BRIEF REVIEW www.jasn.

org

Immune Mechanisms in Arterial Hypertension

Ulrich Wenzel,* Jan Eric Turner,* Christian Krebs,* Christian Kurts,† David G. Harrison,‡ and
Heimo Ehmke§
*Department of Medicine and §Department of Cellular and Integrative Physiology, University Medical Center
Hamburg-Eppendorf, Hamburg, Germany; †Institutes of Molecular Medicine and Experimental Immunology, Rheinische
Friedrich-Wilhelms University, Bonn, Germany; and ‡Division of Clinical Pharmacology, Department of Medicine,
Nashville, Tennessee

ABSTRACT
Traditionally, arterial hypertension and subsequent end-organ damage have been physically induced injury but also a
attributed to hemodynamic factors, but increasing evidence indicates that inflam- cause of hypertension, was further sup-
mation also contributes to the deleterious consequences of this disease. The ported in a 2007 study. 3 That study
immune system has evolved to prevent invasion of foreign organisms and to promote found that the increase in BP caused by
tissue healing after injury. However, this beneficial activity comes at a cost of Ang II infusion was significantly blunted
collateral damage when the immune system overreacts to internal injury, such as in mice lacking the recombinase-activating
prehypertension. Renal inflammation results in injury and impaired urinary sodium gene 1 (RAG-12/2 mice), a strain that lacks
excretion, and vascular inflammation leads to endothelial dysfunction, increased Tand B cells. In these experiments, adop-
vascular resistance, and arterial remodeling and stiffening. Notably, modulation of tive transfer of T cells, but not B cells,
the immune response can reduce the severity of BP elevation and hypertensive end- restored the hypertensive response,3 in-
organ damage in several animal models. Indeed, recent studies have improved our dicating that T cells play an important
understanding of how the immune response affects the pathogenesis of arterial role in generation of arterial hypertension.
hypertension, but the remarkable advances in basic immunology made during the These results have been confirmed in se-
last few years still await translation to the field of hypertension. This review briefly vere combined immunodeficiency mice
summarizes recent advances in immunity and hypertension as well as hypertensive and in Dahl salt-sensitive rats in which
end-organ damage. the RAG-1 or the essential T cell receptor
component CD3 have been deleted using
J Am Soc Nephrol 27: 677–686, 2016. doi: 10.1681/ASN.2015050562
zinc finger nuclease technology.4–6 This
seminal work has caused great interest in
the immunologic aspects of hypertensive
Hypertension is the most common mod- cell death and initiate a tissue response disease.7–10
ifiable risk factor for cardiovascular dis- aimed at removing dead cells and replacing This review will give a brief overview
ease and death. Worldwide, it is estimated them to restore homeostasis. These repair of the components of the innate and
that .1 billion adults have hypertension, processes are a substantial component of adaptive arm of the immune system in
and this figure is projected to climb to the immune response, and it is therefore hypertension and summarize recent ad-
1.5 billion by the year 2025. An improved self-evident that activation of both the in- vances in immunologic research, with a
understanding of the mechanisms un- nate and adaptive arm of the immune sys- special focus on their potential relevance
derlying arterial hypertension and its tem occurs in arterial hypertension. for hypertension and hypertensive end-
subsequent damage to the kidneys, heart, A hint for a role of the immune system organ damage. Very recent findings on
and vascular system is clearly needed. For in hypertension was the observation that the role of dendritic cells as well as CD8+
many years, it was believed that hyper- pressor doses of angiotensin II (Ang II)
tensive end-organ damage is merely the administered for a short time period Published online ahead of print. Publication date
result of an increased hydrostatic pres- resulted in subsequent salt-sensitive hy- available at www.jasn.org.
sure on the vessel walls. Indeed, in 1977 pertension and renal infiltration and
Correspondence: Dr. Ulrich Wenzel, Universitätsklinikum
Beilin stated that pressure, if it is great activation of immune cells. Both of these Hamburg-Eppendorf, III. Medizinische Klinik, Martinistr.
enough, will eventually disrupt any struc- sequelae were reduced by immunosup- 52, 20246 Hamburg, Germany. Email: wenzel@uke.de
ture.1 In intact vessels, pressure mediates pression.2 The concept that inflamma- Copyright © 2016 by the American Society of
cellular stretch, which can in turn lead to tion is not only a consequence of the Nephrology

J Am Soc Nephrol 27: 677–686, 2016 ISSN : 1046-6673/2703-677 677

 BRIEF REVIEW www.jasn.org
and TH17 T cells in hypertension will be
discussed.
INNATE IMMUNITY
Innate immunity is considered to be the
immune system’s first line of defense
against invading pathogens. The term
“innate” refers to the inherent capacity
of this arm of immune defense to be rap-
idly activated by external stimuli without
need for time-consuming, antigen-specific
education or interaction with other cells.
The essential cellular components of innate
immunity are granulocytes, macrophages,
mast cells, and certain subsets of lympho-
cytes, whereas the most important hu-
moral component beside the defensin
system is the complement system.
Complement
The complement system is one of the
oldest components of immunity and is
central to the detection and destruction
of invading pathogens.11 It is a system of
fluid-phase and cell membrane–bound
proteins. Complement activation pro-
duces anaphylatoxins, such as C3a and
C5a, which are chemotactic stimuli and
can activate a variety of immune effector
cell types. Both C3a and C5a serum levels
are significantly increased after induction
of hypertension by Ang II infusion. Inter-
estingly, hearts of C5a knockout mice are
protected from hypertensive cardiac in-
jury.12 Moreover, treatment with a C5aR
antagonist also prevented cardiac remod-
eling in Ang II–induced hypertension.13
Reactive Oxygen Species
While there are several reactive oxygen
species (ROS)-producing enzymes in
mammalian cells, a major source are
the nicotinamide adenine dinucleotide
phosphate-(NADPH) oxidases. Profes-
sional phagocytes use the NADPH oxi-
dase to produce superoxide and kill
invading organisms. Superoxide serves
as a progenitor for numerous other ROS,
including hydrogen peroxide, hydroxyl
radical, and peroxynitrite. The NADPH
oxidases have evolved to have numerous
roles in other cells, including modulation
of sympathetic outflow, vascular tone,
678 Journal of the American Society of Nephrology
and renal sodium reabsorption, all of
which contribute to hypertension.14,15
The sympathetic nervous system and hy-
pothalamic pituitary axis are two major
pathways in which the NADPH oxidases
modulate neuroimmune communica-
tion. The sympathetic nervous system in-
nervates both primary (thymus, bone
marrow) and secondary tissues and lym-
phoid tissues (spleen, lymph nodes), and
most immune cells express receptors for
neurohormones and catecholamines.16
Inhibition of the NADPH oxidase subunit
p22phox in the subfornical organ elimi-
nated the Ang II–induced hypertensive re-
sponse and vascular inflammation.17 In
addition, a peripheral neuroimmune
response in the spleen, mediated by celiac
ganglion efferent nerve fibers, is essential
for the development of hypertension.18
The NADPH oxidase in antigen-presenting
cells plays a role in their activation in hy-
pertension, and inhibition of this enzyme
blunts the vascular inflammation present
in hypertension.19,20
Innate Sensing of Injury
Signature molecules of microbial origin
(pathogen-associated molecular pat-
terns) or molecules that are released by
host cells in response to stress or damage
(damage-associated molecular patterns
[DAMPs]) can activate resident and in-
nate immune cells via action on many
germline-encoded pattern recognition
receptors (PRRs). The inflammatory re-
sponse to cell stress or injury has been
called “sterile inflammation.” 21 The
best-characterized pattern recognition
receptors of the immune system are
toll-like receptors (TLRs). These are ex-
pressed on a variety of immune and so-
matic cells and are activated by a variety
of pathogen-associated molecular pat-
terns and DAMPs to initiate inflamma-
tory responses. TLR4 was elevated in
spontaneously hypertensive rats, and
treatment with an anti-TLR4 antibody
lowered BP in this model. 22 TLR4 is
also increased in cardiomyocytes of the
spontaneously hypertensive rat and
angiotensin-converting enzyme inhibi-
tion lowers its expression.23 G-nitro-L-
arginine-methyl ester (L-NAME)–induced
hypertension is blunted in TLR4-deficient
mice.24 TLR9 is expressed in aortic vas-
cular smooth muscle cells, and its acti-
vation augments contractile responses
in conduit arteries.25 Activation of nico-
tinic acetylcholine receptors in spleno-
cytes inhibits TLR-mediated inflammation
in Wistar-Kyoto rats but paradoxically
increases inflammation in the SHR.26
TLRs likely represent a link between
host-derived “danger” molecules
(DAMPs), low-grade inflammation,
vascular remodeling, and hypertension.
This topic has recently been reviewed
in detail.25,27
Inflammasome
Some pattern recognition receptors
trigger a distinct proinflammatory mech-
anism that involves assembly of cytosolic
protein complexes called inflammasome.
Once assembled, inflammasomes activate
caspase-1, which in turn processes the
proinflammatory IL-1 family cytokines
IL-1b and IL-18 from their inactive to
their active forms. A well described stim-
ulus for inflammasome activation in-
volves the action of extracellular ATP on
the P237 receptor. Cellular damage in-
creases extracellular ATP, which in turn
serves as a danger signal that ultimately
stimulates IL-1 release.28 Interestingly,
P237-deficient mice develop blunted hy-
pertension in response to deoxycorticos-
terone acetate (DOCA) salt challenge,
suggesting that the inflammasome is in-
volved in the pathogenesis of hyperten-
sion.29 Other stimuli for inflammasome
activation include cholesterol and uric
acid crystals. Current studies of mice
lacking components of the inflamma-
some promise to provide additional
insight into the role of inflammation in
hypertension.
Monocytes/Macrophages and
Other Bone Marrow–Derived Cells
Cells of myeloid lineage, including mono-
cytes, macrophages, granulocytes, and
dendritic cells, are major effectors of the
innate immune system. Selective ablation
of lysozyme M-positive myelomonocytic
cells markedly blunts Ang II–induced in-
filtration of these cells into the vascular
wall and attenuates Ang II–induced hy-
pertension and vascular dysfunction.30
J Am Soc Nephrol 27: 677–686, 2016

Osteopetrotic (Op/Op) mice, in which
macrophages are functionally deficient,
exhibit reduced hypertension and vascu-
lar remodeling in response to Ang II or
DOCA salt.31,32 As in the case of other
immune cells, the bone marrow is the
source of circulating monocytes, monocyte-
derived dendritic cells, and most inflam-
matory macrophages. Of interest, bone
marrow transplant studies have empha-
sized the role of the bone marrow in
hypertension. Santisteban et al. have re-
cently shown that transplant of marrow
from spontaneously hypertensive rats to
Wistar-Kyoto rats increases BP in the lat-
ter.33 Likewise, Saleh et al. showed that
transplant of marrow from LNK 2 /2
mice, which are prone to inflammation
and hypertension, markedly enhances
the response to low-dose angiotensin II
infusion in wild-type recipient mice.34
Lymphocytes of the Innate Immune
System
Natural killer (NK) cells are the classic
effector lymphocytes of the innate im-
mune system.35 Only in the last few years
has another population of lymphocytes
that belongs to the innate arm of the im-
mune system been identified and studied
extensively. Because of their antigen-
independent activation and lymphoid
morphology, these cells have been called
“innate lymphoid cells" (ILCs). NK cells
share characteristics of innate lymphoid
cells and, according to the most recent
nomenclature of these cells, are consid-
ered to be “killer” ILCs.36
Innate Lymphoid Cells
NK cells (or “killer” ILCs) recognize
stressed and damaged cells by a reper-
toire of activating and inhibitory NK
cell receptors. Upon activation, NK cells
exert cytotoxic effects on target cells.
In Ang II–induced hypertension, NK
cells migrate into the aortic wall and
become a local source for interferon-g.
Depletion of NK cells reduces Ang II–
induced vascular dysfunction. 37 The
family of “nonkiller” ILCs, which are
also called “helper-like” ILCs, can be fur-
ther divided into three groups that differ
in their cytokine production, transcrip-
tion factor usage, tissue localization, and
J Am Soc Nephrol 27: 677–686, 2016
functional characteristic.36,38,39,40 The
role of these cells in hypertension re-
mains undefined.
Innate-Like T Cell Subsets
It has become evident that certain T cell
subsets that bear T cell receptors with a
restricted repertoire can be activated
independently from antigen directly by
cytokine stimuli. Therefore they are
regarded as being on the border between
innate and adaptive immunity. These
“innate-like” T cells include gd T cells,
NK T cells, and mucosa-associated invari-
ant T cells.41 The gd T cells are a popula-
tion of cells that express the T cell receptor
gd chains. gd T cells are a major source of
IL-17 in hypertension, as discussed below.
The other cells have not been examined
in arterial hypertension.
ADAPTIVE IMMUNITY
B cells, CD4+ cells, and CD8+ T cells are
the major effectors of the adaptive im-
mune system. As noted above, studies of
RAG-1–deficient mice demonstrated
that T cells contribute to the develop-
ment of hypertension. On the basis of
their cytokine production profile and ex-
pression of specific transcription factors,
CD4 + T cells are classified into four
major subsets: T H 1, T H 2, T H 17, and
Figure 1. Polarization of CD4+ cells. Naive CD4+ T cells polarize into TH1, TH2, or TH17
cells or Tregs.
www.jasn.org BRIEF REVIEW
regulatory T cells (Tregs) (Figure 1).
The evidence for a role of the four sub-
types in hypertension is summarized in
Table 1.
TH1 and TH2
Substantial evidence suggests that hy-
pertension skews T cells toward a pro-
inflammatory TH1 phenotype, as indicated
by increased production of the TH1 cyto-
kine IFN-g and a decrease in T H 2-
mediated responses.42 The TH1 response
in hypertension has been examined with
different gene deletion approaches, and
these studies suggest that IFN-g and TH1
polarization contributes to the hyperten-
sion and end-organ damage caused by
angiotensin II or DOCA salt hyperten-
sion challenge.37,43–46 Data on TH2 in hy-
pertension are lacking. In one study,
treatment with IL-4 antibodies lowered
BP in NZB mice.46
TH17
IL-17 is the defining cytokine of TH17
cells. Several isoforms of IL-17 exist,
with IL-17A and -F being the most abun-
dant. Ang II infusion increases IL-17A
production by T cells and IL-17 protein
in the aortic media and the heart.47 The
initial hypertensive response to Ang II
infusion is similar in IL-17A2/2 mice
and wild-type mice. However, hyperten-
sion is not sustained in IL-17A2/2 mice,
Immune Responses and Hypertension 679
680
Table 1. Evidence for a role of the four subtypes in hypertension
Variable
Function
Observations in experimental
arterial hypertension
Effect of knockout
Journal of the American Society of Nephrology
Effect of neutralizing antibodies
Effect of overexpression or
administration
T-bet, T-box expressed in T cells.
J Am Soc Nephrol 27: 677–686, 2016
T H1
Intracellular bacteria, cell
mediated autoimmunity
Increased IFN-g production in Ang
II–induced hypertension42
IFN-g deficiency has no effect on
BP or albuminuria in Ang II–
infused mice44
IFN-g receptor deficiency has no
effect on BP leads to but less
cardiac injury and mixed results
in the kidney in response to Ang
II infusion45
IFN-g deficiency lowers BP in
response to low-dose Ang II43
T-bet- and IFN-g deficiency have
no effect on BP but less vascular
dysfunction in response to Ang
II infusion37
IFN-g antibody has no effect on BP
in hypertensive NZB mice46
Overexpression of IFN-g induces
vascular dysfunction37
TH 2
Helminth infections, allergic
disease
Decreased IL-4 production in Ang
II–induced hypertension42
No data
IL-4 antibody reduces BP in
hypertensive NZB mice46
No data
BRIEF REVIEW
TH17 Treg
Extracellular bacteria, fungi, cell- Downregulation of the immune
mediated autoimmunity response in autoimmunity and
infection
www.jasn.org
Increased IL-17a production in Number of Tregs in the tissue
Ang II–induced hypertension follows the amount of injury
(plasma, aorta, heart)47–49
Increased number of TH17 cells in
kidney of hypertensive mice55
IL-17a deficiency lowers BP and Not done because Treg knockout
reduces hypertensive injury in is lethal
response to Ang II infusion47–49
IL-17a and IL-23p19 deficiency
enhances renal injury in
response to DOCA+Ang II
infusion55
IL-6 deficiency lowers BP and
endothelial dysfunction in
response to Ang II infusion52,53
No effect of IL-17 and IL-23 No data
antibody in response to Ang II
infusion45
Overexpression of IL-17a in the Administration of Tregs lowers BP
skin induces hypertension51 and ameliorates hypertensive
injury in different models of
hypertension65–68
Administration of IL-17 increases
BP50

reaching levels 30 mmHg lower than in
wild-type mice by 4 weeks of Ang II in-
fusion.48 In addition, mice lacking IL-17A
are also protected against aortic stiffening
and cardiac fibrosis after infusion of Ang
II.47,49 Obviously, gd T cell–derived IL-17
mediates the adverse effects of IL-17 in
hypertension.47 In addition, IL-17 treat-
ment increased systolic BP in mice.50
TH17 cells need IL-23 for expansion and
survival. IL-23 receptor antibody treat-
ment or IL-17A antibody treatment of
Ang II–infused mice showed no major ef-
fect on cardiac or renal injury.45 It has to
be kept in mind that antibody treatment
never has an efficiency of 100%, whereas a
genetic approach knocks down the gene
and protein of interest to 0%. Dermal
overexpression of IL-17A induces not
only psoriasis-like lesions but also endo-
thelial dysfunction, vascular oxidative
stress, and arterial hypertension.51 The
importance of IL-17 in hypertension is
supported by studies of IL-6–deficient
mice. IL-6 is needed for polarization of
TH17 cells, and mice lacking this cytokine
have lower BP and less endothelial dys-
function in response to Ang II infu-
sion.52,53 IL-6 may also increase BP by
stimulating epithelial sodium channels
in collecting duct cells.54 Interestingly, in
response to a combination of high-level
Ang II infusion and DOCA salt adminis-
tration, IL-17 deficiency can have adverse
effects. Significantly higher renal injury
was also found in IL-23p19–deficient
mice with DOCA+Ang II–induced hyper-
tension.55 In contrast, neither IL-17A nor
IL-23p19 deficiency changed the degree of
cardiac injury. Collectively, these findings
show that IL-17 plays a major role in the
pathophysiology of hypertension and hy-
pertensive end-organ damage. A different
role is possible in models with severe hy-
pertensive end-organ damage, such as the
combination of DOCA salt and Ang II.
T helper cells were originally consid-
ered to have stable phenotypes without
changing of cytokine expression. How-
ever, experiments with TH17 cells in par-
ticular displayed dramatic instability of
IL-17 secretion in vitro56,57 and in an animal
model of multiple sclerosis (experimental
autoimmune encephalomyelitis). 58,59
Plasticity of TH17 cells in cardiovascular
J Am Soc Nephrol 27: 677–686, 2016
diseases and the potential impact on BP
and tissue damage has not been investi-
gated so far.
A fascinating relation exists between
salt intake and IL-17. Two independent
studies showed that sodium chloride can
exaggerate TH17 production by CD4+
T cells due to activation of the serum and
glucocorticoid-regulated kinase 1, which
stabilizes the IL-23 receptor and rein-
forces the TH17 phenotype.60,61 Thus, a
decreased TH17 response may signifi-
cantly contribute to the beneficial effects
of salt restriction in patients with hyperten-
sion. Serum and glucocorticoid-regulated
kinase 1 is also the link between salt intake
and accelerated allograft rejection.62 Acti-
vation of renal sodium transporters is
blunted in INF-g and IL-17A–deficient
mice in response to Ang II, suggesting
that sodium transporters are an important
link between IFN-g and IL-17 and hyper-
tension.43 Titze and coworkers identified
another important link between sodium
and the immune system. In a series of ele-
gant experiments, these authors found that
high salt intake promotes skin Na+ accu-
mulation and that this in turn causes mac-
rophages to produce factors including
VEGF-C, which modulates skin interstitial
lymphatic density.63 In addition, Na+ accu-
mulates at the site of bacterial skin infec-
tions in humans and mice and boosts
classic macrophage activation, thus help-
ing to ward off skin infection. Thus, salt
deposition might serve as an ancient mech-
anism to aid in immune-mediated pathogen
removal.64
Tregs and IL-10
The main function of Tregs is mainte-
nance of immunologic tolerance. Several
groups have shown that adoptive transfer
of Tregs lowers BP and ameliorates
cardiac and renal injury in different
models of hypertension.65–68 Mice defi-
cient in IL-10, an important product of
Tregs, develop similar degrees of hyperten-
sion in response to angiotensin II, but have
severe endothelial dysfunction and vessels
from these mice show an increased super-
oxide production when incubated with
angiotensin II.69 These and other data sug-
gest that Treg-derived IL-10 mediates the
beneficial effects of Tregs in hypertension.70
www.jasn.org BRIEF REVIEW
IL-2/anti–IL-2 immune complex treatment
of hypertensive mice expands Tregs and
reduces aortic stiffening.71 Administration
of IL-10 lowers BP in preeclampsia.72
CD8+ T Cells
Convincing evidence suggests that T cells
contribute to BP elevation. A major ques-
tion, however, is what T cells are doing to
cause these effects. A recent study has
suggested that CD8+ T cells are a major
source of IFN-g and that these accumu-
late in the kidney in hypertension. Mice
lacking CD8+ T cells developed blunted
hypertensive responses to Ang II, while
mice lacking CD4+ cells are not similarly
protected. Vascular rarefaction in the kid-
ney was noted in wild-type and CD42/2
mice, but not in CD82/2 mice. This in
turn could promote sodium and volume
retention.73 It should be recognized that
mice lacking CD4+ cells also lack Tregs
and this perhaps predisposes these ani-
mals to worsened hypertension.
Antigens and Dendritic Cells
The canonical function of dendritic cells
is activation of T cells.74 After acquiring
antigens, dendritic cells process these to
peptides, migrate to the secondary lym-
phoid organ, and present these antigenic
peptides in the context of MHCs to
T cells. Antigen-activated T cells prolif-
erate and produce clones specific for the
antigen. The kidney harbors a network
of dendritic cells. “Neoantigens” might
be produced in response to early hyper-
tensive mechanical trauma injury by
induction of cell death and release of in-
tracellular antigens that normally are
immune privileged. Interestingly, vari-
ous hypertensive stimuli increase ROS
production in dendritic cells by activa-
tion of the NADPH oxidase. This leads to
lipid oxidation and formation of g
ketoaldehydes or isoketals. Isoketals rap-
idly ligate to protein lysines in the den-
dritic cells, forming proteins that are
interpreted as nonself as shown in Figure
2. Peptides from these proteins are pre-
sented to T cells, leading to their prolif-
eration. In addition, isoketal formation
also promotes production of cytokines,
including IL-1b, IL-6, and IL-23, which
polarize T cells to produce effector
Immune Responses and Hypertension 681
 BRIEF REVIEW www.jasn.org

cytokines. Transfer of isoketal-activated
dendritic cells raises BP in wild-type
mice but not in RAG-12/2 mice that
lack T cells. Moreover, treatment with
isoketal scavengers blunts hypertension
and its associated renal injury in mice.19
A role of dendritic cells in hypertension
was also suggested by prior work using
abatacept, which blocks CD80 and
CD86 on dendritic cells. CD28 binds to
these co-stimulatory molecules on den-
dritic cells and acts as a co-stimulatory
receptor in the activation and maturation
of T lymphocytes. Abatacept treatment
reversed Ang II and DOCA salt–induced
hypertension, confirming a role of T cell
priming by dendritic cells in hypertension.75
Microbiome
The human gut is the natural niche for
.1014 bacteria of .1000 different spe-
cies. The microbiota seem to modulate
immune responses, and increasing data
show that alterations in the microbiota
contribute to immune disorders and car-
diovascular diseases.76,77 Interestingly,
recent data have shown that short-chain
fatty acids produced by gut microbiota
modulate renin release by binding to
olfactory receptors expressed in the re-
nal juxtaglomerular apparatus.78 A link
between microbial content and BP reg-
ulation was also found in Dahl S and R
rats.79 The cross-talk between the gut
microbiota and the renal and cardiovas-
cular systems could be relevant to the

Figure 2. Role of dendritic cells as well as CD4+ and CD8+ cells in hypertension. Hypertension causes lipid oxidation in dendritic cells (DC)
resulting in formation of isoketal adducts of various self-proteins. These isoketal-modified proteins behave like DAMPs and activate
dendritic cells. The dendritic cells secrete cytokines such as IL-1, IL-6, and IL-23. In the renal lymph node or other tissues dendritic cells may
activate CD8+ and CD4+ T cells that migrate into the kidney. CD8+ T cells release cytotoxins such as perforin and granzyme leading to
apoptosis or cell death of peritubular capillaries causing vascular rarefaction. IL-17A and IFN-g released from TH17 and TH1 activate the
renin-angiotensin system and may stimulate or upregulate transport channels in the proximal and distal convoluted tubules, including the
sodium hydrogen exchanger 3 (NHE3) and the sodium chloride cotransporter (NCC). Both in turn causes sodium and volume retention.
Modified from reference 10.

682 Journal of the American Society of Nephrology J Am Soc Nephrol 27: 677–686, 2016
 www.jasn.org BRIEF REVIEW

pathogenesis and treatment of hyperten-
sion. An interesting and unanswered
question is whether salt intake influences
the microbiome and the gut-derived IL-
17 response enhancing the development
of arterial hypertension.
MECHANISMS OF EXPERIMENTAL
MODELS OF HYPERTENSION
How does the immune system cause
hypertension? Convincing data demon-
strate that inflammatory cytokines such
as IL-17, IFN-g, or IL-6 may modulate
sodium reabsorption, as shown in Figure
2. In addition, infiltration of cytotoxic
CD8 T cells into the renal interstitium
may also lead to capillary rarefication,
as shown in Figure 2. The inflammation
associated with hypertension also causes
deposition of collagen in the aortic ad-
ventitia and media with a loss of Wind-
kessel or capacitance function.49
Most data on hypertension and in-
flammation in mice have been obtained
through Ang II or norepinephrine infu-
sion with osmotic mini-pumps or DOCA
salt treatment. These experimental inter-
ventions reproduce several features of
human hypertension. Ang II infusion
resembles the condition in hypertensive
patients with an inappropriately activated
renin-angiotensin system, whereas nor-
epinephrine infusion mimics the state of
patients with an increased sympathetic
drive. DOCA salt treatment models use
enhanced mineralocorticoid activity,
which is increasingly recognized in pa-
tients with resistant hypertension and so-
called low-renin hypertension, based on
the efficacy of mineralocorticoid receptor
blockade in these patients. Furthermore,
new mouse models are necessary to in-
vestigate the influence of genetic variants
conferring an increased susceptibility to
hypertensive renal injury associated with
hypertension, as demonstrated for the
gene that encodes the molecular motor
protein nonmuscle myosin 2a (MYH9).80
SUMMARY
Why should evolution favor immunity
as a regulator of BP? Control of BP and
host defense are essential mechanisms of
homeostasis. Infection can cause hypo-
tension via fluid loss in fever, tachypnea,
and diarrhea. Septicemia induces
inflammation-related vascular fluid los-
ses. Thus, as suggested recently, the risk
of hypotension related to inflammation
might have favored selection of mecha-
nisms that link immune activation to BP
increases for short-term survival bene-
fits. Such an evolutionary force may be
responsible for the fact that important
antimicrobial effectors such as IL-17 or
ROS have direct hypertensive effects by
vasoconstriction or sodium retention.81
Synthesis of all of the available evi-
dence has led us to propose the following
hypothesis as a mechanism for inflam-
mation and hypertension (Figure 3).
Small increases in prohypertensive fac-
tors, such as Ang II, salt retention, or
aldosterone, activate the innate immune
system that triggers or aggravates hyper-
tension. This process includes comple-
ment activation and release of DAMPs
that activate TLRs. These mechanisms
can damage the kidney directly. Hyper-
tensive stimuli also induce NADPH

Figure 3. Working hypothesis describing the role of immunity in hypertension. Hypertensive factors such as Ang II, salt, or aldosterone lead
to a cascade of events: They directly activate the innate immune system. This process includes complement activation and release of
DAMPs, which can activate toll-like receptors and also the inflammasome. On the one hand these mechanisms damage the kidney directly.
On the other hand, they promote the release of cryptic antigens and ROS production, isoketal formation, and alteration of proteins in
dendritic cells. These nonself recognized proteins are presented to T cells. Polarized CD4+ and CD8+ T cells migrate into the heart, vessels,
and kidney and mediate the hypertensive end-organ damage or aggravate this damage, as in the case of kidney arterial hypertension due
to salt and volume retention. In addition activation of cells, such as monocytes/macrophages, gd T cells, NK cells and ILCs may mediate or
aggravate hypertensive renal injury. Modified from reference 7. CNS, central nervous system, nAg, neoantigen.

J Am Soc Nephrol 27: 677–686, 2016 Immune Responses and Hypertension 683
 BRIEF REVIEW www.jasn.org
oxidase–dependent ROS production in
dendritic cells, which leads to formation
of neoantigens that can activate adaptive 7.
immune cells. Activation of innate-like
lymphocytes, such as gd T cells and NK
cells, as well as the adaptive immune sys-
8.
tem, consequently aggravates renal injury.
Our hypothesis will almost certainly
require refinement as new information 9.
becomes available. Are there clinical con-
sequences? The major reason to treat
hypertension is to prevent end-organ
10.
damage. While BP-lowering is clearly im-
portant to reach this goal, prevention of
local inflammation that accompanies hy-
pertensive end-organ damage should also 11.
to be addressed. Currently, no drugs are
available to accomplish this latter goal.10 12.
In addition, vaccines could be a therapeu-
tic option for prevention or treatment of
arterial hypertension.
13.
DISCLOSURES
None.
14.
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