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NDT Advance Access originally published online on January 8, 2007
Nephrology Dialysis Transplantation 2007 22(4):992-995; doi:10.1093/ndt/gfl757
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Salt-sensitive hypertension—update on novel findings

Bernardo Rodriguez-Iturbe1 and Nosratola D. Vaziri2

1Renal Service, Hospital Universitario, Universidad del Zulia and Centro de Investigaciones Biomédicas, IVIC-Zulia, Maracaibo, Venezuela and 2The Division of Nephrology and Hypertension, University of California Irvine, Irvine California, USA

Correspondence and offprint requests to: B. Rodriguez-Iturbe, Hospital Universitario, Avenida Goajira s/n, Maracaibo, Estado Zulia, Venezuela. Email: bri{at}iamnet.com

Keywords: Ca exchanger; Na–K-ATPase; oxidative stress; renal angiotensin; renal inflammation; salt-retention



   Introduction
Top
 Introduction
How does sodium retention...
 Mechanisms of sustained sodium...
 References
 
The association between a high salt intake and hardened pulse was already known 4500 years ago [1], but our understanding of the central role played by the kidneys in the sodium-driven increase in blood pressure is rooted in the studies of Guyton and co-workers [2], who postulated that restoration of sodium balance after salt intake depends on a natriuretic response, driven by a transient rise in blood pressure. In essence, the blood pressure increment serves as a physiological response directed to maintain sodium balance and extracellular volume (ECV) within normal limits. Impairment of the mechanisms responsible for the pressure-natriuresis relationship will shift the curve ‘to the right’, so that higher blood pressure levels are needed to achieve the increments in urinary sodium excretion required to maintain homeostasis and the system is thereby reset at a higher blood pressure level.

Sodium loading is almost uniformly associated with an increase in blood pressure in normotensive and hypertensive individuals [3]. Therefore, the notion of salt sensitivity implies an exaggerated response to changes in sodium balance. The most widely used method of assessing salt sensitivity is that proposed by Weinberger et al. [3], which is based on the difference between the blood pressure found after administration of 2 l of saline and the blood pressure found after sodium depletion, using a low Na diet (10 mMol/day) plus oral furosemide. Salt sensitivity was defined as a difference of ≥10 mmHg between salt-loaded and salt-depleted states and salt-resistance, a difference of ≤5 mmHg. Using these criteria, salt sensitivity was found in 51% of the hypertensive population (73% of African-American hypertensive patients) and 26% of the normotensive individuals [3].

While the problem of reproducibility has plagued many studies, Weinberger and co-workers have reported follow-up studies showing that a salt-sensitive state is persistent and reproducible over time and that salt-sensitive normotensive individuals develop hypertension more frequently than their salt-resistant counterparts [4]. Furthermore, salt-sensitive hypertensive patients have a 3-fold higher incidence of cardiovascular events [5]. Interestingly, salt sensitivity is associated with increased mortality independent of blood pressure [6]. As described later, this phenomenon points to the adverse direct actions of sodium.



   How does sodium retention cause essential hypertension?
Top
 Introduction
 How does sodium retention...
Mechanisms of sustained sodium...
 References
 
The most compelling evidence for the role of the kidney in pathogenesis of hypertension comes from cross-transplantation studies between hypertensive and normotensive strains of rats [7]. All of these studies have shown that ‘hypertension travels with the donor kidney’. The central role of the kidney is further supported by the observations that nearly all genetic mutations and polymorphisms associated with hypertension share the common characteristic of causing impaired sodium excretion [9].

While it has long been accepted that sodium retention tends to be associated with hypertension, the mechanisms involved have been debated for some time. Guyton and co-workers [2,9] postulated that sodium retention caused ECV expansion and, inasmuch as ECV expansion does not directly increase blood pressure, they proposed that ECV expansion would increase cardiac output, which would raise tissue perfusion to levels exceeding the metabolic needs. The relative surplus of blood supply was, in turn, thought to trigger an ‘autoregulatory’ response in the tissues leading to vasoconstriction and increased peripheral vascular resistance.

While increase in ECV is not directly demonstrable in patients with essential hypertension, the exaggerated natriuresis in response to saline administration speaks in favour of an expanded intravascular volume. However, the results of studies aimed at assessing ECV have been contradictory, as they have shown that total exchangeable sodium is [10] or is not [11] increased in patients with essential hypertension. The apparent disparity in reported values may simply reflect different phases of the disease. This view is consistent with the elegant model proposed by Stevo Julius [12] envisioning transition from a high cardiac out put (hence ECV expansion) and normal systemic vascular resistance early in the course of essential hypertension to a normal cardiac output (hence normal ECV) and increased systemic vascular resistance at a later phase. On the other hand, the concept of circulatory ‘autoregulation’ is difficult to reconcile with observations that show the lack of association between cardiac output and peripheral vascular resistance [12].

The possibility that peripheral vascular resistance could be increased by an endogenous inhibitor of the Na+–K+-ATPase pump, produced or released as a consequence of ECV expansion, was raised almost simultaneously by Haddy and Overbeck [13] and by Blaustein [14]. Endogenous ouabain-like compounds could inhibit Na+–K+-ATPase pump, causing a steady state increase in cytosolic sodium that can raise cytosolic Ca++ by activating Na+/Ca++ exchanger (NCX). The rise in cytosolic Ca++ can, in turn, augment myocardial contractility and promote vasoconstriction [15]. Recent work by Dostanic-Larson et al. [16] has shown that the Na+–K+-ATPase pump has glycoside-binding sites and chronic administration of ouabain results in hypertension in the wild-type, but not in the knockout mice for the {alpha}1 and {alpha}2 isoforms of the pump.

Plasma levels of several endogenous Na+–K+-ATPase inhibitors, such as marinobufagenin and hypertension-associated protein, have been reported to be increased in hypertensive patients [17]. However, endogenous ouabain has been studied most extensively and its plasma level has been found to be increased in hypertensive animals and humans [18]. Recent investigations have focused on the potential clinical use of an ouabain antagonist, rostafuroxin [19] and a selective NCX inhibitor, SEA0400. The results of these preliminary experiments have been promising [20]

In addition to effects mediated by ECV expansion, high salt intake and/or Na concentration can exert a direct hypertensive action. For instance, high sodium concentration stimulates cardiac myoblast and smooth muscle cell hypertrophy [21] and high salt intake leads to up-regulation of angiotensin type 1 receptor [22]. Furthermore, increased sodium concentration may lead to activation of NF-{kappa}B (the general transcription factor for pro-inflammatory cytokines and chemokines) in proximal tubular cells [23]. This phenomenon may be relevant to the pathogenesis of intra-renal inflammation that, as will be discussed later, plays a role in the development of salt sensitive hypertension. The role of NF-{kappa}B activation in the pathogenesis of hypertension is evidenced by a recent demonstration that its pharmacologic inhibition ameliorates hypertension in spontaneously hypertensive rats [24]. Finally, increased sodium concentration in hypothalamic region of the brain, which is sensitive to changes in sodium concentration, may heighten angiotensin-mediated sympathetic tone and raise arterial pressure [25]. Collectively, these observations have prompted de Wardener et al. [26] to highlight the potential hypertensive effects of modest changes in plasma sodium concentration. Recognizing the pleiotrophic effects of sodium, Ritz and associates [27] have recently proposed that it may act as a systemic toxin in uraemic patients.

Several recent studies have demonstrated the direct effect of sodium on the production of TGF-ß. Sanders [28] has shown up-regulation of TGF-ß mRNA in kidney cortex within 1 day of increasing salt intake. Along with his coworkers, he has further demonstrated the importance of this phenomenon in the progression of several forms of renal disease and hypertension as an expected consequence of reduction in nephron units. In addition, new evidence has uncovered a direct effect of TGF-ß on blood pressure. Zacchigna et al. [29] demonstrated that the unrestricted conversion of pro-TGF-ß to active TGF-ß results in hypertension. These authors showed that mice lacking emilin 1 (a widely distributed endogenous inhibitor of TGF-ß) have reduced vessel diameter, increased peripheral vascular resistance and hypertension.



   Mechanisms of sustained sodium retention and salt-sensitive hypertension
Top
 Introduction
 How does sodium retention...
 Mechanisms of sustained sodium...
References
 
Accumulating evidence has shown how a variety of genetic mutations and polymorphisms of sodium channels and related proteins in the kidney result in dysregulation of sodium metabolism and/or salt-sensitive hypertension. Among them, mutations affecting synthesis and circulating levels of mineralocorticoids (glucocorticoid-remediable aldosteronism, defective aldosterone synthesis, apparent mineralocorticoid excess), mutations of the mineralocorticoid receptor (Pregnancy-progesterone exacerbated hypertension) and mutations affecting renal ion channels (Liddle syndrome, recessive PHAI, Gittelman syndrome, Bartter syndrome) have been reviewed recently by Lifton et al. [8]. Other genetic variants which may be associated with hypertension include the Gly460Trp variant of the {alpha}-adducin gen, which increases sodium-potassium pump activity, the Arg40Ser variant of the glucagon gene, which can reduce cAMP production and impair natriuresis, as well as mutations of the serum- and glucocorticoid-regulated kinase (SGK1), which enhance aldosterone–induced expression of sodium channels [30]. In addition, genes involved in arachidonic acid metabolism have been postulated to play a role in hypertension [31]. Recently, Nakagawa et al. [32] have shown that alteration in the Cyp4a10 gene (a member of the cytochrome P450 family) which is involved in the functional regulation of sodium channel, may cause salt-sensitive hypertension.

In addition to specific genetic defects, other conditions have been associated with a tendency towards sodium retention and hypertension. For instance, Johnson and associates [33] have championed the role of uric acid as a cause of hypertension and suggested that the increasing prevalence of essential hypertension is related to the rising serum uric acid in the population. They have shown that it activates renin–angiotensin system, causes endothelial dysfunction, and promotes smooth muscle cell proliferation; they reported that 90% of the children with essential hypertension have high uric acid levels.

Insulin stimulates sodium reabsorption and as such, hyper-insulinemia may play a role in the pathogenesis of hypertension in metabolic syndrome. Experimental evidence has suggested that salt sensitivity is associated to insulin resistance [34]. Published data on the relationship between insulin level and hypertension in humans have been contradictory [35,36]. However, according to a recent report, insulin resistance seems to contribute to left ventricular hypertrophy in hypertensive patients [37].

Brenner and co-workers [38] proposed that a pre-natal reduction in nephron numbers can limit the capacity to excrete sodium and, as such, may be a cause of essential hypertension. This proposition has received support from careful autopsy studies by Keller and associates [39], performed on patients who had suffered accidental deaths. The authors found that hypertensive patients had fewer numbers of large glomeruli compared to their normotensive control counterparts.

The role of renal inflammation, oxidative stress and intra-renal angiotensin activity in the pathogenesis and maintenance of hypertension and a tendency to sodium retention has been covered in recent reviews from our group [40,41] and shall not be discussed here. Worth mentioning, however, are recent investigations supporting the relevance of this pathophysiology in salt-sensitive hypertension, demonstrating that activation of NF-{kappa}B and upregulation of TNF-{alpha} correlate with hypertension in the Dahl salt-sensitive rats [24], that immune suppression ameliorates salt-sensitive hypertension [42], and that antioxidant and immunosuppressive therapies improve pre-natally programmed hypertension [43]. Recent work has shown that a high salt intake increases Ang II concentration in proximal tubular fluid [44] and that increased intra-renal Ang II in salt-sensitive hypertension is probably due to tubulo-interstitial inflammation [45,46]

Pertinent to the relationship between inflammation and oxidative stress in salt-sensitive hypertension, exciting new research has shown that oxidative stress enhances Na/K/2Cl co-transport and luminal Na/H exchange [47]. It should be noted that a high salt intake drives oxidative stress by increasing NAD(P)H oxidase [48], by inhibiting l-arginine transport in renal medulla [49] and by down-regulating nitric oxide synthase isotypes [50].

The physiopathology of salt-driven hypertension formulated more than 30 years ago, and present day information on the mechanisms involved are shown in Figure 1. The side-by-side comparison illustrates how the theoretical construct of Guyton and co-workers has served as the framework upon which subsequent investigations have built our understanding of salt-sensitive hypertension.


Figure 1
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  		Fig. 1. Aetiopathogenesis of salt-sensitive hypertension. The different mechanisms recognized today as important in salt-sensitive hypertension (right side of the figure) expand and clarify aspects of the theoretical construct formulated more than 3 decades ago by Guyton and co-workers (left side of the figure), derived from their conceptual and experimental work on the pressure–natriuresis relationship. Immune cell infiltration, oxidative stress and angiotensin II activity within the kidney are likely a common event in most, if not all, forms of salt-sensitive hypertension [44,45]. ECF, extracellular fluid; PVR, peripheral vascular resistance; SNS, sympathetic nervous system; TGF-ß, transforming growth factor- ß; ROS, reactive oxygen species; LVH, left ventricular hypertrophy; AT1r, angiotensin type 1 receptors; Ca (cyt), cytosolic calcium; NCX, sodium–calcium exchanger.

 
Conflict of interest statement. None declared.



   References
Top
 Introduction
 How does sodium retention...
 Mechanisms of sustained sodium...
 References
 

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Received for publication: 29. 9.06
Accepted in revised form: 20.11.06


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