Lewis K.

Dahl Memorial Lecture

Autoimmunity in the Pathogenesis of Hypertension
Bernardo Rodriguez-Iturbe

want to express my thanks for being selected to present the

2015 Lewis K. Dahl Lecture. This award has a long and
proud tradition in the hypertension field, and the list of previous awardees is so impressive that finding myself in their
company is an honor indeed.
The groundbreaking research of Lewis Kitchener Dahl
on the role of salt and genetics in hypertension originated
in his earlier interest on the relationship between salt intake
and blood pressure,1 and his best known contribution, the
salt-resistant and salt-sensitive rat strains,2,3 have been and
will continue to be used in hypertension research all over
the world. At present, the Dahls salt-sensitive (SS) rat is
used to examine the genetic characteristics of hypertension
using targeted mutagenesis of genes associated with human
hypertension.4 Yet, among Dr Dahls many seminal contributions, I, as a nephrologist, have a predilection for his studies
of cross-transplantation of kidneys between salt-sensitive and
salt-resistant rats showing that the high blood pressure and
normal blood pressure responses to a high-salt diet travel with
the kidney5,6 because these experiments demonstrated that the
kidney had a central role in the pathogenesis of hypertension.
Less cited among their works, Lewis Dahl and his coworkers also made observations on the histological findings in the
kidneys that are of particular relevance to the subject of this
conference. They reported that renal lesions did not occur in
R (resistant) rats on either diet, were minimum to mild in S
(sensitive) rats on the diet low in salt, and were moderate to
severe in S rats on the diet high in salt.7 I will take these observations as the starting point to review the evidence that renal
inflammation is a key element in the role of the kidney in the
pathogenesis of the elevation of the blood pressure.

Subtle Renal Inflammation and the

Pathogenesis of Hypertension
The finding of lymphocyte infiltration in tubulointerstitial
areas of the kidney was reported in the 3 biopsy studies done in
the course of lumbar sympathectomies that in the 1950s were
used as a treatment for hypertension.810 It is interesting that
Gareau and Cartier9 stated that it was impossible by the histological examination of the biopsies to define if the interstitial
nephritis influences the progression to nephrosclerosis or if it
is the cause of hypertension. The most detailed observations
were presented in the work of Sommers et al10 who described
in detail arteriolar changes, tubular ischemia, and inflammation in tubulointerstial areas. Collections of lymphocytes were

found not only in association with severe injury but also in

as many as 20% of the biopsies that were otherwise normal.
Similar findings are evident in protocol renal biopsies taken
from kidneys of hypertensive cadaveric donors with normal
renal function used for transplantation (Figure1).
In 1999, Richard Johnsons group11 demonstrated the
importance of subtle renal injury in the development of SS
hypertension. Their studies focused on the functional and
histological characteristics resulting from angiotensin II infusion. They showed that after angiotensin exposure, the renal
function and blood pressure returned to normal, but subtle
renal injury persisted, and the rats developed hypertension if
given a high-salt diet. These studies prompted an evaluation
of the effects of immune suppression with mofetil mycophenolate (MMF) administered during angiotensin II infusion.
MMF administration did not modify the elevation of blood
pressure induced by angiotensin II but suppressed the associated inflammation and prevented the subsequent salt-sensitive
hypertension.12 Similar findings were found in other models of
induced SS hypertension1315 and in the spontaneously hypertensive rat.16 An additional observation, surprising at that time,
was the finding, by double staining methodology, that as many
as 40% of the infiltrating lymphocytes expressed angiotensin
II.12 This finding was confirmed in several other models of
inflammation-induced SS hypertension.1315 Elegant investigations by Hoch et al17 subsequently showed that T lymphocytes
express angiotensinogen, angiotensin-converting enzyme, and
renin and produce angiotensin II; furthermore, endogenously
produced angiotensin II increased T cell activation.
Studies done by Jaime Herreras group18,19 using micropuncture technique showed that SS hypertension was associated with afferent and efferent glomerular vasoconstriction,
and the protection offered with MMF treatment resulted from
correction of glomerular hemodynamics that takes place in
association with the suppression of inflammation and angiotensin II activity (Figure2). In fact, the severity of SS hypertension directly correlates with the degree of inflammation
and angiotensin II concentrations in the kidney.20
The pivotal role of renal tubulointerstitial inflammation in
the pathogenesis of hypertension21 has been firmly established
by numerous studies from various groups of investigators,
including our own, using a variety of anti-inflammatory agents
and strategies of immune suppression applied to experimental
and genetic models of hypertension (reviewed in RodrguezIturbe et al22,23). Of special interest are the investigations by

From the Department of Nephrology, Hospital Universitario and Instituto Venezolano de Investigaciones Cientficas (IVIC)-Zulia, Maracaibo, Venezuela.
Correspondence to Bernardo Rodriguez-Iturbe, Servicio de Nefrologa, 9 Piso Hospital Universitario de Maracaibo, Avenida Goajira s/n, Maracaibo,
Estado Zulia, Venezuela. E-mail brodrigueziturbe@gmail.com
(Hypertension. 2016;67:477-483. DOI: 10.1161/HYPERTENSIONAHA.115.06418.)
2015 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org

DOI: 10.1161/HYPERTENSIONAHA.115.06418

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477

478HypertensionMarch 2016
Mattson and his coworkers that focused in the Dahls SS rats
and showed that suppression of the inflammation, observed
since the initial studies of Jaffe et al,7 ameliorated the severity
of hypertension.24,25 In humans, our group26 studied the effects
of immunosuppressive therapy in 8 hypertensive patients with
normal renal function that received MMF as a treatment for
psoriasis or rheumatoid arthritis. Hypertension was ameliorated during 3 months treatment with MMF, independently of
dietary or treatment changes, and blood pressure increased to
pretreatment levels when MMF was stopped. Urinary excretion of tumor necrosis factor- was correlated with blood
pressure values (Figure3).
The mechanisms by which inflammation worsens hypertension have been reviewed recently23 and include effects
derived from microglial activation in the central nervous system,2729 perivascular infiltration of immune cells with impairment in the vasodilatation response,3032 and impairment in
the physiology of renal pressure-natriuresis. The latter is
directly related to the severity of renal inflammation and to
the renal angiotensin overproduction.33 Recent studies have
shown that local generation of angiotensin II is a key element
in the inflammation-induced impairment of pressure natriuresis: Gianni et al,34 using an inbred line of mice that express
ACE only in myelomonocytic cells, have demonstrated that
absence of renal ACE prevents the salt-driven hypertension
that follows transient inhibition of nitric oxide synthase, in
association with reduction in renal inflammation and injury,
likely because the lack of renal ACE suppresses local generation of angiotensin II below a critical level.

Innate and Adaptive Immunity in the

Pathogenesis of Hypertension
The interest on the role played by the immune system in the
pathogenesis of hypertension has increased rapidly in the last

Figure 1. Lymphocyte infiltration in a protocol pretransplant

renal biopsy from a cadaveric kidney donor with essential
hypertension. The patient was a 51-year-old female with
subarachnoid hemorrhage treated with captopril 25 mg twice a
day, furosemide 50 mg daily, serum creatinine 53.0 mol/L (0.6
mg/dL), and serum urea nitrogen 8.9 mmol/L (25 mg/dL). Immune
infiltrate resembles the findings reported by Sommers et al.10
Immunoperoxidase staining with anti-CD3.

10 to 15 years35,36; yet, nearly half a century ago, several studies examined the participation of the immune system in the
pathogenesis of hypertension. In the model of renal infarction and in deoxycorticosterone acetate-salt hypertension, the
lymph nodes37 and spleen cells38 were found to transfer hypertension to normotensive recipients, and Svendsen39,40 showed
that an intact thymus was necessary for the development of
hypertension in the late (salt-dependent) phase of deoxycorticosterone acetate-salt hypertension and for the hypertension
associated with renal infarction. However, contrasting data
suggested that the immune system had a protective role in
hypertension.41,42
The specific role of lymphocytes in hypertension was
shown in the elegant experiments of Guzic et al30 in the recombination-activating gene 1 knockout mice (rag1/) mice that is
devoid of lymphocytes. Their studies showed that the rag1/
mice is resistant to angiotensin IIinduced hypertension and
recovers the hypertensive response with the adoptive transfer
of T cells. Studies by Crowley et al43 showed that angiotensin II stimulates lymphocyte responses in hypertension. The
same group added important insight into the mechanisms of
angiotensin-induced hypertension using bone marrow chimeras lacking angiotensin type IA receptors. They showed that
bone marrowderived angiotensin type IA receptors actually
exert a protective role, ameliorating macrophage infiltration
and hypertensive response, possibly regulating vasoactive
cytokines.44 Recently, Mattson et al45 using zinc finger nuclease technology induced a null mutation of rag1 in the Dahl
SS rat and demonstrated that depletion of mature lymphocytes blunted the infiltration of lymphocytes in the kidney and
ameliorated hypertension and kidney injury resulting from a
high-salt diet. The balance between a proinflammatory T cell
reactivity and the inflammatory suppression induced by T regulatory cells is a key element in the development of hypertension as demonstrated by the amelioration of hypertension with
the adoptive transfer of T regulatory cells in several models of
hypertension.31,32,46
The participation of the innate and the adaptive immune
responses in the development of the inflammation in hypertension is the subject of considerable interest.22,23 Several elements in the hypertension-induced tissue injury are capable
of acting as danger-associated molecular patterns that activate
the innate immunity. In the deoxycorticosterone acetate-salt
hypertension model47 and in the Dahl SS rat,48 the elements
of the inflammasome are overexpressed. In the spontaneously
hypertensive rat, the priming signals for inflammasome activation, including overexpression of Toll-like receptors 2 and
449 and nuclear factor kappa B activation,50 have been demonstrated, and mRNA stimulation with overexpression of all the
components of the canonical nod-like receptor pyrin 3 inflammasone are present (unpublished).
The role of self-antigens promoting hypertension by
activating the adaptive immunity has been suspected by the
existence of agonistic (prohypertensive) antibodies directed
to adrenergic and angiotensin receptors and of IgG and
IgM autoantibodies in hypertensive patients (reviewed in
Rodrguez-Iturbe et al23 and Mathis et al51). Recently, Michael
Ryans group have used a murine model of systemic lupus
erythematosus, characterized by a multiorgan inflammation

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Rodriguez-Iturbe Autoimmunity in Hypertension 479

Figure 2. Glomerular hemodynamic studies done after 5 weeks

of high (4%) salt diet in rats previously exposed to a 2 week
infusion with angiotensin II (Ang II) alone or in association with
mofetil mycophenolate (Ang II-MMF). The increase in blood
pressure (A) and renal inflammation (B) with a high-salt diet
is associated with afferent (C) and efferent (D) glomerular
vasoconstriction and reduction in renal plasma flow (E) and
single nephron glomerular filtration rate (F). Administration of
MMF suppresses inflammation, corrects hemodynamic changes,
and ameliorates salt-induced hypertension. Data from Franco et
al18 with graphic modifications. Data are meanSE.

in response to self-antigens and autoantibody (antinuclear)

production to explore the relationship between the humoral
cell response and hypertension. They showed that depleting B
cells before the development of systemic lupus erythematosus
with the administration of anti-CD20 antibody (equivalent to
rituximab in humans) reduced the formation of autoantibodies, decreased tumor necrosis factor- expression, and ameliorated hypertension.52 The prohypertensive role of tumor
necrosis factor-mediated inflammation has been shown in
several studies that inhibited this cytokine with a tumor necrosis factor- receptor fusion protein bound to the cristallisable
fragment of IgG (etanercept).5355 Participation of the adaptive immunity in hypertension was also shown in the studies
of Vinh et al56 that examined the effects of suppressing the
costimulation required for antigen-induced T cell activation
and demonstrated that mice lacking B7 ligands or treated with
CTLA4 (Abatacept) to block T cell costimulation showed
inhibited cytokine production, reduced of vascular T cell accumulation and resistance to angiotensin-induced hypertension.
Recent studies have focused on the generation of endogenous antigens resulting from the high blood pressure.
David Harrisons group5759 investigated the role of gamma
ketoaldehydes (isoketals) formed as a consequence of lipid

peroxidation induced by reactive oxygen species, and our

group has focused on heat shock proteins (HSP) locally
formed as a response to cellular stress.6062 Both of these elements are of potential clinical relevance. Isoketals react with
intracellular proteins and produce protein adducts that are
taken up by dendritic cells and presented to the major histocompatibility complex type I lymphocyte receptor. Elegant
studies showed that scavengers of isoketals (2 hydrobenzylamine) prevented hypertension in angiotensin IIinduced and
in deoxycorticosterone acetate-salt hypertension.57 Our own
studies focused on HSP70 and were prompted by the recognition of the role of HSPs in the activation of immunity. HSP70
may trigger innate immune responses acting as a dangerassociated molecular pattern because it is a ligand of toll-like
receptor 2 and toll-like receptor 4 and enhance nod-like receptor pyrin 3 expression.6365 In addition, HSP70 stimulates the
maturation of dendritic cells.6668 HSP70 may be recognized
as an autoantigen itself,69 and it may act as a chaperone for the
presentation of allopeptides for their recognition as antigenic
molecules to major histocompatibility complex class I and
class II molecules in dendritic cells.70,71
In several models of experimentally induced salt-sensitive hypertension, we have found a lymphocyte proliferative
response to HSP70,61 and recently, we have found similar
findings in the spontaneously hypertensive rat (unpublished).
Relevance of HSP70 in human hypertension is suggested by
the demonstration of IgG ant-HSP70 antibodies in essential
hypertension.72 In addition, lymphocytes of hypertensive
patients have a higher than normal HSP70 expression in
response to heat stress73 and present a proliferative reaction

Figure 3. Treatment during 3 months with mofetil mycophenolate

(MMF) to 8 patients with psoriasis and rheumatoid arthritis who
had grade I essential hypertension and normal renal function
resulted in a reduction of blood pressure and urinary excretion of
tumor necrosis factor- (TNF-). Data from Herrera et al.26 Data
are meanSD. *P<0.05.

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480HypertensionMarch 2016

Figure 4. Effects of short-term mofetil

mycophenolate mofetil (MMF) treatment
on the postocclusion flow-mediated
dilatation (FMD). The patient is a
36-year-old male of mixed race with
chronic kidney disease who had a mean
ambulatory blood pressure of 172/100
mmHg, despite receiving minoxidil 50
mg/d, valsartan 320 mg/d, carvedilol 75
mg/d, and nifedipine 120 mg/d. FMD of
13% (percent increase from preocclusion
measurement) of the right brachial artery
before the administration of MMF (left
side) increased to 55% after 2 weeks of
treatment with MMF, 1 g twice daily (right
side) in association with a reduction of the
mean ambulatory blood pressure to levels
of 153/70 mmHg. Blood pressures shown
in the figure are those taken at the time of
the FMD studies.

when challenged with HSP70.61,62 Interestingly, polymorphism in 3 genes in the HSP70 family (HSPA 1A, HSP1B,
and HSPA 1L) are associated with an increased risk of hypertension in the Uygur ethnicity in China.74
To test the relevance of HSP70-driven immune reactivity in hypertension, we induced tolerance to HSP70 in the
model of SS hypertension resulting from transient inhibition
of nitric oxide synthase. In this model, NW-nitro-l-argininemethyl ester is administered orally for 3 weeks. After a washout period of 1 week, when the blood pressure returns to
normal, the rats are given a high-salt diet that then results in
hypertension. The development of SS hypertension is associated with delayed-type hypersensitivity and a clonal CD4 T
cell proliferation in response to HSP70. The kidneys present
overexpression of interleukin-6 and tubulointerstitial accumulation of immune cells. To induce tolerance in this model, we
selected a well-preserved amino acid sequence of mycobacterial HSP70 (139153 1A/1B) that had been used by Praken et
al75,76 and Wendling et al77 to induce protective immune tolerance against adjuvant (nonbacterial) arthritis. The HSP70
amino acid sequence was administered intraperitoneally in
the wash-up period after NW-nitro-l-arginine-methyl ester
was discontinued. The result was an interleukin-10 regulatory T cell response that was associated with correction of the
immune reactivity to HSP70, suppression of the renal immune
cell infiltration, and prevention of the hypertension induced
by a high-salt diet. Furthermore, the adoptive transfer of T
cells from tolerized animals to animals with SS hypertension
corrected hypertension. The role of renal immune reactivity
to HSP70 was also additionally explored in normotensive rats
that were sensitized to HSP70. In these rats, we induced renal
expression of HSP70 with infusion in both renal veins of HSP
gene. This strategy resulted in tubulointerstitial accumulation
of immune cells and the increase in blood pressure when a
high-salt diet was given.62

Mattson78 has recently reviewed the mechanism whereby

infiltrating immune cells amplify SS hypertension and renal
damage: the initial increase in blood pressure induced by a
high-salt diet leads to antigen or neoantigen formation that,
in turn, results in the infiltration and activation of immune
cells in the kidneys with local release of free oxygen radicals,
angiotensin II, and cytokines. These events result in blunting
of pressure natriuresis and further development of hypertension and renal injury.

Unanswered Questions of Clinical Relevance

From my perspective, several pressing questions on the relationship between hypertension and autoimmunity merit investigation at the present time:
What are the mechanisms of engagement, participation, and suppression of the inflammasome in essential
hypertension?
What antigens are responsible for T cell and B cell autoimmune responses in essential hypertension?
Is immune suppression/tolerance a valuable adjunct to
antihypertensive drugs in the management of patients
with severe resistant hypertension?
We have an extensive array of medications that lower the
blood pressure. These medications have a well-deserved reputation of efficacy and safety, and the long-term use of immunosuppressive therapy is not justified in the usual hypertensive patient.
Nevertheless, we posit that in selected cases of uncontrolled
essential hypertension, resistant to treatment with 3 drugs at
full therapeutic doses, a trial of transient (2 months) treatment
with MMF, is worth considering if there are no contraindications to the use of this drug. These patients may present considerable difficulties in their management, and some of them are
presently referred for renal denervation with mixed results. We
have treated 2 of such patients and obtained a marked reduction

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Rodriguez-Iturbe Autoimmunity in Hypertension 481

of the blood pressure after 1 week of treatment with 2 g of
MMF daily, and this response allowed a substantial decrease
in the dose of antihypertensive medication. The amelioration
of hypertension associated with administration of MMF was
accompanied with a marked improvement in the postocclusive flow-mediated vasodilatation (Figure4). We interpreted
this finding as compatible with MMF-induced correction of
the impaired vasodilatation that experimental studies3032 have
shown to be associated with perivascular inflammation. These
observations suggest the need of clinical studies to define
whether short-term immunosuppressive treatment has a place
in the treatment of severe uncontrolled hypertension.
Continued investigation on the role of autoimmunity in
hypertension may open new therapeutic strategies that may
have an impact in the management of a disease that presently
affects >30% of the adult world population.79

Sources of Funding
Research in the author laboratory funded by FONDECYT LOCTI
grant 1306 and Grants from the Asociacin de Amigos del Rin,
Maracaibo, Venezuela

Disclosures
None.

References
1. Dole VP, Dahl LK, Cotzias GC, Eder HA, Krebs ME. Dietary treatment
of hypertension; clinical and metabolic studies of patients on the rice-fruit
diet. J Clin Invest. 1950;29:11891206. doi: 10.1172/JCI102357.
2. Dahl LK, Heine M, Tassinari L. Effects of chronia excess salt ingestion.
Evidence that genetic factors play an important role in susceptibility to
experimental hypertension. J Exp Med. 1962;115:11731190.
3. Dahl LK, Heine M, Tassinari L. Role of genetic factors in susceptibility
to experimental hypertension due to chronic excess salt ingestion. Nature.
1962;194:480482.
4. Rudemiller NP, Mattson DL. Candidate genes for hypertension: insights
from the Dahl S rat [published online ahead of print April 15, 2015]. Am J
Physiol Renal Physiol. doi:10.1152/ajprenal.00092.2015. http://ajprenal.
physiology.org/content/early/2015/04/13/ajprenal.00092.2015.
5. Dahl LK, Heine M, Thompson K. Genetic influence of renal homografts
on the blood pressure of rats from different strains. Proc Soc Exp Biol
Med. 1972;140:852856.
6. Dahl LK, Heine M, Thompson K. Genetic influence of the kidneys on
blood pressure. Evidence from chronic renal homografts in rats with
opposite predispositions to hypertension. Circ Res. 1974;34:94101.
7. Jaff D, Sutherland LE, Barker DM, Dahl LK. Effects of chronic excess
salt ingestion. Morphologic findings in kidneys of rats with differing
genetic susceptibilities to hypertension. Arch Pathol. 1970;90:116.
8. Heptinstall RH. Renal biopsies in hypertension. Br Heart J.
1954;16:133141.
9. Gareau RJ, Cartier GE. [Histological study of 55 renal biopsies in hypertensive patients]. Union Med Can. 1955;84:11341142.
10. Sommers SC, Relman AS, Smithwick RH. Histologic studies of kidney biopsy specimens from patients with hypertension. Am J Pathol.
1958;34:685715.
11. Lombardi D, Gordon KL, Polinsky P, Suga S, Schwartz SM, Johnson
RJ. Salt-sensitive hypertension develops after short-term exposure to
Angiotensin II. Hypertension. 1999;33:10131019.
12. Rodrguez-Iturbe B, Pons H, Quiroz Y, Gordon K, Rincn J, Chvez M,
Parra G, Herrera-Acosta J, Gmez-Garre D, Largo R, Egido J, Johnson
RJ. Mycophenolate mofetil prevents salt-sensitive hypertension resulting from angiotensin II exposure. Kidney Int. 2001;59:22222232. doi:
10.1046/j.1523-1755.2001.00737.x.
13. Quiroz Y, Pons H, Gordon KL, Rincn J, Chvez M, Parra G, HerreraAcosta J, Gmez-Garre D, Largo R, Egido J, Johnson RJ, RodrguezIturbe B. Mycophenolate mofetil prevents salt-sensitive hypertension
resulting from nitric oxide synthesis inhibition. Am J Physiol Renal
Physiol. 2001;281:F38F47.

14. Alvarez V, Quiroz Y, Nava M, Pons H, Rodrguez-Iturbe B. Overload proteinuria is followed by salt-sensitive hypertension caused by renal infiltration of immune cells. Am J Physiol Renal Physiol. 2002;283:F1132F1141.
doi: 10.1152/ajprenal.00199.2002.
15. Vanegas V, Ferrebuz A, Quiroz Y, Rodrguez-Iturbe B. Hypertension in
page (cellophane-wrapped) kidney is due to interstitial nephritis. Kidney
Int. 2005;68:11611170. doi: 10.1111/j.1523-1755.2005.00508.x.
16. Rodrguez-Iturbe B, Quiroz Y, Nava M, Bonet L, Chvez M, HerreraAcosta J, Johnson RJ, Pons HA. Reduction of renal immune cell infiltration results in blood pressure control in genetically hypertensive
rats. Am J Physiol Renal Physiol. 2002;282:F191F201. doi: 10.1152/
ajprenal.0197.2001.
17. Hoch NE, Guzik TJ, Chen W, Deans T, Maalouf SA, Gratze P, Weyand
C, Harrison DG. Regulation of T-cell function by endogenously produced
angiotensin II. Am J Physiol Regul Integr Comp Physiol. 2009;296:R208
R216. doi: 10.1152/ajpregu.90521.2008.
18. Franco M, Tapia E, Santamara J, Zafra I, Garca-Torres R, Gordon KL,
Pons H, Rodrguez-Iturbe B, Johnson RJ, Herrera-Acosta J. Renal cortical
vasoconstriction contributes to development of salt-sensitive hypertension
after angiotensin II exposure. J Am Soc Nephrol. 2001;12:22632271.
19. Snchez-Lozada LG, Tapia E, Johnson RJ, Rodrguez-Iturbe B. HerreraAcosta J. Glomerular hemodynamic changes associated with arteriolar
lesions and tubulointerstitial inflammation. Kidney Int. 2003;64 (suppl
86):S9S14.
20. Franco M, Martnez F, Quiroz Y, Galicia O, Bautista R, Johnson RJ,
Rodrguez-Iturbe B. Renal angiotensin II concentration and interstitial
infiltration of immune cells are correlated with blood pressure levels in
salt-sensitive hypertension. Am J Physiol Regul Integr Comp Physiol.
2007;293:R251R256. doi: 10.1152/ajpregu.00645.2006.
21. Johnson RJ, Herrera-Acosta J, Schreiner GF, Rodriguez-Iturbe B. Subtle
acquired renal injury as a mechanism of salt-sensitive hypertension. N
Engl J Med. 2002;346:913923. doi: 10.1056/NEJMra011078.

22. Rodrguez-Iturbe B, Pons H, Quiroz Y, Lanaspa MA, Johnson RJ.
Autoimmunity in the pathogenesis of hypertension. Nat Rev Nephrol.
2014;10:5662. doi: 10.1038/nrneph.2013.248.
23. Rodrguez-Iturbe B, Pons H, Quiroz Y, Johnson RJ. The immunological basis of hypertension. Am J Hypertens. 2014;27:13271337. doi:
10.1093/ajh/hpu142.
24. De Miguel C, Das S, Lund H, Mattson DL. T lymphocytes mediate
hypertension and kidney damage in Dahl salt-sensitive rats. Am J Physiol
Regul Integr Comp Physiol. 2010;298:R1136R1142. doi: 10.1152/
ajpregu.00298.2009.
25. De Miguel C, Guo C, Lund H, Feng D, Mattson DL. Infiltrating T lymphocytes in the kidney increase oxidative stress and participate in the
development of hypertension and renal disease. Am J Physiol Renal
Physiol. 2011;300:F734F742. doi: 10.1152/ajprenal.00454.2010.

26. Herrera J, Ferrebuz A, MacGregor EG, Rodriguez-Iturbe B.
Mycophenolate mofetil treatment improves hypertension in patients with
psoriasis and rheumatoid arthritis. J Am Soc Nephrol. 2006;17(12 suppl
3):S218S225. doi: 10.1681/ASN.2006080918.

27. Marvar PJ, Thabet SR, Guzik TJ, Lob HE, McCann LA, Weyand
C, Gordon FJ, Harrison DG. Central and peripheral mechanisms of
T-lymphocyte activation and vascular inflammation produced by angiotensin II-induced hypertension. Circ Res. 2010;107:263270. doi:
10.1161/CIRCRESAHA.110.217299.
28. Lob HE, Marvar PJ, Guzik TJ, Sharma S, McCann LA, Weyand C, Gordon
FJ, Harrison DG. Induction of hypertension and peripheral inflammation
by reduction of extracellular superoxide dismutase in the central nervous
system. Hypertension. 2010;55:277283, 6p following 283. doi: 10.1161/
HYPERTENSIONAHA.109.142646.
29. Sriramula S, Cardinale JP, Francis J. Inhibition of TNF in the brain
reverses alterations in RAS components and attenuates angiotensin
II-induced hypertension. PLoS One. 2013;8:e63847. doi: 10.1371/journal.
pone.0063847.
30. Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S,
Goronzy J, Weyand C, Harrison DG. Role of the T cell in the genesis of
angiotensin II induced hypertension and vascular dysfunction. J Exp Med.
2007;204:24492460. doi: 10.1084/jem.20070657.
31. Kasal DA, Barhoumi T, Li MW, Yamamoto N, Zdanovich E, Rehman A,
Neves MF, Laurant P, Paradis P, Schiffrin EL. T regulatory lymphocytes
prevent aldosterone-induced vascular injury. Hypertension. 2012;59:324
330. doi: 10.1161/HYPERTENSIONAHA.111.181123.
32. Viel EC, Lemari CA, Benkirane K, Paradis P, Schiffrin EL. Immune regulation and vascular inflammation in genetic hypertension. Am J Physiol Heart
Circ Physiol. 2010;298:H938H944. doi: 10.1152/ajpheart.00707.2009.

Downloaded from http://hyper.ahajournals.org/ by guest on February 26, 2016

482HypertensionMarch 2016
33. Franco M, Tapia E, Bautista R, Pacheco U, Santamaria J, Quiroz Y,
Johnson RJ, Rodriguez-Iturbe B. Impaired pressure natriuresis resulting
in salt-sensitive hypertension is caused by tubulointerstitial immune cell
infiltration in the kidney. Am J Physiol Renal Physiol. 2013;304:F982
F990. doi: 10.1152/ajprenal.00463.2012.
34. Giani JF, Bernstein KE, Janjulia T, Han J, Toblli JE, Shen XZ, Rodriguez-Iturbe
B, McDonough AA, Gonzalez-Villalobos RA. Salt sensitivity in response to
renal injury requires renal angiotensin-converting enzyme. Hypertension.
2015;66:534542. doi: 10.1161/HYPERTENSIONAHA.115.05320.
35. Ryan MJ. Immune mechanisms in hypertension. In Granger ND, Granger
J, eds, Colloquium Series on Integrated System Physiology. San Rafael,
CA: Morgan & Claypool Life Sciences; 2013:3344.
36. Ryan MJ. An update on immune system activation in the pathogenesis of hypertension. Hypertension. 2013;62:226230. doi: 10.1161/
HYPERTENSIONAHA.113.00603.
37. Okuda T, Grollman A. Passive transfer of autoimmune induced hypertension in the rat by lymph node cells. Tex Rep Biol Med. 1967;25:257264.
38. Olsen F. Transfer of arterial hypertension by splenic cells from DOCAsalt hypertensive and renal hypertensive rats to normotensive recipients.
Acta Pathol Microbiol Scand C. 1980;88:15.
39. Svendsen UG. Evidence for an initial, thymus independent and a chronic,
thymus dependent phase of DOCA and salt hypertension in mice. Acta
Pathol Microbiol Scand A. 1976;84:523528.
40. Svendsen UG. The importance of thymus in the pathogenesis of the
chronic phase of hypertension in mice following partial infarction of the
kidney. Acta Pathol Microbiol Scand (A). 1977;85:539547.
41. Ba D, Takeichi N, Kodama T, Kobayashi H. Restoration of T cell
depression and suppression of blood pressure in spontaneously hypertensive rats (SHR) by thymus grafts or thymus extracts. J Immunol.
1982;128:12111216.

42. Tuttle RS, Boppana DP. Antihypertensive effect of interleukin-2.
Hypertension. 1990;15:8994.
43. Crowley SD, Frey CW, Gould SK, Griffiths R, Ruiz P, Burchette JL,
Howell DN, Makhanova N, Yan M, Kim HS, Tharaux PL, Coffman TM.
Stimulation of lymphocyte responses by angiotensin II promotes kidney
injury in hypertension. Am J Physiol Renal Physiol. 2008;295:F515
F524. doi: 10.1152/ajprenal.00527.2007.
44. Crowley SD, Song YS, Sprung G, Griffiths R, Sparks M, Yan M, Burchette
JL, Howell DN, Lin EE, Okeiyi B, Stegbauer J, Yang Y, Tharaux PL, Ruiz
P. A role for angiotensin II type 1 receptors on bone marrow-derived cells in
the pathogenesis of angiotensin II-dependent hypertension. Hypertension.
2010;55:99108. doi: 10.1161/HYPERTENSIONAHA.109.144964.
45. Mattson DL, Lund H, Guo C, Rudemiller N, Geurts AM, Jacob H. Genetic
mutation of recombination activating gene 1 in Dahl salt-sensitive rats
attenuates hypertension and renal damage. Am J Physiol Regul Integr
Comp Physiol. 2013;304:R407R414. doi: 10.1152/ajpregu.00304.2012.
46. Barhoumi T, Kasal DA, Li MW, Shbat L, Laurant P, Neves MF, Paradis
P, Schiffrin EL. T regulatory lymphocytes prevent angiotensin II-induced
hypertension and vascular injury. Hypertension. 2011;57:469476. doi:
10.1161/HYPERTENSIONAHA.110.162941.
47. Krishnan M, Dowling JK, Ling YH, et al. Inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induced hypertension in
mice [published online ahead of print June 23, 2015]. Br J Pharmacol. doi:
10.1111/bph.13230. http://onlinelibrary.wiley.com/doi/10.1111/bph.13230/
abstract;jsessionid=C6A4ADA6CCB44C8515D42F00DCFA79EB.f03t04.
48. Qi J, Zhao XF, Yu XJ, Yi QY,Shi HL, Tan H, Fan XY, Gao HL, Yue
LY, Feng ZP, Kang YM. Targeting interleukin-1 beta to suppress sympathoexcitation in hypothalamic paraventricular nucleus in Dahl saltsensitive hypertensive rats [published online ahead of print August 25,
2015]. Cardiovasc Toxicol. doi: 10.1007/s12012-015-9338-7. http://link.
springer.com/article/10.1007%2Fs12012-015-9338-7.
49. Bomfim GF, Echem C, Martins CB, Costa TJ, Sartoretto SM, Dos Santos
RA, Oliveira MA, Akamine EH, Fortes ZB, Tostes RC, Webb RC,
Carvalho MH. Toll-like receptor 4 inhibition reduces vascular inflammation in spontaneously hypertensive rats. Life Sci. 2015;122:17. doi:
10.1016/j.lfs.2014.12.001.
50. Rodrguez-Iturbe B, Ferrebuz A, Vanegas V, Quiroz Y, Mezzano S, Vaziri
ND. Early and sustained inhibition of nuclear factor-kappaB prevents
hypertension in spontaneously hypertensive rats. J Pharmacol Exp Ther.
2005;315:5157. doi: 10.1124/jpet.105.088062.
51. Mathis KW, Broome HJ, Ryan MJ. Autoimmunity: an underlying factor in
the pathogenesis of hypertension. Curr Hypertens Rep. 2014;16:424. doi:
10.1007/s11906-014-0424-1.
52. Mathis KW, Wallace K, Flynn ER, Maric-Bilkan C, LaMarca B, Ryan
MJ. Preventing autoimmunity protects against the development of

hypertension and renal injury. Hypertension. 2014;64:792800. doi:

10.1161/HYPERTENSIONAHA.114.04006.
53. Sriramula S, Francis J. Tumor necrosis factor - alpha is essential for angiotensin II-induced ventricular remodeling: role for oxidative stress. PLoS
One. 2015;10.
54. Song XA, Jia LL, Cui W, Zhang M, Chen W, Yuan ZY, Guo J, Li HH, Zhu
GQ, Liu H, Kang YM. Inhibition of TNF- in hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by inhibiting neurohormonal excitation in spontaneously hypertensive rats. Toxicol
Appl Pharmacol. 2014;281:101108. doi: 10.1016/j.taap.2014.09.004.
55. Gilbert EL, Mathis KW, Ryan MJ. 17-Estradiol protects against the progression of hypertension during adulthood in a mouse model of systemic
lupus erythematosus. Hypertension. 2014;63:616623. doi: 10.1161/
HYPERTENSIONAHA.113.02385.
56. Vinh A, Chen W, Blinder Y, Weiss D, Taylor WR, Goronzy JJ, Weyand CM,
Harrison DG, Guzik TJ. Inhibition and genetic ablation of the B7/CD28
T-cell costimulation axis prevents experimental hypertension. Circulation.
2010;122:25292537. doi: 10.1161/CIRCULATIONAHA.109.930446.
57. Kirabo A, Fontana V, de Faria AP, et al. DC isoketal-modified proteins
activate T cells and promote hypertension. J Clin Invest. 2014;124:4642
4656. doi: 10.1172/JCI74084.
58. Trott DW, Thabet SR, Kirabo A, Saleh MA, Itani H, Norlander AE, Wu
J, Goldstein A, Arendshorst WJ, Madhur MS, Chen W, Li CI, Shyr Y,
Harrison DG. Oligoclonal CD8+ T cells play a critical role in the development of hypertension. Hypertension. 2014;64:11081115. doi: 10.1161/
HYPERTENSIONAHA.114.04147.
59. Xiao L, Kirabo A, Wu J, Saleh MA, Zhu L, Wang F, Takahashi
T, Loperena R, Foss JD, Mernaugh RL, Chen W, Roberts J II,
Osborn JW, Itani HA, Harrison DG. Renal denervation prevents
immune cell activation and renal inflammation in angiotensin
II-induced hypertension. Circ Res. 2015;117:547557. doi: 10.1161/
CIRCRESAHA.115.306010.
60. Rodrguez-Iturbe B, Vaziri ND, Herrera-Acosta J, Johnson RJ. Oxidative
stress, renal infiltration of immune cells, and salt-sensitive hypertension:
all for one and one for all. Am J Physiol Renal Physiol. 2004;286:F606
F616. doi: 10.1152/ajprenal.00269.2003.
61. Parra G, Quiroz Y, Salazar J, Bravo Y, Pons H, Chavez M, Johnson RJ,
Rodriguez-Iturbe B. Experimental induction of salt-sensitive hypertension is associated with lymphocyte proliferative response to HSP70.
Kidney Int. 2008;74 (suppl.111):S55S59.
62. Pons H, Ferrebuz A, Quiroz Y, Romero-Vasquez F, Parra G, Johnson RJ,
Rodriguez-Iturbe B. Immune reactivity to heat shock protein 70 expressed
in the kidney is cause of salt-sensitive hypertension. Am J Physiol Renal
Physiol. 2013;304:F289F299. doi: 10.1152/ajprenal.00517.2012.
63. Bauernfeind F, Ablasser A, Bartok E, Kim S, Schmid-Burgk J, Cavlar T,
Hornung V. Inflammasomes: current understanding and open questions.
Cell Mol Life Sci. 2011;68:765783. doi: 10.1007/s00018-010-0567-4.
64. Land WG. Role of heat shock protein 70 in innate alloimmunity. Front
Immunol. 2011;2:89. doi: 10.3389/fimmu.2011.00089.
65. Mathur S, Walley KR, Wang Y, Indrambarya T, Boyd JH. Extracellular
heat shock protein 70 induces cardiomyocyte inflammation and contractile dysfunction via TLR2. Circ J. 2011;75:24452452.

66. Kuppner MC, Gastpar R, Gelwer S, Nssner E, Ochmann O,
Scharner A, Issels RD. The role of heat shock protein (hsp70) in
dendritic cell maturation: hsp70 induces the maturation of immature dendritic cells but reduces DC differentiation from monocyte precursors. Eur J Immunol. 2001;31:16021609. doi:
10.1002/1521-4141(200105)31:5<1602::AID-IMMU1602>3.0.CO;2-W.
67. Bethke K, Staib F, Distler M, Schmitt U, Jonuleit H, Enk AH, Galle PR,
Heike M. Different efficiency of heat shock proteins (HSP) to activate
human monocytes and dendritic cells: superiority of HSP60. J Immunol.
2002;169:61416148.
68. Wang Y, Kelly CG, Singh M, McGowan EG, Carrara AS, Bergmeier LA,
Lehner T. Stimulation of Th1-polarizing cytokines, C-C chemokines, maturation of dendritic cells, and adjuvant function by the peptide binding
fragment of heat shock protein 70. J Immunol. 2002;169:24222429.
69. Todryk SM, Gough MJ, Pockley AG. Facets of heat shock protein 70 show
immunotherapeutic potential. Immunology. 2003;110:19.
70. Land WG, Memer K. Tissue injury-induced initiation of the adaptive immune response. Transplantation. 2012;93:e38. doi: 10.1097/
TP.0b013e31824e7642.
71. Stocki P, Morris NJ, Preisinger C, Wang XN, Kolch W, Multhoff G,
Dickinson AM. Identification of potential HLA class I and class II epitope precursors associated with heat shock protein 70 (HSPA). Cell Stress
Chaperones. 2010;15:729741. doi: 10.1007/s12192-010-0184-z.

Downloaded from http://hyper.ahajournals.org/ by guest on February 26, 2016

Rodriguez-Iturbe Autoimmunity in Hypertension 483

72. Pockley AG, De Faire U, Kiessling R, Lemne C, Thulin T, Frostegrd J.
Circulating heat shock protein and heat shock protein antibody levels in
established hypertension. J Hypertens. 2002;20:18151820.
73. Kunes J, Poirier M, Tremblay J, Hamet P. Expression of hsp70 gene in
lymphocytes from normotensive and hypertensive humans. Acta Physiol
Scand. 1992;146:307311. doi: 10.1111/j.1748-1716.1992.tb09424.x.
74. Li JX, Tang BP, Sun HP, Feng M, Cheng ZH, Niu WQ. Interacting contribution of the five polymorphisms in three genes of Hsp70 family to
essential hypertension in Uygur ethnicity. Cell Stress Chaperones.
2009;14:355362. doi: 10.1007/s12192-008-0089-2.
75. Prakken BJ, van der Zee R, Anderton SM, van Kooten PJ, Kuis W, van Eden
W. Peptide-induced nasal tolerance for a mycobacterial heat shock protein 60
T cell epitope in rats suppresses both adjuvant arthritis and nonmicrobially
induced experimental arthritis. Proc Natl Acad Sci U S A. 1997;94:32843289.
76. Prakken BJ, Wendling U, van der Zee R, Rutten VP, Kuis W, van Eden
W. Induction of IL-10 and inhibition of experimental arthritis are

specific features of microbial heat shock proteins that are absent for
other evolutionarily conserved immunodominant proteins. J Immunol.
2001;167:41474153.
77. Wendling U, Paul L, van der Zee R, Prakken B, Singh M, van Eden W. A
conserved mycobacterial heat shock protein (hsp) 70 sequence prevents
adjuvant arthritis upon nasal administration and induces IL-10-producing
T cells that cross-react with the mammalian self-hsp70 homologue. J
Immunol. 2000;164:27112717.
78. Mattson DL. Infiltrating immune cells in the kidney in salt-sensitive hypertension and renal injury. Am J Physiol Renal Physiol. 2014;307:F499
F508. doi: 10.1152/ajprenal.00258.2014.
79. Go AS, Mozaffarian D, Roger VL, et al; American Heart Association
Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics2014 update: a report from the American
Heart Association. Circulation. 2014;129:e28e292. doi: 10.1161/01.
cir.0000441139.02102.80.

Downloaded from http://hyper.ahajournals.org/ by guest on February 26, 2016

Autoimmunity in the Pathogenesis of Hypertension

Bernardo Rodriguez-Iturbe
Hypertension. 2016;67:477-483; originally published online December 7, 2015;
doi: 10.1161/HYPERTENSIONAHA.115.06418
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