Blood Purif 2008;26:45–48
DOI: 10.1159/000110563
Pathophysiology of Salt-Sensitive
Hypertension:
A New Scope of an Old Problem
Martha Franco a Laura G. Sanchez-Lozada a Rocio Bautista a Richard J. Johnson c
Bernardo Rodriguez-Iturbe b
a
Department of Nephrology, Instituto Nacional de Cardiología I. Ch., Mexico City, Mexico;
b
Hospital Universitario, Instituto de Investigaciones Biomédicas, Universidad del Zulia, Maracaibo, Venezuela;
c
Division of Nephrology, Hypertension and Transplantation, University of Florida, Gainesville, Fla., USA
Key Words
Salt-sensitive hypertension ⴢ Angiotensin II ⴢ Microdialysis ⴢ
Tubulointerstitial inflammation ⴢ Renal hemodynamics
Abstract
It has been recognized for many years that salt intake is one
of the main environmental factors responsible for the devel-
opment of hypertension. More than 30 years ago, Guyton
and co-workers postulated a relationship between blood
pressure and natriuresis which maintains sodium balance
and extracellular volume; thus an impaired ability of the kid-
ney to excrete sodium requires an increase in blood pressure
to increase natriuresis and correct the sodium balance, re-
sulting in hypertension. Currently, the mechanisms respon-
sible for the alterations mentioned above remain under
investigation. Among them, microvascular and tubulointer-
stitial injury induce salt retention and development of salt-
sensitive hypertension that appears to be mediated in part
by lymphocytes and macrophages infiltrating the tubuloin-
terstitium that produce angiotensin II and stimulate oxida-
tive stress. In the post-angiotensin salt-sensitive hyperten-
sion model, angiotensin levels are elevated despite systemic
angiotensin II levels being suppressed, and the local angio-
tensin II levels correlate with the presence of intrarenal
inflammation and cortical vasoconstriction. Under these
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conditions, blockade of the angiotensin II AT1 receptors
ameliorate cortical vasoconstriction. Thus, the renal angio-
tensin system in association with interstitial immune infil-
trating cells may play a pivotal role in the development and
maintenance of salt-sensitive hypertension.
Copyright © 2008 S. Karger AG, Basel
The association between high sodium intake and sys-
temic hypertension is well known. In fact, high salt inges-
tion is considered one of the main environmental factors
that influences blood pressure [1].
The prevalence of essential hypertension as well as
deleterious cardiovascular complications is higher in in-
dustrialized societies, in which salt intake varies from
100 to 500 mEq/day. In contrast, in societies in which in-
take is !50 mEq/day, a lower incidence of systemic hyper-
tension is observed [2]. Salt-sensitive hypertension is de-
fined as an increment in mean arterial pressure 110 mm
Hg when a high salt diet is ingested, after receiving a di-
uretic dose and/or a low sodium diet [3].
In this regard, salt sensitivity increases with age, being
present in approximately 50% of hypertensive individu-
als !40 years and increasing to 80% in those 160 years
[3–7]. The mechanisms involved in the development of
salt sensitivity remain currently under investigation.
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Martha Franco, MD, PhD
Nephrology Department, Instituto Nacional de Cardiología I. Ch.
Juan Badiano No. 1, Mexico City, Tlalpan 14080 (Mexico)
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Tel. +52 55 5573 6902, Fax +52 55 5573 7716
E-Mail marthafranco@lycos.com

Genetic causes, transient RAS activation,
hyperactivity SNS, hyperuricemia, reduced number
of nephrons, etc.
Transient elevation of BP
Reflex constriction of preglomerular vessels
Glomerular hypertension
Transient renal vasoconstriction
Transient renal ischemia
Adhesion molecules
Proinflammatory cytokines,
chemotactic and growth factors
Macrophage and T-cell infiltration
Afferent arteriolopathy
Oxidative stress
f NO, F Ang II
F Vascular resistance Peritubular capillary loss
Sustained tendency to Na retention
Salt-sensitive hypertension
Fig. 1. Pathogenesis of salt-sensitive hypertension. The diverse
mechanisms recognized today as important in the development
of salt-sensitive hypertension are shown (see text for details).
Pathophysiology of Salt-Sensitive Hypertension
Several hypotheses have been postulated to explain
the specific mechanisms responsible of the defect in renal
sodium excretion. These include genetic alterations [8],
heterogeneity in activation of the intrarenal renin-angio-
tensin system [9], medullary ischemia [10], and congeni-
tal or acquired reduction in nephron number [11]. In this
regard, one study reported that patients with established
hypertension have a lower number of nephrons com-
pared to control subjects of the same age [12].
Recently we have proposed a pathway for the develop-
ment of hypertension that includes several of these pro-
posed mechanisms. In the initial phase, the kidneys are
functionally and structurally normal; however hyperac-
tivity of the sympathetic nervous system or the transient
stimulation of the renin-angiotensin system induce tran-
sient elevations of blood pressure that override the capac-
46 Blood Purif 2008;26:45–48
ity of the autoregulatory mechanism and induce arterio-
lar and peritubular capillary injury. In clinical studies, up
to 40% of patients have labile hypertension in the initial
stage, characterized by an increase in the activity of the
sympathetic nervous system with decreased parasympa-
thetic tone [13, 14]. Under physiological conditions an el-
evation of blood pressure causes a reflex vasoconstriction
of preglomerular vessels response that reduces the trans-
mission of the increased pressure to the glomeruli and
post-glomerular capillaries. This response is observed in
the cortical nephrons, in the juxtamedullary nephrons
and in medullary vessels; however the response may not
be sufficient, resulting in transmission of excessive pres-
sure to the glomerular and peritubular capillaries. Glo-
merular hypertension and the focal loss of peritubular
capillaries favor glomerular and tubulointerstitial injury
[15]. In support to this hypothesis, transient stimulation
of the sympathetic system with temporal infusion with
Tubular
phenylephrine in rats, induced marked increase in blood
effects pressure, microvascular and tubulointerstitial lesions
and salt-sensitive hypertension [16] (fig. 1).
Despite the fact that the kidney receives 20% of the
cardiac output, in the outer medulla the oxygen tension
is low due to the countercurrent mechanism and the high
metabolic activity of the renal tubules. Thus, repetitive
periods of vasoconstriction may induce tissue ischemia
with the overexpression of adhesion molecules and che-
mokines, resulting in infiltration of mononuclear cells
that release oxidative molecules, decrease nitric oxide
availability and induce local generation of angiotensin II
(Ang II) [17].
In addition, liberation of cytokines and growth factors
induced hypertrophy of the wall of the preglomerular
vessels that, coupled with the local production of vaso-
constrictive factors, may increase vascular resistance, de-
crease glomerular blood flow, reduce single nephron glo-
merular filtration rate, and stimulate sodium retention
with its increase in blood pressure. As blood pressure in-
creases, the renal perfusion pressure increases to aid in
relieving the ischemia, thereby helping correct glomeru-
lar filtration rate and the renal sodium excretion. In some
areas of the kidney the increment in perfusion pressure
may not be able to relieve ischemia due to the loss of the
microvasculature, leading to persistent salt sensitivity.
The consequence is a shift of the natriuresis curve to a
level of higher arterial pressure.
The participation of microvascular and tubulointer-
stitial injury in the genesis of hypertension has been dem-
onstrated in experimental models of hypertension. For
example, it is well known that the infusion of Ang II can
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Johnson /Rodriguez-Iturbe
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induce hypertension, renal vasoconstriction, arteriolar
hypertrophy and injury, peritubular capillary loss and
mild tubulointerstitial injury. Stopping the Ang II infu-
sion after 14 days results in normalization of blood pres-
sure. However, these animals are now salt-sensitive, for
placement on a high salt diet rapidly results in hyperten-
sion and renal vasoconstriction. A causal relationship be-
tween functional and structural damage was demon-
strated with the administration of mycophenolate mofetil
(MMF) during the initial Ang II infusion, as it did not
prevent the acute increase in blood pressure in response
to Ang II, but it did prevent the inflammatory and micro-
vascular injury and the subsequent salt-sensitive hyper-
tension and renal cortical vasoconstriction [18].
Other models have also been reported in which the
tubulointerstitial and vascular injury are associated with
the development of salt-sensitive hypertension. These in-
clude: transient inhibition of nitric oxide, systemic hy-
poxia, cyclosporine nephrotoxicity, aging and chronic
proteinuria [19]. In spontaneous hypertensive rats, tubu-
lointerstitial inflammation is also involved in the devel-
opment of hypertension. In this model the increased af-
ferent resistance as well as tubulointerstitial inflamma-
tion appear before the development of hypertension [20].
MMF administration decreased blood pressure only dur-
ing the time of administration, and it correlated with the
decrease in interstitial macrophages and lymphocytes
and a reduction in intrarenal oxidants. Recurrence of hy-
pertension was associated with accumulation of inflam-
matory cells in the interstitium. These findings suggest
that the increase in afferent resistance may induce persis-
tent ischemia which causes an accumulation of inflam-
matory cells with recurrence of hypertension [21, 22]. Ac-
cordingly, the two most important factors that appear to
contribute to the generation and maintenance of hyper-
tension include injury to the microvasculature and the
interstitial inflammatory reaction (which consists pri-
marily of T cells and macrophages) [23].
The mechanism by which immune infiltration con-
tributes to the pathogenesis of hypertension may be re-
lated to the sodium retention secondary to intrarenal
Ang II. Ang II is expressed by infiltrating T cells and
macrophages in experimental models of hypertension
[24–26]. These inflammatory cells express angiotensin-
converting enzyme [27], suggesting that they may be syn-
thesizing Ang II.
Studies from Nishiyama et al. [28] in the Ang II infu-
sion model reported that renal interstitial Ang II may
function as a separate compartment from the systemic
circulation. Recently we demonstrated that the intersti-
tial Ang II is increased in the post-Ang II model of salt-
sensitive hypertension [29]. A strong correlation was
shown between the level of renal Ang II and blood pres-
sure and the interstitial inflammatory response; renal
Ang II levels were also reduced by the MMF during the
prior exogenous Ang II infusion [29]. In contrast to the
increase in intrarenal Ang II that occurs in this model,
plasma Ang II was suppressed. The strong correlation of
interstitial Ang II, the number of Ang-II-positive cells by
immunostaining, and the blood pressure suggest an ex-
quisite relationship between interstitial Ang II with blood
pressure [30]. Our studies are in agreement with observa-
tions showing that blockade of Ang II AT1 receptors with
candesartan and MMF-induced reduction of interstitial
inflammation have similar effects on glomerular hemo-
dynamics and blood pressure [30].
These studies support the role of interstitial immune
cells in the pathogenesis of salt-sensitive hypertension,
and may serve as potential guideline to future clinical
studies. Recent studies in patients with grade I essential
hypertension that received MMF for 3 months as treat-
ment for psoriasis or rheumatoid arthritis, showed ame-
lioration of the hypertension and reduction of urinary
inflammatory cytokines [31]. Taken together, the find-
ings summarized above suggest that strategies directed
to prevent the infiltration of inflammatory cells or that
are aimed at blocking intrarenal Ang II generation or ox-
idant production may be useful in preventing or treating
salt-sensitive hypertension.

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