
previously associated with AT1 receptor activation and is involved in
other signaling pathways, including those linked to certain cytokine
receptors. Deletion of Arhgef1 from smooth muscle specifically
attenuated acute vasoconstrictor responses to angiotensin II but
not to other vasoconstrictors such as phenylephrine, thromboxane
or endothelin. Furthermore, both the absence of Arhgef1 in smooth
muscle and treatment with a JAK2 inhibitor generated robust resistance to angiotensin-dependent hypertension.
The studies of Wirth et al.16 and Guilluy et al.17 reinforce the
importance of vascular pathways in the pathogenesis of hypertension.

VOLUME 17 | NUMBER 11 | NOVEMBER 2011 nature medicine

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2011 Nature America, Inc. All rights reserved.

Furthermore, these pathways seem to have a crucial but previously

unsuspected role in sodium-dependent hypertension. It has been suggested that with sodium retention, volume expansion and the ensuing
rise in blood pressure, tissue perfusion is also increased. This triggers
autoregulatory processes leading to augmented tone in peripheral
vessels and consequent increases in peripheral vascular resistance.
Inhibition of vascular signaling pathways may blunt this autoregulatory response, resulting in reduced vascular resistance and lower blood
pressure. But because this autoregulatory response may be protective, it
will be interesting to see whether the propensity for end-organ damage
is augmented by its absence. Moreover, the beneficial consequences
of blocking these vascular pathways in hypertension may also reflect
attenuated vasoconstriction in the renal circulation, preserving blood
flow in the kidney and facilitating sodium excretion.
Hypertension as an autoimmune disease
The importance of inflammation in cardiovascular disease is well
established18. Although previous studies implicated immune mechanisms in hypertension19,20, studies by Guzik et al.14 established a role
for the adaptive immune response in promoting increased blood pressure. These investigators found that mice with targeted disruption of
the recombinase-activating protein-1 (Rag-1), and thus lacking T and
B cells, were resistant to the development of hypertension14. Adoptive
transfer of T but not B cells restored the hypertensive response. Guzik
and his colleagues further showed a characteristic pattern of infiltration of T cells into the adventitia of blood vessels and that T cell
expression of NADPH oxidase and cytokines such as interleukin-17
(IL-17)21 were necessary for maximal elevation of blood pressure.
Crowley et al.22 confirmed the requirement for the adaptive immune
system in hypertension by showing that severe combined immunodeficiency mice were also resistant to hypertension.
Among the questions raised by these studies is whether the T cell
response contributing to hypertension reflects immunity to specific antigens or is simply a nonspecific bystander response to tissue
injury. Recent studies from the Harrison group suggest that an antigen-specific T cell response drives hypertension23. Two signals are
required for full activation of T cells by an antigen. The first signal is
triggered by interaction between the T cell antigen receptor and a peptide antigen bound in the groove of a major histocompatibility complex protein on an antigen-presenting cell. The second co-stimulatory
signal is delivered by a specific interaction between receptor-ligand
pairs; the prototype of these types of pairs is the binding of CD28 on
T cells to the B7 ligands CD80 or CD86 on antigen-presenting cells.
If the T cell receptor engages the antigenmajor histocompatibility
complex in the absence of co-stimulation, the T cell is not activated
and may instead undergo apoptosis. In angiotensin II salt hypertension and DOCA salt hypertension, Vinh et al.23 found that blockade
of co-stimulatory signaling attenuated hypertension, preventing the
perivascular infiltration of T cells and their release of cytokines. Mice
genetically deficient for B7 ligands were similarly resistant to hypertension, indicating that activation of T cells through co-stimulation
is crucial in hypertension. Although the identity of the activating
antigen(s) is not clear, elevation of blood pressure seems to be an
obligatory initiating event for triggering the immune response. For
example, Marver et al.24 found that ablative lesions of the central nervous system or treatment with the vasodilator drug hydralazine, both
of which prevent blood pressure elevation from angiotensin II infusion, also abrogated T cell activation and perivascular infiltrates. The
pathways leading from increased blood pressure to immune activation
are not clear. End-organ injury or generation of oxygen free radicals

nature medicine VOLUME 17 | NUMBER 11 | NOVEMBER 2011

associated with the hypertensive state could generate neoantigens

or activate innate and co-stimulatory pathways, promoting a loss of
tolerance to self antigens. In this regard, identification of the specific
antigens that drive other cardiovascular diseases, such as atherosclerosis, or even common autoimmune diseases, including rheumatoid
arthritis, has proven quite challenging18.
A key question raised by this work is whether the immune system
has a role in human hypertension. Many patients with hypertension have been treated with immunosuppressive agents for a variety
of autoimmune disorders ranging from rheumatoid arthritis to
inflammatory bowel disease as well as to prevent the rejection of organ
transplants. Insights into the effects of these agents on blood pressure could be obtained from a retrospective analysis of older clinical
trials. However, there are several potential confounders in this
approach, including the off-target actions of agents such as calcineurin
inhibitors and corticosteroids, comorbidities in the study cohorts,
such as kidney disease, and the effects of treatment on chronic pain.
Although it seems unlikely that potent immunosuppressive agents
would be used to treat uncomplicated hypertension, they might be
used in patients with refractory disease and/or a high burden of complications. In contrast, as the key immune pathways that contribute to
blood pressure elevation are identified, specific interventions might
be devised to ameliorate hypertension while minimizing the immuno
suppressive burden.
Genetics of hypertension: a hard nut to crack
Epidemiological and familial aggregation studies have established that
there is a significant heritability component for blood pressure, which
contributes to 3050% of its variability in populations. Unraveling
the genetics of hypertension holds promise for providing an unbiased approach for understanding its pathogenesis, risk profiling and
identifying therapeutic targets. But, similar to other complex human
diseases, the identification of genetic mechanisms in prevalent hypertension has been difficult despite extensive efforts. Even in relatively
simple animal models such as spontaneously hypertensive or Dahl
salt-sensitive rat strains, few causal genes have been identified. By
contrast, there has been substantial progress in identifying genetic
variants responsible for most of the Mendelian disorders with large
effects on blood pressure. In work done primarily by Lifton et al.25,
mutations of more than 20 genes have been found to be responsible
for those rare disorders. To a great extent, these mutations act by
changing renal salt excretion, providing additional evidence for the
major role of excretory function of the kidney as a final determinant
of blood pressure.
Although these discoveries and the in-depth characterization of
mutations responsible for extreme changes in blood pressure have provided major advances in understanding the physiology of blood pressure control in humans25, the vast majority of the genetic contribution
to blood pressure remains unexplained. This is probably because of
the complexity of the trait and the likelihood that blood pressure
variation in the general population is determined by many genes that
each have a small effect. As such, very large sample sizes are needed
to identify variants using approaches such as genome-wide association studies (GWASs). Recently, two large GWASs, the Global Blood
Pressure Genetics (BPGen) Consortium and the Cohorts for Heart and
Aging Research in Genome Epidemiology (CHARGE) Blood Pressure
Consortium, each comprising approximately 30,000 subjects, reported
their results26,27. The major genetic analyses in these studies focused
on systolic and diastolic blood pressures as quantitative traits, as these
variables provided greater statistical power than categorical outcomes

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review
Table 1 Genetic loci associated with blood pressure, hypertension or both in two or more large-population GWASs

2011 Nature America, Inc. All rights reserved.

Chromosome

Nearest gene

1p36

MTHFR (NPPA, NPPB)a

3q22
3q26

ULK4
MECOM (MDS1)

4q21

FGF5

5p13
10p12
10q24

NPR3 a
CACNB2
CYP17A1a

11p15

PLEKHA7

12q21

ATP2B1

12q24

SH2B3

12q24
15q24

TBX5-TBX3
CSK

17q21
20q13

ZNF652
GNAS-EDN3a

aGenes

Function

Studies

Methylene-tetrahydrofolate reductase; has been associated with changes in

plasma homocysteine levels and pre-ecclampsia, atrial natriuretic and brain
natriuretic peptides.
Serine-threonine kinase of unknown function.
Little is known about the functions of MECOM, myelodysplasia syndrome
protein 1.
Fibroblast growth factor 5; stimulates cell growth and proliferation and is
associated with angiogenesis.
Natriuretic peptide clearance receptor.
Subunit of voltage-gated calcium channel expressed in heart.
Cytochrome p450 enzyme mediating the first step in mineralocorticoid and
glucocorticoid synthesis. Also involved in sex steroid synthesis.
Plextrin-homology domain containing family member A7; expressed in zona
adherens of epithelial cells.
Encodes plasma membrane calcium- or calmodulin-dependent ATPase
expressed in endothelium.
Also known as lymphocyte-specific adaptor protein (LNK), may regulate
hematopoietic progenitors and inflammatory signaling pathways in endothelium.

CHARGE, Global BPGen, AGEN-BP,

ICBPGWAS

T box genes involved in regulation of developmental processes.

Cytoplasmic tyrosine kinase involved in angiotensin II-dependent vascular
smooth muscle cell contraction.
Zinc-finger protein 652.
GNAS encodes the subunit of the G proteinmediating -receptor signal
transduction; EDN3 encodes endothelin 3, the precursor for the ligand of the
endothelin B receptor.

CHARGE, ICBPGWAS
CHARGE, Global BPGen, AGEN-BP,
ICBPGWAS
Global BPGen, AGEN-BP, ICBPGWAS
Global BPGen, ICBPGWAS

CHARGE, ICBPGWAS
Global BPGen, ICBPGWAS
Global BPGen, AGEN-BP, ICBPGWAS
AGEN-BP, ICBPGWAS
CHARGE, ICBPGWAS
CHARGE, Global BPGen, AGEN-BP,
ICBPGWAS
CHARGE, ICBPGWAS
CHARGE, Global BPgen, AGEN-BP,
ICBPGWAS
CHARGE, Global BPGen, ICBPGWAS

with a previously identified function related to blood pressure.

such as hypertension, which was also assessed in both studies.

Together, these GWAS identified 14 distinct loci having statistically
significant associations (P < 5 108) with these blood pressure
traits26,27. In both studies, there was significant overlap between the
genetic regions associated with systolic and diastolic blood pressure,
reflecting the tight correlation of these two variables. Subsequently,
the Asian Genetic Epidemiology Network Blood Pressure (AGEN-BP)
Working Group reported another GWAS of an ethnically distinct
population of approximately 20,000 East Asians and identified a
number of significant associations with blood pressure28, including
five new loci and confirmation of seven loci previously reported by
Global BPGen and CHARGE26,27. More recently, the International
Consortium for Blood Pressure Genome-Wide Association Studies
(ICBPGWAS) published results of a GWAS with a multistage design
in more than 200,000 individuals of European descent, which is the
largest blood pressure GWAS to date29. This study identified 29 variants associated with systolic blood pressure, diastolic blood pressure
or both, 16 of which were previously unidentified.
Table 1 lists loci associated with blood pressure identified by two
or more of these large GWASs along with the putative functions of
the genes located closest to the single nucleotide polymorphisms
with peak statistical significance. Although many of these loci do
not have obvious connections to pathways known to affect blood
pressure, CYP17A, which was strongly associated with blood pressure in all four studies, encodes a cytochrome P450 enzyme involved
in the synthesis of mineralocorticoids and has been implicated in
a syndrome of congenital adrenal hyperplasia and hypokalemic
hypertension30. In addition, the region at chromosome 1p36 includes
NPPA and NPPB, encoding atrial natriuretic peptide (ANP) and Btype or brain natriuretic peptide (BNP), respectively. Deletion of
Nppa in mice causes salt-sensitive hypertension31 and, in a cohort of
more than 14,000 individuals of European descent, significant associations were found between common variants in NPPA and NPPB

1406

and circulating natriuretic peptide levels, blood pressure and risk

for hypertension32. An additional member of the natriuretic peptide
system, NPR3, encoding the clearance receptor for natriuretic peptides, was also identified as a blood pressure locus. Endothelins are
another class of vasoactive hormone implicated in blood pressure
regulation. EDN3, encoding the endothelin 3 peptide, was also associated with blood pressure in two of the large GWAS. Endothelin 3 is
an agonist for the endothelin B receptor that has been linked to saltsensitive hypertension33. Although not directly connected to blood
pressure, a previous study also found an association between a variant
in SH2B3 and risk for myocardial infarction34. It is hoped that further
characterization, validation and functional analysis of these loci may
yield new insights into hypertension pathogenesis.
These large GWASs are massive efforts that carry with them great
expectations for advancing the field. Their results underscore the
prevailing view that there are many genetic variants influencing the
blood pressure in the human population. So far, however, each of the
identified loci imparts only a very small effect on blood pressure.
For example, it has been estimated that the 29 loci identified so far
explain only ~0.9% of the phenotypic variance for systolic and diastolic blood pressure29. In addition, one can only derive limited mechanistic information from association studies, and it has been suggested
that GWAS signals rarely track to causal polymorphisms35. Likewise,
epigenetic factors would not be detected in a GWAS. It is possible
that some of the missing genetic control may be caused by variants
too rare to be picked up by GWAS but have relatively large effects on
risk35. This possibility is highlighted by the results of a study from
the Lifton laboratory36. Among a cohort of more than 5,000 members
of the Framingham Heart Study, Ji et al.36 searched for mutations
in three genes, SLC12A3 (NCCT), SLC12A1 (NKCC2) and KCNJ1
(ROMK), associated with the recessive disorders Bartters syndrome
and Gitelmans syndrome, which are characterized by large reductions in blood pressure. Within this cohort, the authors documented

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2011 Nature America, Inc. All rights reserved.

30mutations in these three genes that were inferred to have functional

consequences. In the heterozygous state, these variants were associated with lower blood pressure and protection from hypertension.
Along with their implications for the genetic architecture of hypertension, these studies further emphasize the contribution of altered renal
salt handling in blood pressure variation in the general population.
With the rapid developments of next generation sequencing tools,
applications of whole-genome and exome sequencing may be useful to further uncover the genetic mechanisms of hypertension. For
example, in a recent study, Choi et al.37 used whole-exome sequencing
to identify a common genetic pathway in the development of primary
hyperaldosteronism, one of the more frequent causes of secondary
hypertension. Going forward, application of these more advanced
technologies to the issue of the genetics behind hypertension has
great promise.
New approaches for treating hypertension
As discussed in the introduction, control rates for hypertension
worldwide have been disappointing, and the causes of these low rates
are multifactorial. Although there are a number of antihypertensive
drugs on the market, only a few new drugs have been approved for
hypertension over the past decade, and most of these newer agents
inhibit well established targets such as the RAS. Moreover, the current
pipeline of new drugs for hypertension is limited. Although it is clear
that lifestyle modification and specific dietary regimens can lower
blood pressure independent of pharmacological therapy38, there has
been some recent notable work on other new approaches that might
be useful adjuncts to drug treatment.
Vaccines for hypertension. Strategies for developing vaccines for
hypertension have been proposed in which the immunogen is a key
protein involved in hypertension pathogenesis. A potential advantage
of this approach would be the development of long-lasting immunity,
obviating the need for daily dosing of medication and thereby avoiding
problems with treatment compliance, a major barrier for achieving blood pressure targets in many individuals. However, there are
potential problems with this approach. First is the technical obstacle
of inducing a robust immune response against an autologous protein.
In addition, many of the potentially attractive candidate target molecules are neurohormonal mediators that act as a part of physiological
systems aimed at protecting intravascular volume and preventing low
blood pressure and shock. Because immunological inhibition cannot
be discontinued or reversed during episodes of acute illness and
hemodynamic compromise, there are concerns about the long-term
safety of this approach.
Tissot et al.39 recently reported the results of a phase 2 trial of a vaccine against angiotensin II, the eight-amino-acid peptide responsible
for the primary effects of the RAS on blood pressure. The vaccine is
composed of angiotensin II linked to a recombinant protein derived
from the RNA virus Qb. Subjects with mild to moderate hypertension
who received sequential injections of this immunogen developed high
titers of IgG antibodies against angiotensin II. At the highest dose of
immunogen, these individuals developed maximal levels of antibody
and experienced a modest but statistically significant reduction in
systolic blood pressure, especially during the early morning. Aside
from transient myalgias and fever immediately following the injections, there were no other substantial adverse events. In particular,
there were no reported episodes of syncope (fainting) or hypotension. These results support the feasibility of vaccination in producing
immunity against a key vasoactive hormone, but the extent of blood

nature medicine VOLUME 17 | NUMBER 11 | NOVEMBER 2011

pressure reduction was far less than is typically achieved with pharmacological blockade of the RAS. No adverse hemodynamic events
associated with vaccination were observed, but the potential for such
events might be exaggerated if blood pressure lowering were enhanced
with a more effective vaccine.
Getting on your nerves to control blood pressure. The sympathetic
nervous system exerts an over-riding impact on control of blood pressure, and important neurogenic components of human hypertension
have been clearly established40. The potent antihypertensive efficacy
of drugs such alpha- or beta-sympathetic blockers, which antagonize
the sympathetic nervous system, is strong evidence for the key contribution of the sympathetic nervous system to hypertension in humans.
However, this class of agents also has a broad range of adverse side
effects including lethargy, dry mouth and impotence, rendering them
unpopular with patients. Control of blood pressure by the sympathetic
nervous system is mediated by regulation of key physiological para
meters including heart rate, vascular tone and renal sodium excretion.
Among the pathways for neurogenic control, sympathetic innervation of the kidney seems to be particularly important. For example,
increased activity of sympathetic nerves supplying the kidney is
associated with enhanced sodium reabsorption and development of
hypertension, whereas renal denervation lowers blood pressure in
several experimental models of hypertension40. Moreover, a recent
paper41 indicates that -adrenergic input directly modulates kidney
expression of the serine-threonine protein kinase WNK4, which is a
regulator of the sodium-chloride cotransporter that is the target for
thiazide diuretics.
On the basis of such a rationale, Esler and his colleagues pursued
the development of a percutaneous, catheter-based approach for renal
denervation in individuals with refractory hypertension42,43. They
recently published the results of a prospective randomized trial42 that
support the utility of this modality for lowering blood pressure. The
study enrolled 106 individuals with resistant hypertension whose
blood pressures were not controlled through the use of three or more
antihypertensive medications. Subjects were randomized to undergo
bilateral renal nerve ablation with a radiofrequency catheter or to
be continued on medical therapy alone. Both groups were followed
for 6 months and their blood pressures were monitored. There were
no serious complications from the renal nerve ablation procedure.
Although the blood pressures in the control group did not change
significantly, there were statistically significant and sustained reductions in blood pressure in the renal denervation group, with more
than 80% of individuals in this group experiencing a fall in systolic
blood pressure of more than 10 mm Hg. Renal noradrenaline spillover
was reduced in subjects after denervation, indicating efficient interruption of renal efferent nerves. However, ablation of afferent renal
nerves may also contribute to the efficacy of the procedure. Although
efferent nerves have the potential to regenerate after surgical ligation,
afferent sensory fibers appear to have a reduced capacity for regrowth,
which perhaps explains the durable efficacy of renal nerve ablation
observed to at least 12 months after the procedure43. Moreover, renal
denervation was also associated with evidence of attenuated central
sympathetic responses, perhaps because of elimination of afferent signals from renal nerves to the central nervous system. This
reduced central sympathetic activation may also contribute to blood
pressure lowering.
Irrespective of the underlying mechanisms, the apparent efficacy of
this procedure is very promising. Another randomized trial is planned
in the United States to begin in the near future, and if these positive

1407

review

Brain

SNS

Systemic
resistance
vessels

SNS

Vasoactive
hormones
Kidney

Hydraulic
vascular injury
Antigen
shedding

Nephron

2011 Nature America, Inc. All rights reserved.

Peritubular
vasculature

Immune
cells

Katie Vicari

Inflammation

Figure 3 Regulatory mechanisms for blood pressure are targets for

therapy in hypertension. A sustained increase in arterial pressure
(hypertension) reflects a failure of one or more regulatory mechanisms
spanning multiple physiological systems. Nevertheless, there are final
common pathways that have a dominant influence on blood pressure,
including the regulation of sodium excretion by the kidney, activity of the
central and sympathetic nervous systems and contractile processes in
the vasculature. These pathways are targets of current antihypertensive
therapies. Recent work suggests that these therapeutic strategies might
be further refined to improve their clinical benefit. Furthermore, new and
previously unsuspected mechanisms affecting hypertension pathogenesis
have emerged, including immune and inflammatory response pathways14
as well as skin microenvironments that affect the disposition of dietary
sodium and its impact on extracellular fluid volume13, which may also be
useful therapeutic targets. SNS, sympathetic nervous system.

results and lack of adverse effects are confirmed, renal denervation

is likely to be widely adopted for individuals with refractory hypertension. Moreover, as this procedure is a strategy for reducing the
need for daily drug therapy, additional studies in individuals with
less severe hypertension will probably follow. There are other devicebased approaches in clinical testing for the treatment of hypertension,
for example, carotid baroreceptor stimulation44. These new interventions for targeted modulation of sympathetic nerve activity may
be very useful adjuncts to traditional pharmacological therapies for
improving blood pressure control without accumulating an additional
burden of side effects typically associated with broadly acting sympatholytic drugs.
Conclusions
As depicted in Figure 3, normal control of blood pressure requires
complex integration of regulatory mechanisms across multiple physiological systems. A sustained increase in arterial pressure therefore
reflects a failure of one or more of these controls. As such, the defining
characteristic of hypertension, elevated blood pressure, is a very nonspecific manifestation of a range of potential causative mechanisms.
Researchers inability to distinguish the causes of hypertension in
individual people is a major obstacle for developing more personalized and effective approaches to clinical management. Accordingly,
a renewed effort at refining clinical phenotypes is crucial to advance
the field. Although there has been steady progress in unraveling the
genetics of hypertension, more precise clinical phenotyping facilitated
by the mechanistic studies highlighted in this review should promote
further progress in defining these genetic mechanisms.

1408

Despite the physiological complexity of hypertension, there are

final common pathways with important influence on the development of blood pressure elevation. Some of these pathways are now
well established targets of current therapies and include the regulation of sodium excretion by the kidney, activity of the central and
sympathetic nervous systems and contractile processes in the vasculature. However, recent work suggests that these strategies could be
further refined to improve clinical benefit, for example, by specifically
inhibiting sodium reabsorptive pathways in the renal proximal tubule,
blocking very precise molecular pathways promoting maladaptive
vasoconstriction and interrupting sympathetic innervation of the kidney by radiofrequency ablation. Furthermore, new and previously
unsuspected mechanisms affecting hypertension pathogenesis have
emerged from recent studies, including immune and inflammatory
response pathways as well as microenvironments in the skin that
affect the disposition of dietary sodium and its impact on extracellular fluid volume. Future studies will assess the therapeutic value of
manipulating these newly identified pathways.
Acknowledgments
The authors work in this area has been supported by the US National Institutes of
Health (HL056122), the Veterans Affairs Research Administration and the Edna
and Fred L. Mandel Jr. Foundation.
COMPETING FINANCIAL INTERESTS
The author declares no competing financial interests.
Published online at http://www.nature.com/naturemedicine/.
Reprints and permissions information is available online at http://www.nature.com/
reprints/index.html.
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