Recent advances in understanding peripheral and gut immune cell-mediated salt-sensitive hypertension and nephropathy

Abstract

Hypertension is the primary modifiable risk factor for cardiovascular, renal, and cerebrovascular diseases and is considered the main contributing factor to morbidity and mortality worldwide. Approximately 50% of hypertensive and 25% of normotensive people exhibit salt sensitivity of blood pressure, which is an independent risk factor for cardiovascular disease. Human and animal studies demonstrate that the immune system plays an important role in the etiology and pathogenesis of salt sensitivity of blood pressure, kidney damage, and vascular diseases. Antigen-presenting and adaptive immune cells are implicated in salt-sensitive hypertension and salt-induced renal and vascular injury. Elevated sodium activates antigen-presenting cells (APCs) to release proinflammatory cytokines including interleukin (IL)-6, tumor necrosis factor-α, IL-1β, and accumulate isolevuglandin-protein adducts. In turn, these activate T-cells release pro-hypertensive cytokines including IL-17A. Moreover, high salt intake is associated with gut dysbiosis, leading to inflammation, oxidative stress, and blood pressure elevation but the mechanistic contribution to salt-sensitivity of blood pressure is not clearly understood. Here, we discuss recent advances in research investigating the etiology, potential biomarkers, and therapeutic targets for salt-sensitive hypertension as they pertain to the gut microbiome, immunity, and inflammation.

Introduction

Hypertension is defined as systolic and/or diastolic blood pressure higher than 140 mmHg and 90 mmHg respectively according to the International Society of Hypertension guidelines.¹ Ischemic heart disease remains a leading cause of death globally in women, with hypertension as the primary modifiable risk factor for the development of cardiovascular and associated diseases.^2,3 In the United States, approximately half of the adult population exhibits arterial blood pressure levels in the hypertensive range, and cardiovascular disease (CVD) and hypertension were the primary causes of death in 2015.⁴ Hypertension is also the primary risk factor for chronic kidney disease (CKD) and kidney failure.⁴

Salt sensitivity of blood pressure (SSBP) is characterized by acute changes in blood pressure that mirror dietary salt intake. Over the past several years, it has become evident that immune cell activation contributes to salt-induced blood pressure elevation.^5–9 Both the innate and adaptive immune systems have been implicated in the development of salt-sensitive hypertension and kidney damage.^6,9–12 The kidney and its role in electrolyte and volume regulation has been extensively studied in the pathogenesis of salt-sensitive hypertension but mounting evidence demonstrates a crucial role for extrarenal mechanisms. Extensive research has been done on the interplay of the renin-angiotensin-aldosterone system with factors such as endothelial dysfunction, ¹⁶ but there is increasing interest and need to discover novel mechanisms contributing to the pathogenesis of SSBP. ¹⁷ Notably, recent studies have implicated the gut microbiome as a critical component in extrarenal blood pressure regulation but the underlying mechanisms are not known.^13–15 Moreover, the contribution of the gut microbiome and immune cell activation to SSBP is not clearly understood.

A major barrier to progress in research to discover novel mechanisms and therapies for SSBP is that there is no feasible diagnosis. Current diagnosis involves salt-loading and depletion protocols which are costly and labor intensive, making it difficult to phenotype people for salt sensitivity and conduct large-scale clinical studies. Whereas the advent of state-of-the art immunological, genetic, and other research tools has accelerated research and our general understanding of disease pathogenesis, studies to determine the cause-effect relationship among mechanisms for SSBP are still primitive. Here, we review the interplay between many of these regulators, such as immune cell activation, inflammation, and gut microbiome, and discuss how they interact in the etiology of SSBP. We also discuss potential feasible tools for diagnosing and developing treatments for SSBP.

SALT-SENSITIVITY OF BLOOD PRESSURE

SSBP differs from general hypertension both in terms of presentation as well as potential mechanisms. A meta-analysis revealed that blood pressure is more sensitive to sodium intake in hypertensive patients than in normotensive people,¹⁸ and it is normally distributed.¹⁹ Studies indicate that around 50% of hypertensive and 25% of normotensive people exhibit SSBP, which is an independent risk factor for CVD.^18–21 A comprehensive study performed across several decades by Weinberger showed that people with salt sensitivity are more prone to cardiovascular morbidity and mortality than salt-resistant individuals.^22,23 Epidemiological findings further indicate that reducing salt intake alleviates hypertension and cardiovascular risk.^{24 25}

The relationship between salt consumption and CVD is inconclusive and warrants further investigation. Some studies have posited a direct correlation between salt intake and life expectancy worldwide.²⁶ However, other results found that low and high sodium intake non-significantly increased mortality rates, with ideal sodium intake between 1500 and 2300 mg in older patients aged between 71–80.²⁷ While the relation to overall mortality deserves further research, high dietary sodium consumption is rising worldwide and is implicated in salt-sensitive hypertension, CVD, and autoimmune diseases.^22,28,29 Thus, a greater understanding of the underlying mechanisms of SSBP and salt-induced disease pathogenesis is important.

CLASSICAL AND RECENT CONCEPTS OF SALT-SENSITIVITY OF BLOOD PRESSURE

Conventionally, the inception of SSBP is considered from a renal mechanism. Dr. Dahl’s seminal work laid the foundation of SSBP when he generated salt-sensitive and salt-resistant rat strains six decades ago.³⁰ The kidney transplantation study by Dr. Dahl et al. established the role of the kidney in the SSBP in rats.³¹ Dr. Guyton postulated that the relationship between acute pressure and natriuresis maintains blood pressure homeostasis in a healthy kidney individual ³². As per Dr. Guyton, blood pressure homeostasis following an acute salt load is achieved by the pressure natriuresis relationship in the kidneys after a salt-induced expansion of plasma volume, which restores baseline blood pressure levels in a healthy individual.³² He further hypothesized that salt-sensitive hypertension develops if Na⁺ excretion dysfunction exists in the kidney.³² The renal angiotensin system,^33,34 renal tubular Na⁺ channels,^35,36 and sympathetic system changes^37,38 occur in salt-sensitive hypertension; however, hemodynamic studies provided evidence that the pressure-natriuresis relationship alone cannot explain the pathogenesis of SSBP. In fact, the hemodynamic changes due to salt load and depletion, along with renal Na⁺ balance and plasma volume, do not differ in salt-sensitive and salt resistant patients.^39,40 However, salt sensitivity is characterized by an absence of the systemic vasodilator response to salt in salt-sensitive individuals. The vasodilatory response to salt was present in salt resistance normotensives.^39,40 In a clinical study investigating 24-hour hemodynamic changes in salt-sensitive versus salt-resistant individuals, Laffer et al. showed that following salt loading, salt-sensitive individuals exhibited higher total peripheral resistance and subsequently higher mean arterial pressure compared to salt-resistant individuals. They also showed that salt depletion resulted in an equal reduction of cardiac output in both groups; in contrast, salt resistant individuals exhibited a significant increase in total peripheral resistance.³⁹ A recent study used whole-genome sequencing data from 14 studies participating in the Trans-Omics in Precision Medicine Whole-Genome Sequencing Program and sequence kernel association tests found that variants of SCNN1D, which encodes the δ subunit of ENaC and is poorly expressed in human kidney, is associated with blood pressure and estimated glomerular filtration rate. This study concluded that variants in extrarenal ENaCs, in addition to renal ENaCs, influence blood pressure and kidney function.⁴¹

Our understanding of body salt handling has greatly changed in the last 2 decades following the seminal studies showing that sodium can be stored in tissue interstitium without commensurate water ^42,43. These studies showed that vast amounts of sodium can be stored in the interstitium of skin and skeletal muscles through ionic interactions with glycosaminoglycans ^42,44. An important outcome of these studies is that hypertension correlates with increased sodium deposition concentrations, suggesting that sodium storage in tissues helps regulate blood pressure and salt sensitivity. Our studies show that ENaC in APCs contributes to SSBP in human and experimental animal studies ^6,7,9,45. Taken together, these studies suggest an extrarenal mechanism contributes to SSBP. However, extrarenal mechanisms can still impact and worsen kidney function to contribute to SSBP.

INFLAMMATION IN BLOOD PRESSURE REGULATION

Inflammation is an adaptive response to injury that involves interactions among cell surfaces, extracellular matrix, and proinflammatory cytokines. Multiple studies suggest hypertensive individuals show increased serum inflammatory markers, including C-reactive protein, interleukin (IL)-6, and tumor necrosis factor (TNF)-α.^46–48 The innate and adaptive immune subsystems are strongly interactive and have crucial roles in the development of salt-sensitive hypertension and kidney damage. The role of innate and adaptive immune systems in SSBP is described below.

REACTIVE OXYGEN SPECIES AND ISOLEVUGLANDINS IN INFLAMMATION AND SALT-SENSITIVITY OF BLOOD PRESSURE

Reactive oxygen species (ROS), which can be induced by hypertensive stimuli such as excess extracellular sodium and angiotensin II have been implicated in essential hypertension.^7,9,11 We recently found that excess extracellular sodium enters APCs via ENaC and increases NADPH oxidase activity leading to increased ROS production.^7,9,11 This promotes oxidation of arachidonic acid and formation of IsoLGs through the isoprostane endoperoxide pathway.^11,49 The IsoLGs covalently bind to lysines on proteins and form lipid-protein adducts that permanently alter protein structure and function. These altered proteins are recognized as foreign and induce an autoimmune-like state in hypertension.¹¹ Thus, IsoLGs provide a potential mechanistic connection between oxidative stress and SSBP (Figure 1).^6,11,50

Figure 1.

The peroxidation of arachidonic acid to isolevuglandins (IsoLGs) via reactive oxygen species (ROS) released from NADPH oxidase. Extracellular sodium ions enter the cell through epithelial sodium channels (ENaCs), leading to the activation of NADPH oxidase via protein kinase C. Activated NADPH oxidase releases ROS, which oxidizes arachidonic acid to IsoLG. IsoLGs then bind to a lysine residue in a peptide chain to create a lipid-protein adduct, leading to T-cell activation, cytokine release, and ultimately salt-sensitive hypertension.

INNATE IMMUNE CELLS AND INFLAMMATORY BIOMARKERS IN SALT-SENSITIVE HYPERTENSION

In the last 20 years, attention has increasingly been paid to the role of innate immune cells and their proinflammatory responses in salt-sensitive hypertension.^51,52 As previously reviewed,^53,54 innate and adaptive immunometabolism has been found to be impacted by sodium intake. Immunometabolism involves understanding of how the metabolic processes within immune cells influence their function and how immune responses, in turn, impact cellular metabolism.⁵⁵ Various studies have linked salt intake with energy balance and regulation of other hormones.⁵⁴ Studies on immunometabolism have primarily focused on TH17 cells and T regulatory cells, which rely on the SGK1–FOXO1 axis, thus increasing susceptibility to autoimmune diseases.^56,57,58 Macrophage metabolism and homeostasis have also been shown to be impacted by sodium via mitochondrial-dependent pathways.⁵⁹

Innate APCs including macrophages and dendritic cells (DCs) are the first responders in immune responses.⁶⁰ Importantly, myeloid cells, including monocytes, macrophages, and DCs, infiltrate the kidney and lead to end-organ injury in experimental models of salt-sensitive hypertension.^11,61 We and others have shown that high sodium promotes ROS production and IsoLG formation,⁷ which is associated with increased production of proinflammatory cytokines, including IL-6, IL-18, TNFα, and IL-1β by APCs ^6,7,9,11,62. We recently found that high salt activates NLRP3 (NOD-like receptor family, pyrin domain-containing 3) inflammasome in APCs, resulting in increased production of IsoLGs and proinflammatory cytokine IL-1β and contributes to SSBP.⁶ Scavenging of IsoLGs with 2-HOBA attenuated inflammation and salt-sensitive hypertension in mice.⁶ M1 macrophages are proinflammatory by nature, secrete proinflammatory cytokines, such as IL-1β, IL-6, and TNF-⍺, and present antigens to T cells, contributing to the activation of adaptive immune responses. In contrast, M2 macrophages are anti-inflammatory, secrete anti-inflammatory cytokine IL-10, and play an important role in angiogenesis. A significant increase in renal M1 macrophages and upregulation of IL-6, the cluster of differentiation 14 (CD14), Ly96, and TLR4 receptors are observed in APCs in high salt-treated rats.⁶³ These cytokines have been implicated in the development of salt-sensitive hypertension.^{6,7,9,11,62,63} Together, these studies demonstrate that the innate immune response contributes to the pathogenesis of salt-sensitive hypertension (Figure 2A). However, some studies have noted the opposite effect of salt on inflammation. A high salt diet ameliorated macroscopic colitis in IL-10-deficient mice,⁶⁴ increased the serum glucocorticoid hormone corticosterone, thereby tightening the blood-brain barrier and reducing autoimmunity.⁶⁵ These conflicting results highlight the necessity for more research to understand salt-induced inflammation and disease pathogenesis.

Figure 2: Overview of immune-mediated mechanisms. (A) Overview of the role of antigen-presenting cell (APC) and T-cell interaction in salt-sensitive hypertension.

Extracellular sodium enters APCs through epithelial sodium channels, resulting in the intracellular influx of calcium via the sodium-calcium ion exchanger. The increased calcium levels in APCs activate protein kinase C, which subsequently phosphorylates p47phox, thus activating NADPH oxidase. Activated NADPH oxidase produces reactive oxygen species (ROS), leading to the generation of isolevuglandins (IsoLGs), which react with lysine residues on proteins to form IsoLG adducts. These IsoLG adducts are presented to T-cells on major histocompatibility complexes (MHCs). The interaction between B7-CD28 and MHC/T-cell receptors on APCs and T-cells promotes tissue damage through the activation and infiltration of T-cells. This interaction also leads to the secretion of cytokines, including IL-17, IL-21, TNF-α, and IFN-γ. (B) Role of myeloid and adaptive immune cells, including monocytes (MO) and dendritic cells (DC), in salt-sensitive hypertension. Increased interstitial sodium ions induce the formation of neoantigens and proinflammatory cytokines that can polarize lymphocytes, resulting in sodium retention, immune cell infiltration, and organ damage.

LYMPHATICS, INFLAMMATION AND RENAL DAMAGE

Innate and adaptive immunity play important roles in the pathophysiology of kidney disease.⁷⁵ Chronic inflammation results in the recruitment and stimulation of immune cells, leading to the secretion of cytokines, which exacerbate renal disease progression.⁷⁶ Recruitment of monocytes and DCs into the kidneys has been associated with renal inflammation, damage, and fibrosis.^69,77–80 Activated M1 macrophages also infiltrate kidney tissue and cause tissue damage and fibrosis.⁸¹ Emerging evidence suggests an interplay between lymphangiogenesis and inflammation in kidney disease.⁸² Lymphatic vessels were previously thought to sprout from preexisting local lymphatic networks,⁸³ however, recent data show that M1 macrophages can transdifferentiate into lymphatic endothelial cells, suggesting that lymphangiogenesis is an additional mechanism linking inflammation to renal disease.⁸⁴

Therapies that exhibit anti-inflammatory effects are known to improve kidney health and diminish the risk of developing kidney disease in high-risk individuals.⁸⁵ The sodium-glucose cotransporter 2 inhibitor empagliflozin attenuates inflammasome activation and subsequent IL-1β.⁸⁶ Empagliflozin also attenuates diabetes and slows kidney disease progression.⁸⁷ Mechanistically, empagliflozin decreases NLRP3 activation, thereby decreasing IL-1β and TNF-α production in macrophages via increased serum β-hydroxybutyrate and decreased serum insulin. Many of these studies remain in essential hypertension-associated kidney disease and studies are needed to understand the renal and immune interplay in salt sensitivity of blood pressure.

ENDOTHELIAL CELLS IN SALT-SENSITIVE HYPERTENSION

Endothelial cell dysfunction is a characteristic feature of salt-sensitive hypertension and is mainly associated with the inability to upregulate the production of nitric oxide (NO) in response to high salt intake.⁸⁸ Emerging evidence suggests that endothelial cells exhibit immune cell-like functions including acting as APCs.^89–91 Moreover, we have shown that dysfunctional endothelial cells can activate monocytes during hypertension. Endothelial cells express chemo-attractants and adhesion molecules that attract immune cells, which adhere to the endothelium and access the interstitial space.^91,92 In salt-sensitive hypertension, endothelial cells exhibit dysfunction in the L-arginine/NO pathway, resulting in reduced secretion of NO and blood pressure elevation.⁹³ High salt levels damage the endothelial glycocalyx, resulting in increased sodium entry into endothelial cells via ENaC and the activation of NADPH oxidase.⁹⁴ When activated, NADPH oxidase produces ROS that react with endothelial NO, producing peroxynitrite and reducing BH₄ availability,⁹⁵ which increases the production of superoxide by endothelial nitric oxide synthase and exacerbates endothelial dysfunction.⁹⁶ Thus, oxidative stress resulting from high salt intake contributes to the development of hypertension and CVD via a mechanism involving endothelial dysfunction.^97,98 The inability of endothelial cells to produce NO leads to endothelial stiffness that contributes to overall vascular stiffness (Figure 3).⁹⁹

Figure 3. Endothelial nitric oxide pathway in salt-sensitive hypertension.

The negatively charged endothelial glycocalyx acts as a barrier and provides storage of sodium ions in the cardiovascular system, such that it inactivates ~700 mg sodium, which is contained in an average meal [13]. In fact, a 5% increase in plasma sodium above the normal concentration leads to endothelial dysfunction due to an estimated 25% endothelial stiffness. Damage to endothelial glycocalyx facilitates entry of sodium into endothelial cells via epithelial sodium channels (ENaCs) expressed on the endothelial luminal surface, resulting in endothelial dysfunction, immune system activation, and hypertension development.

Several surrogate markers associated with endothelial damage or dysfunction in individuals with salt-sensitive hypertension include endothelin-1, asymmetric dimethylarginine and endocan, intercellular adhesion molecule-1, vascular cell adhesion protein-1, matrix metalloproteinases, von Willebrand factor, the soluble adhesion molecule E-selectin, CD62E⁺/E-selectin-activated endothelial microparticles, ANGPTL2, endoglin, annexin V⁺ endothelial apoptotic microparticles, serum homocysteine, 24-h urinary albumin excretion, and tissue inhibitor of metalloproteinases type 1.¹⁰⁰ Although the measurement of endothelial NO metabolites in plasma and urine remains controversial, some studies provide evidence of a significant decrease in plasma and urinary nitrites in salt-sensitive hypertension.¹⁰¹ Overall, more studies are required to validate the use of these biomarkers in clinical settings as well as to determine reference ranges.

GUT MICROBIOME-MEDIATED OXIDATIVE STRESS AND INFLAMMATION IN SALT SENSITIVE HYPERTENSION

Mounting evidence demonstrates the crucial role of extrarenal mechanisms in the modulation of salt-induced hypertension. Recent studies implicate the gut microbiome as a critical component in extrarenal blood pressure regulation.¹⁰² The gut microbiome, mainly characterized by its symbiotic properties, harbors a community of microorganisms (or microbiota), as well as a structural materials and metabolites, playing a vital role in human physiology.^103,104 A disturbance in gut microbiome equilibrium, or dysbiosis, is associated with dysregulation of metabolic and physiological functions, but the significance of gut health as an extrarenal mechanism of blood pressure regulation in salt-sensitive hypertension is not fully understood.¹⁰⁵

Excess dietary salt intake influences the gut-kidney axis in hypertension through regulation of the immune system and oxidative stress. We found that a high salt diet increased infiltration of CD45⁺, CD3⁺, CD4⁺, and CD8⁺ cells in mouse mesenteric arterials.¹⁰⁶ Moreover, a high salt diet also increased infiltration of the mesentery by CD11c+ cells, with a concomitant increase in surface expression of CD86 and accumulation of IsoLG-protein adducts, leading to inflammation and gut microbiota-dependent salt-induced hypertension.¹⁰⁶ Moreover, high salt treatment in mice depletes levels of Lactobacillus murinus and a marked increase in TH-17 cells, which contribute to hypertension.¹⁰⁷ Another murine study showed that in germ-free mice, compared to colonized littermate, pro-inflammatory Th17 cells were higher, and this was associated with renal damage.¹⁰⁹ Finally, Dahl salt-sensitive rats fed a high salt diet exhibit alterations in the gut microbiota, inflammation and renal damage,²⁵ suggesting a link between gut gut-dysbiosis and the kidney in salt-sensitive hypertension. Together, these findings suggest a role for gut microbiota in salt-induced hypertension (Figure 4), but the specific mechanisms in salt sensitivity of blood pressure are yet to be elucidated.

Figure 4. The interplay among excess dietary sodium intake, gut microbiota, and salt-sensitive hypertension.

Elevated sodium consumption can cause dysbiosis and immune cell activation, which contributes to cardiovascular pathophysiology and hypertension-related illness. Increased production of reactive oxygen species (ROS) by NADPH oxidase is linked to excess dietary sodium consumption and can induce oxidative stress in the gut and kidney, a hypertensive stimulus. Trimethylamine N-oxide (TMAO), a metabolite secreted by gut bacteria and immune cell activator, induces superoxide production, which is also conducive to oxidative stress. Furthermore, the gut microbiome accommodates bacterial metabolites, such as short-chain fatty acid (SCFA), acting as signaling molecules through their interactions with G-coupled protein receptors (e.g., Olf78, GPR41), ultimately influencing blood pressure. SCFAs can also incite an inflammatory response by binding to free fatty acid Receptor (FFAR) 2 and GPR109A, which induces hyperpolarization and leads to NLRP3 activation and proinflammatory cytokine production. Thus, the intimate interaction between immune cells and gut microbiome plays a governing role in the modulation of SSBP.

Gut microbiome metabolites, such as short-chain fatty acids (SCFAs), act as signaling molecules and interact with specific G-protein-coupled receptors such as Olf78 and FFAR3 (also known as GPR41), leading to increased or decreased blood pressure, respectively ¹¹⁰. High salt affects the levels of SCFAs in humans and mice. SCFAs are important regulators of intestinal and immune homeostasis.^111,112 Studies are needed to determine how high salt via immune mechanisms affects the SCFA synthesis and salt sensitivity of blood pressure. Beyond FFAR2, colonic microbiotas convert dietary nutrients such as choline, phosphatidylcholine, and L-carnitine from trimethylamine (TMA) to trimethylamine N-oxide (TMAO), which is associated with cardiovascular disease (Figure 4).^113,114 High dietary salt caused a significant increase and decreased levels of TMAO in the plasma and urine, respectively, of Sprague Dawley rats,¹¹⁵ and TMAO drives immune activation, including macrophages and T cells in mice.¹¹⁶ Together, these studies suggest that the gut microbiome plays a vital role in modulating proinflammatory immune responses, oxidative stress, and SSBP. Further studies are needed to determine how high salt drives immune cell activation by modulating TMAO synthesis.

FUTURE PERSPECTIVES:

Although the advent of advanced immunological, genetic, molecular, and other experimental tools has accelerated research seeking to understand the mechanistic contribution of immune cells to SSBP and organ damage, the cause-and-effect relationships among the immune system, salt-sensitive hypertension, and kidney damage warrants further investigation. Moreover, anti-inflammatory medicines have been limited in treating hypertension, as precise manipulation of the immune system may be required to protect against organ damage in hypertension without inducing excessive immunosuppression.¹³³ Even though some anti-inflammatory medicines show potential for treating hypertension, currently available options are limited and pose grave risks for severe immunosuppression and CVD.¹³⁴ Thus, further research is needed to investigate specific inflammatory immune cell subpopulations to identify better antihypertensive therapeutic targets. Currently, available methodologies for phenotyping humans for salt sensitivity are laborious, cumbersome, and costly, which poses significant barriers to conducting extensive studies.¹⁹ Finally, the interplay between other dietary items, such as fiber ¹³⁵ contributing to SCFA, in modulating the gut microbiome alongside salt may offer greater insight into the confluence of factors that must be considered in developing therapies that go beyond salt restriction. Although there are currently no feasible diagnosis and therapy for SSBP, we have highlighted some potential biomarkers and therapeutic targets based on emerging evidence highlighted in this review (Supplementary Tables S1 and S2).

CONCLUSION

Substantial evidence from animal and human studies, clinical trials of Na⁺ restriction and supplementation, and epidemiological studies implicate salt sensitivity as an independent risk factor for cardiovascular, stroke, and kidney disease. Evidence from animal and human studies demonstrates that innate and adaptive immune cells play a role in the inception and amplification of salt-induced hypertension, but the specific mechanisms in SSBP are yet to be explored. It is imperative to identify the underlying mechanisms of SSBP to find simpler, quicker, and more cost-effective approaches to phenotype and design personalized medicine for SSBP.

Nonstandard Abbreviations and Acronyms

APC

Antigen Presenting cells

CCL

Chemokine (C-C motif) ligand

CKD

Chronic Kidney disease

CVD

Cardiovascular Disease

CXCL

Chemokine (C-X-C motif) ligand

DC

Dendritic cell

ENaC

Epithelial Sodium Channel

IFN

Interferon

IL

Interleukin

IsoLG

Isolevuglandin

NCC

Sodium Chloride Cotransporter

NHE3

Sodium hydrogen Exchanger 3

NKCC

Na–K–Cl Cotransporter

NO

Nitric Oxide

ROS

Reactive Oxygen Species

SCFA

Short Chain Fatty Acid

SSBP

Salt sensitivity of Blood Pressure

TMAO

Trimethylamine N-oxide

TNF

Tumor Necrosis Factor