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 Table of Contents  
EDITORIAL
Year : 2016  |  Volume : 1  |  Issue : 2  |  Page : 65-68

The hot button issue of salt-sensitive hypertension


Department of Physiology, Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA 70112, USA

Date of Web Publication19-Dec-2016

Correspondence Address:
Dewan S. A. Majid
Department of Physiology, Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA 70112
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2468-838X.196077

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How to cite this article:
Majid DS, Navar L G. The hot button issue of salt-sensitive hypertension. BLDE Univ J Health Sci 2016;1:65-8

How to cite this URL:
Majid DS, Navar L G. The hot button issue of salt-sensitive hypertension. BLDE Univ J Health Sci [serial online] 2016 [cited 2019 Aug 20];1:65-8. Available from: http://www.bldeujournalhs.in/text.asp?2016/1/2/65/196077

The emergence of "BLDE University Journal of Health Sciences" looks promising for scientists in biomedical research arena within India and beyond. As the main emphasis of this journal is to develop an interactive research interest and discussion among the various sections of scientists from the biomedical, clinical and population research fields, a topic of "salt-sensitive hypertension (SSH)" seems ideal to be discussed in the editorial column in this early issue of the journal. Although researchers and clinicians in various fields have sought for decades to understand how salt sensitivity develops in humans, the mechanisms responsible for the increases in blood pressure (BP) in response to high salt (HS) intake are complex and only partially understood. Despite abundant experimental, interventional, and epidemiological observations demonstrating an association between salt and BP, skepticism still remains as to how HS intake can be mechanistically linked to increase in BP. Our inability to explain why salt intake raises BP in some individuals (described as "salt sensitive") but not in others (termed as "salt resistant") have hampered the development of a comprehensive theory as to what causes high BP in most individuals. Thus, a comprehensive evaluation of epidemiological, clinical, and laboratory data is critical to understand the relationship of salt intake and the induction of hypertensive disease conditions in general human population.

SSH is characterized by increases in BP in response to increases in dietary salt intake and is associated with an enhanced risk of cardiovascular and renal morbidity, particularly with the aging population. The increasing cost of management of patients with SSH and associated renal injury (RI), which are hallmarks of chronic cardiovascular (cardiovascular disease [CVD]) and renal diseases (chronic kidney disease [CKD]), has posed a major socioeconomic burden on population health and national economies through the world. Our inability to control these CVD and CKD episodes and their complications in the human population is mainly due to our lack of comprehensive understanding of the pathophysiology of SSH. Although it is generally believed that dietary HS intake is related with hypertension and other complications of CVD and CKD in humans, the epidemiological data over the years do not provide any uniformity in the effects of HS intake in the population.[1],[2],[3],[4],[5],[6],[7] Furthermore, dietary salt restriction usually exerts small and inconsistent effects to reduce BP in the general population. Except in some patients, whose conditions are more prone to have salt sensitivity, there is little relationship between the magnitude of reduction in sodium intake and the BP effects in general population.[1],[2],[6] Studies in laboratories also reveal that BP in normal animals is not responsive to salt loading, but this reactivity is altered in models which are conditioned by increased involvement of other factors that facilitate salt retention by the kidney and induces salt-sensitivity. HS intake alone causes minimal changes in BP but exaggerates hypertensive response induced by elevated angiotensin II (Ang II)[8] or by nitric oxide (NO) inhibition.[9],[10] Alterations in kidney function, due either to primary renal disease or inappropriate hormonal influences on the kidney, lead to a reduced ability of the kidneys to excrete sodium and are a cardinal characteristic in all forms of hypertension. Chronic HS intake particularly exacerbates the consequent development of elevated arterial pressures in such deregulated conditions of renal handling of sodium.

Emerging data indicate that an enhancement in angiotensinogen (AGT) generation by the kidneys is a cardinal characteristic that is associated with progression of SSH and RI. Although chronic HS intake alone does not cause changes in the intrarenal AGT or urinary AGT (uAGT) excretion rate, changes in AGT are markedly exacerbated during chronic Ang II infusions which are also associated with greater degrees of RI.[8],[11] The reason for such exacerbation is not yet clearly understood and remains a hot button issue in this area of research. Various studies have demonstrated that chronic Ang II infusion augments AGT expression in proximal tubule cells leading to increases in AGT secretion into the tubular fluid and eventual increases in uAGT excretion rate.[12],[13],[14] The increased intratubular AGT thus provides substrate for increased generation of tubular segments. Eventually, the increased AGT that has been secreted into the tubular fluid is excreted in the urine leading to the use of uAGT excretion rate as a measure of increased intrarenal AGT formation. Many of the effects of Ang II in angiotensin dependent hypertension are mediated indirectly through activation of other systems that amplify its hypertensinogenic actions including oxidative stress. While it is clear that AT1 receptor activation is a key factor in the stimulation of AGT, it is also apparent that full manifestation of the effect requires the presence of other growth factors and pro-inflammatory cytokines.[14] The uAGT excretion rate is highly correlated with kidney Ang II content but not with plasma Ang II concentration.[12] These data suggest that uAGT provides a specific index of intrarenal AGT production in Ang II-dependent hypertension and elevated uAGT excretion rates have been observed in patients with SSH.[15] Such inappropriate renal responses to HS intake on intrarenal AGT formation modulate renal hemodynamics and tubular reabsorptive function to enhance sodium retention.

Oxidative stress has been linked with both Ang II dependent and independent forms of hypertension that are usually associated with salt sensitivity. These conditions often involve inappropriately elevated intrarenal Ang II levels, and oxidative stress levels induced by an imbalance between NO and superoxide (O2 ) generation in the kidney. An increase in renal production of O2 leads to sodium retention in the body by enhancing tubular sodium (Na+ ) reabsorption that contributes to salt-sensitivity.[9],[10] However, it is also known that an interaction between NO and O2 that usually forms peroxynitrite (ONOO ) plays mainly a protective role in maintaining normal kidney function.[9] Although much is known about the actions of NO and O2 on the renal tubules, the specific role for ONOO to regulate Na+ reabsorption is not yet clearly defined. Moreover, the regulation of ONOO in SSH is not yet clarified. ONOO formation is increased by Ang II as well as by HS intake as these factors stimulate both NO and O2 production. However, an impairment in NO formation, either due to pharmacological inhibition or due to uncoupling of NO synthase (NOS) activity or its gene deletion, reduce the formation of ONOO in the tissue. It has also been demonstrated that chronic HS intake in knockout mice lacking the gene for endothelial NOS (which would have caused less formation of ONOO compared to wild-type mice) result in an augmented salt sensitivity and hypertension.[10] These findings suggest mainly a protective role for ONOO in the development of SSH and associated RI. However, when HS intake is combined with continuous Ang II infusion, there is more sustained increases in O2 formation inducing oxidative stress condition which would contribute to the exacerbation of uAGT and increased RI.[8],[13] Thus, there is substantial evidence for a critical role of oxidative stress and/or ONOO in the development SSH and RI.[4],[9]

A general consensus also persists that SSH and RI are inflammatory conditions induced by many pro-inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF-α) interleukin-6 (IL-6), IL-17 and also interferon-g.[4],[16],[17],[18] Among these pro-inflammatory cytokines, TNF-α is particularly implicated in the pathophysiology of SSH in many studies as its formation is enhanced by factors that are associated with salt sensitivity and hypertension such as increases in Ang II level[19],[20] or generalized inhibition of NO.[21],[22] Moreover, TNF-α antagonism has been demonstrated to attenuate hypertension in many animal models of SSH.[23],[24],[25] However, the results of TNF-α antagonism are variable in clinical studies with hypertensive patients.[26],[27],[28],[29] Thus, the involvement of TNF-α in the development of SSH and RI remains unclear. Consideration of such anti-TNF-α therapy is also seems not suitable in certain conditions as it enhances infection risk due to immunosuppression. In this regard, it has been reported that anti-TNF-α therapy is associated with enhanced susceptibility to tuberculosis reactivation.[30] The variability of the effects of TNF-α antagonism in clinical studies could be due to a differential role of two cell surface receptors TNF-α receptors, type 1 (TNFR1) and type 2 (TNFR2). TNF-α exerts its biological responses through interaction with these two receptors which are differentially expressed and regulated in the kidneys. While the precise roles of these receptors in various conditions are still not well delineated, activation of TNFR1 and TNFR2 trigger distinct signaling pathways on TNF-α binding, which in turn result in cellular responses that promote tissue injury on one hand and also provide protective, beneficial responses on the other hand. While TNFR2 generally plays a role in chronic Ang II-induced RI,[31] TNFR1 usually induces natriuresis suggesting a counter-regulatory mechanism in SSH opposing salt retention.[32],[33] Recent preliminary studies in our laboratory have demonstrated that chronic HS intake enhances TNFR1 protein expression while HS intake coupled with chronic Ang II treatment reduces TNFR1 expression and increases TNFR2 expression in the renal tissues of mice.[34] These preliminary studies also demonstrated that the increase in uAGT excretion as well as in systemic BP induced by chronic Ang II infusion coupled with HS intake is enhanced in knockout mice lacking TNFR1 gene compared to that in wild-type mice.[34] These results indicate that TNFR1 activity mitigates the hypertensive response to chronic Ang II infusion with HS intake, at least in part, by attenuating the increase in intrarenal AGT. An increase in TNFR1 activity would facilitate natriuresis and thus, minimizes the BP changes during HS intake alone. However, when HS intake is coupled with Ang II administration, renal AGT formation increased due to the reduction in TNFR1 activity and/or increases in TNFR2 activity. Thus, these data indicate that a differential activation of TNFR1 and TNFR2 signaling pathways may be involved in enhanced intrarenal AGT formation during HS intake in the conditions of elevated Ang II. In normal condition, chronic HS intake induces enhances TNFR1 activity and minimizes TNFR2 activity causing suppression of intrarenal AGT formation which induces natriuresis and thus, resulting minimal changes in BP. However, such reactivity of TNF-α receptors reverses during HS intake in conditions as in elevated Ang II and/or in NO deficiency that induces an increase in intrarenal AGT generation. Such cross-reactivity of TNF-α receptors and AGT formation in the kidney during HS intake in oxidative stress conditions would cause: (1) Anti-natriuresis to induce salt and water retention leading to increase in plasma volume and thus resulting hypertension and (2) enhancement in pro-inflammatory responses to induce RI [Figure 1]. Thus, it is suggested that a dysfunctional axis of TNF-α, TNF receptors (TNFR), and AGT formation ("TNF-TNFR-AGT axis") is involved in the pathophysiology of SSH and RI during chronic HS intake in oxidative stress conditions induced by elevated Ang II level and/or NO deficiency. Accordingly, a more detailed understanding of the interactive mechanism by which intrarenal AGT formation are augmented by altered activation of TNF-α receptors in chronic HS intake conditions will reveal more effective approaches for the prevention and treatment of SSH and RI. Targeted therapy with specific receptor antagonism for TNF-α would be a novel strategy in the management of SSH and associated RI as opposed to generalized anti-TNF-α therapy which could enhance the infection risk due to generalized immune suppression.
Figure 1: Prospective mechanism how chronic high salt intake induces salt-sensitive hypertension and renal injury by altering intrarenal angiotensinogen formation via differential activities of tumor necrosis factor-alpha receptors, type 1 and tumor necrosis factor-alpha receptors, type 2. Normal responses to high salt intake is denoted by "green arrows" and the responses in nitric oxide deficiency/ elevated angiotensin II level is denoted by "red arrows." TNF-α=Tumor necrosis factor-alpha, TNFR1=Tumor necrosis factor-alpha receptor type 1, TNFR2=Tumor necrosis factor-alpha receptor type 2, AGT=Angiotensinogen

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In summary, we propose that an inappropriate renal response to HS intake due to dysregulation of intrarenal renin-angiotensin system, oxidative stress and/or inflammatory intrarenal cytokines are the key factors modulating renal hemodynamics and tubular reabsorptive function to cause inappropriate sodium retention coupled with increased production of vasoconstrictor agents including Ang II that leads to the development of SSH. Future studies with mainly translational approaches should be directed toward delineating the complexities of the interactions between these key factors and the altered activation of TNF-α receptors which would further unravel the mechanistic mysteries influencing salt sensitivity and hypertension in humans. Such studies will also help identify the reason for the heterogeneity in the BP response to HS intake in the general population.

Acknowledgments

The authors would like to acknowledge the excellent secretarial assistance of Ms. Debbie M. Olavarrieta (Department of Physiology, Tulane University School of Medicine) in typing and formatting this manuscript.

 
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