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Background: Salt sensitivity of blood pressure (SSBP), characterized by acute changes in blood pressure with changes in dietary sodium intake, is an independent risk factor for cardiovascular disease and mortality in people with and without hypertension. We previously found that elevated sodium concentration activates antigen-presenting cells (APCs), resulting in high blood pressure, but the mechanisms are unknown. Here, we hypothesized that APC-specific JAK2 (Janus kinase 2) through STAT3 (signal transducer and activator of transcription 3) and SMAD3 (small mothers against decapentaplegic homolog 3) contributes to SSBP., Methods: We performed bulk or single-cell transcriptomic analyses following in vitro monocytes exposed to high salt and in vivo high sodium treatment in humans using a rigorous salt-loading/depletion protocol to phenotype SSBP. We also used a myeloid cell-specific CD11c + JAK2 knockout mouse model and measured blood pressure with radiotelemetry after N-omega-nitro-L-arginine-methyl ester and a high salt diet treatment. We used flow cytometry for immunophenotyping and measuring cytokine levels. Fluorescence in situ hybridization and immunohistochemistry were performed to spatially visualize the kidney's immune cells and cytokine levels. Echocardiography was performed to assess cardiac function., Results: We found that high salt treatment upregulates gene expression of the JAK/STAT/SMAD pathway while downregulating inhibitors of this pathway, such as suppression of cytokine signaling and cytokine-inducible SH2, in human monocytes. Expression of the JAK2 pathway genes mirrored changes in blood pressure after salt loading and depletion in salt-sensitive but not salt-resistant humans. Ablation of JAK2, specifically in CD11c + APCs, attenuated salt-induced hypertension in mice with SSBP. Mechanistically, we found that SMAD3 acted downstream of JAK2 and STAT3, leading to increased production of highly reactive isolevuglandins and proinflammatory cytokine IL (interleukin)-6 in renal APCs, which activate T cells and increase production of IL-17A, IL-6, and TNF-α (tumor necrosis factor-alpha)., Conclusions: Our findings reveal the APC JAK2 signaling pathway as a potential target for the diagnosis and treatment of SSBP in humans., Competing Interests: None.

Background: The mechanisms by which salt increases blood pressure in people with salt sensitivity remain unclear. Our previous studies found that high sodium enters antigen-presenting cells (APCs) via the epithelial sodium channel and leads to the production of isolevuglandins and hypertension. In the current mechanistic clinical study, we hypothesized that epithelial sodium channel-dependent isolevuglandin-adduct formation in APCs is regulated by epoxyeicosatrienoic acids (EETs) and leads to salt-sensitive hypertension in humans., Methods: Salt sensitivity was assessed in 19 hypertensive subjects using an inpatient salt loading and depletion protocol. Isolevuglandin-adduct accumulation in APCs was analyzed using flow cytometry. Gene expression in APCs was analyzed using cellular indexing of transcriptomes and epitopes by sequencing analysis of blood mononuclear cells. Plasma and urine EETs were measured using liquid chromatography-mass spectrometry., Results: Baseline isolevuglandin + APCs correlated with higher salt-sensitivity index. Isolevuglandin + APCs significantly decreased from salt loading to depletion with an increasing salt-sensitivity index. We observed that human APCs express the epithelial sodium channel δ subunit, SGK1 (salt-sensing kinase serum/glucocorticoid kinase 1), and cytochrome P450 2S1. We found a direct correlation between baseline urinary 14,15 EET and salt-sensitivity index, whereas changes in urinary 14,15 EET negatively correlated with isolevuglandin + monocytes from salt loading to depletion. Coincubation with 14,15 EET inhibited high-salt-induced increase in isolevuglandin + APC., Conclusions: Isolevuglandin formation in APCs responds to acute changes in salt intake in salt-sensitive but not salt-resistant people with hypertension, and this may be regulated by renal 14,15 EET. Baseline levels of isolevuglandin + APCs or urinary 14,15 EET may provide diagnostic tools for salt sensitivity without a protocol of salt loading., Competing Interests: Disclosures None.

Significance: Salt sensitivity of blood pressure (SSBP) is an independent risk factor for mortality and morbidity due to cardiovascular disease, and disproportionately affects blacks and women. Several mechanisms have been proposed, including exaggerated activation of sodium transporters in the kidney leading to salt retention and water. Recent Advances: Recent studies have found that in addition to the renal epithelium, myeloid immune cells can sense sodium via the epithelial Na + channel (ENaC), which leads to activation of the nicotinamide adenine dinucleotide phosphate oxidase enzyme complex, increased fatty acid oxidation, and production of isolevuglandins (IsoLGs). IsoLGs are immunogenic and contribute to salt-induced hypertension. In addition, aldosterone-mediated activation of ENaC has been attributed to the increased SSBP in women. The goal of this review is to highlight mechanisms contributing to SSBP in blacks and women, including, but not limited to increased activation of ENaC, fatty acid oxidation, and inflammation. Critical Issues: A critical barrier to progress in management of SSBP is that its diagnosis is not feasible in the clinic and is limited to expensive and laborious research protocols, which makes it difficult to investigate. Yet without understanding the underlying mechanisms, this important risk factor remains without treatment. Future Directions: Further studies are needed to understand the mechanisms that contribute to differential blood pressure responses to dietary salt and find feasible diagnostic tools. This is extremely important and may go a long way in mitigating the racial and sex disparities in cardiovascular outcomes. Antioxid. Redox Signal. 35, 1477-1493.

Salt sensitivity of blood pressure is an independent risk factor for cardiovascular mortality not only in hypertensive but also in normotensive adults. The diagnosis of salt sensitivity of blood pressure is not feasible in the clinic due to lack of a simple diagnostic test, making it difficult to investigate therapeutic strategies. Most research efforts to understand the mechanisms of salt sensitivity of blood pressure have focused on renal regulation of sodium. However, salt retention or plasma volume expansion is not different between salt-sensitive and salt-resistant individuals. In addition, over 70% of extracellular fluid is interstitial and, therefore, not directly controlled by renal salt and water excretion. We discuss in this review how the seminal work by Harry Goldblatt paved the way for our attempts at understanding the mechanisms that underlie immune activation by salt in hypertension. We describe our findings that sodium, entering antigen-presenting cells via an epithelial sodium channel, triggers a PKC (protein kinase C)- and SGK1 (serum/glucocorticoid kinase 1)-stimulated activation of nicotinamide adenine dinucleotide phosphate oxidase, which, in turn, enhances lipid oxidation with generation of highly reactive isolevuglandins. Isolevuglandins adduct to proteins, with the potential to generate degraded peptide neoantigens. Activated antigen-presenting cells increase production of the TH17 polarizing cytokines, IL (interleukin)-6, IL-1β, and IL-23, which leads to differentiation and proliferation of IL-17A producing T cells. Our laboratory and others have shown that this cytokine contributes to hypertension. We also discuss where this sodium activation of antigen-presenting cells may occur in vivo and describe the multiple experiments, with pharmacological antagonists and knockout mice that we used to unravel this sequence of events in rodents. Finally, we describe experiments in mononuclear cells obtained from normotensive or hypertensive volunteers, which confirm that analogous processes of salt-induced immunity take place in humans.

Elevated cardiovascular risk including stroke, heart failure, and heart attack is present even after normalization of blood pressure in patients with hypertension. Underlying immune cell activation is a likely culprit. Although immune cells are important for protection against invading pathogens, their chronic overactivation may lead to tissue damage and high blood pressure. Triggers that may initiate immune activation include viral infections, autoimmunity, and lifestyle factors such as excess dietary salt. These conditions activate the immune system either directly or through their impact on the gut microbiome, which ultimately produces chronic inflammation and hypertension. T cells are central to the immune responses contributing to hypertension. They are activated in part by binding specific antigens that are presented in major histocompatibility complex molecules on professional antigen-presenting cells, and they generate repertoires of rearranged T-cell receptors. Activated T cells infiltrate tissues and produce cytokines including interleukin 17A, which promote renal and vascular dysfunction and end-organ damage leading to hypertension. In this comprehensive review, we highlight environmental, genetic, and microbial associated mechanisms contributing to both innate and adaptive immune cell activation leading to hypertension. Targeting the underlying chronic immune cell activation in hypertension has the potential to mitigate the excess cardiovascular risk associated with this common and deadly disease.

The development of high blood pressure is influenced by genetic and environmental factors, with high salt intake being a known environmental contributor. Humans display a spectrum of sodium-sensitivity, with some individuals displaying a significant blood pressure rise in response to increased sodium intake while others experience almost no change. These differences are, in part, attributable to genetic variation in pathways involved in sodium handling and excretion. ENaC (epithelial sodium channel) is one of the key transporters responsible for the reabsorption of sodium in the distal nephron. This channel has an important role in the regulation of extracellular fluid volume and consequently blood pressure. Herein, we review the role of ENaC in the development of salt-sensitive hypertension, and present mechanistic insights into the regulation of ENaC activity and how it may accelerate sodium-induced damage and dysfunction. We discuss the traditional role of ENaC in renal sodium reabsorption and review work addressing ENaC expression and function in the brain, vasculature, and immune cells, and how this has expanded the implications for its role in the initiation and progression of salt-sensitive hypertension.

Purpose of Review: The main goal of this article is to discuss the role of the epithelial sodium channel (ENaC) in extracellular fluid and blood pressure regulation., Recent Findings: Besides its role in sodium handling in the kidney, recent studies have found that ENaC expressed in other cells including immune cells can influence blood pressure via extra-renal mechanisms. Dendritic cells (DCs) are activated and contribute to salt-sensitive hypertension in an ENaC-dependent manner. We discuss recent studies on how ENaC is regulated in both the kidney and other sites including the vascular smooth muscles, endothelial cells, and immune cells. We also discuss how this extra-renal ENaC can play a role in salt-sensitive hypertension and its promise as a novel therapeutic target. The role of ENaC in blood pressure regulation in the kidney has been well studied. Recent human gene sequencing efforts have identified thousands of variants among the genes encoding ENaC, and research efforts to determine if these variants and their expression in extra-renal tissue play a role in hypertension will advance our understanding of the pathogenesis of ENaC-mediated cardiovascular disease and lead to novel therapeutic targets.

Purpose of Review: This review describes recent findings regarding the epithelial Na channel (ENaC) and its roles in physiologic and pathophysiologic states. We discuss new insights regarding ENaC's structure, its regulation by various factors, its potential role in hypertension and nephrotic syndrome, and its roles in the immune system and vasculature., Recent Findings: A recently resolved structure of ENaC provides clues regarding mechanisms of ENaC activation by proteases. The use of amiloride in nephrotic syndrome, and associated complications are discussed. ENaC is expressed in dendritic cells and contributes to immune system activation and increases in blood pressure in response to NaCl. ENaC is expressed in endothelial ENaC and has a role in regulating vascular tone., Summary: New findings have emerged regarding ENaC and its role in the kidney, immune system, and vasculature.

Mutations in genes encoding subunits of the epithelial Na + channel (ENaC) can cause early onset familial hypertension, demonstrating the importance of this channel in modulating blood pressure. It remains unclear whether other genetic variants resulting in subtler alterations of channel function result in hypertension or altered sensitivity of blood pressure to dietary salt. This study sought to identify functional human ENaC variants to examine how these variants alter channel activity and to explore whether these variants are associated with altered sensitivity of blood pressure to dietary salt. Six-hundred participants of the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study with salt-sensitive or salt-resistant blood pressure underwent sequencing of the genes encoding ENaC subunits. Functional effects of identified variants were examined in a Xenopus oocyte expression system. Variants that increased channel activity included three in the gene encoding the α-subunit (αS115N, αR476W, and αV481M), one in the β-subunit (βS635N), and one in the γ-subunit (γL438Q). One α-subunit variant (αA334T) and one γ-subunit variant (βD31N) decreased channel activity. Several α-subunit extracellular domain variants altered channel inhibition by extracellular Na + (Na + self-inhibition). One variant (αA334T) decreased and one (αV481M) increased cell surface expression. Association between these variants and salt sensitivity did not reach statistical significance. This study identifies novel functional human ENaC variants and demonstrates that some variants alter channel cell surface expression and/or Na + self-inhibition., (Copyright © 2016 the American Physiological Society.)

Sodium retention is a major clinical feature of nephrotic syndrome. The mechanisms responsible for sodium retention in this setting have been a subject of debate for years. Excessive sodium retention occurs in some individuals with nephrotic syndrome in the absence of activation of the renin-angiotensin-aldosterone system, suggesting an intrinsic defect in sodium excretion by the kidney. Recent studies have provided new insights regarding mechanisms by which sodium transporters are activated by factors present in nephrotic urine. These mechanisms likely have a role in the development of hypertension in nephrotic syndrome, where hypertension may be difficult to control, and provide new therapeutic options for the management of blood pressure and edema in the setting of nephrotic syndrome., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

The kidney has a central role in the regulation of blood pressure, in large part through its role in the regulated reabsorption of filtered Na(+). Epithelial Na(+) channels (ENaCs) are expressed in the most distal segments of the nephron and are a target of volume regulatory hormones. A variety of factors regulate ENaC activity, including several aldosterone-induced proteins that are present within an ENaC regulatory complex. Proteases also regulate ENaC by cleaving the channel and releasing intrinsic inhibitory tracts. Polymorphisms or mutations within channel subunits or regulatory pathways that enhance channel activity may contribute to an increase in blood pressure in individuals with essential hypertension.