Interplay of Renal, Vascular, and Immune Signaling in Salt Sensitivity of Blood Pressure: AP-1 as an Emerging Therapeutic Target

Abstract

Some individuals develop elevated blood pressure in response to increased dietary sodium intake, a phenotype known as salt sensitivity of blood pressure (SSBP). Our understanding of SSBP has expanded beyond the traditional view of sodium overload and fluid retention to recognize it as a complex immunoinflammatory process that contributes to progressive damage across multiple organs, particularly the kidneys and vasculature. High-salt exposure can activate immune cells, leading to increased production of reactive oxygen species (ROS), reduced nitric oxide (NO) bioavailability, and the release of pro-inflammatory cytokines. This persistent low-grade inflammation disrupts renal and vascular homeostasis and further exacerbates immune dysregulation. Growing evidence suggests that dysregulation of key transcriptional regulators, including hypoxia-inducible factor-1α (HIF-1α), mineralocorticoid receptor (MR), nuclear factor-κB (NF-κB), and activator protein-1 (AP-1), may play an important role in the development of SSBP by modulating immune activation, renal sodium handling, vascular dysfunction, and inflammatory signaling pathways. This review provides an overview of the current understanding of renal, vascular, and immune cell crosstalk in SSBP and highlights the emerging role of AP-1 as an important mechanistic regulator and potential therapeutic target.

Graphical Abstract

1. Introduction

Hypertension refers to the chronic elevation of systemic arterial blood pressure and is observed in approximately one-third of the adult population worldwide (1). This chronic condition increases the risk of cardiovascular complications such as heart failure, stroke, and kidney disease, thus ranking it among the leading causes of morbidity and mortality worldwide (2). Several contributing factors, including lifestyle, genetic predisposition, and medications, can influence blood pressure regulation. Among these factors, an important determinant in the development and progression of hypertension is salt sensitivity of blood pressure (SSBP), defined as an exaggerated change in blood pressure in response to changes in sodium intake. Individuals showing this response are termed salt-sensitive (SS) (3-5). More than half of hypertensive individuals and about one-quarter of normotensive individuals are estimated to be SS, and this condition enhances their risk of developing cardiovascular disease and mortality (4). Furthermore, two large meta-analyses have confirmed that reducing salt intake lowers blood pressure, and that there is a direct and steady relationship between salt intake and blood pressure (6, 7).

Although many clinical and experimental studies have associated high salt intake with hypertension, the exact mechanisms through which these associations lead to hypertension are still not fully understood. One major reason for this lack of understanding is that individuals vary greatly in their blood pressure response to a high-sodium diet (HSD) (8-10). Some individuals experience a marked increase in blood pressure, whereas others exhibit little or no change; the latter are known as salt-resistant (SR) (3, 11). In humans, this trait is continuously distributed; hence, there are no clearly defined cutoff values that separate SS and SR individuals. Salt sensitivity can also be found in both hypertensive and normotensive individuals. In a normotensive population, salt sensitivity may indicate a higher risk of developing SSBP later in life, while SR individuals are less likely to become hypertensive (12). Consistent with these findings, epidemiological studies support the concept that SSBP is an independent risk factor for hypertension, kidney dysfunction, and cardiovascular disease. These risks persist even beyond the direct effects of elevated blood pressure, which underscores the important long-term health consequences of SSBP (13-16).

According to the classical pressure-natriuresis hypothesis, hypertension may develop when a factor impairs renal excretory function and shifts the pressure-natriuresis relationship toward higher arterial pressures (17). However, recent experimental findings challenge the previous concept of salt sensitivity, which primarily attributes the condition to sodium overload and plasma volume expansion. From a mechanistic point of view, the vasculature is critically involved in the pathogenesis of SSBP through processes such as decreased vascular compliance, endothelial dysfunction, fibrosis, and oxidative stress (18-20). Furthermore, SSBP is increasingly recognized as a condition involving immune cell activation and inflammation. These processes can lead to damage in multiple organs, particularly the kidneys and blood vessels (21). Therefore, understanding the biological processes that drive SSBP and the factors that regulate them is important for the development of targeted preventive and therapeutic interventions.

Several other factors may also influence the renal, vascular, and immune mechanisms involved in SSBP. Tissue sodium storage and lymphatic function can affect sodium distribution and clearance, while sympathetic and immune signaling may connect the nervous system with renal, vascular, and inflammatory responses (22-24). Dietary potassium and chloride can further influence renal sodium handling and blood pressure responses (25-27). In addition, factors such as the gut microbiota, circadian rhythms, aging, sex hormones, and genetic and epigenetic differences may help explain interindividual variation in responses to high salt intake (28-37). Although these factors may interact with the pathways discussed in this review, they are beyond its primary scope and are therefore not discussed in detail. Instead, we focus on the renal, vascular, and immune mechanisms that contribute to SSBP and their dynamic, bidirectional interactions, which can establish self-reinforcing feedback loops that sustain elevated blood pressure and promote target-organ injury. We further examine transcriptional regulators, particularly activator protein-1 (AP-1), as potential integrators of inflammatory and vascular signaling and as an emerging therapeutic candidate in SSBP.

2. Literature Search Methodology

A comprehensive literature search was conducted using PubMed/MEDLINE and Scopus to identify studies relevant to SSBP, AP-1 signaling, renal sodium handling, vascular dysfunction, immune regulation, oxidative stress, and inflammation. Search terms included combinations of "salt-sensitive hypertension," "salt sensitivity of blood pressure," "AP-1," "activator protein-1," "c-Fos," "c-Jun," "renal sodium transport," "mineralocorticoid receptor," "HIF-1α," "NF-κB," "immune cells," "oxidative stress," "transcriptional regulators in SSBP," "renal inflammation," "vascular remodeling," and "vascular dysfunction." Only articles published in English were included. Priority was given to peer-reviewed original research articles and high-quality review articles. Foundational studies establishing key physiological and molecular concepts were included where relevant, together with recent evidence available at the time of manuscript preparation. Human studies were preferentially cited where available; however, because mechanistic evidence regarding AP-1 in SSBP remains limited, relevant animal and in vitro studies were also included to provide mechanistic insight. The selected literature was evaluated with respect to the molecular mechanisms, pathophysiology, and therapeutic implications discussed in this review.

Because SSBP is a complex and heterogeneous phenotype, this review incorporates evidence from diverse experimental models that address different aspects of its pathophysiology. Studies demonstrating a differential blood pressure response to dietary sodium were considered direct evidence of salt sensitivity, whereas DOCA-salt, L-NAME/high salt, and angiotensin II models were interpreted primarily as evidence of salt-associated or salt-exacerbated hypertension unless salt-dependent blood pressure responses were specifically demonstrated. In vitro and ex vivo studies were considered evidence of sodium-responsive cellular or tissue mechanisms rather than independent evidence of SSBP. Similarly, findings from unrelated inflammatory or autoimmune models were used only as mechanistic context. This framework was applied throughout the review to distinguish salt sensitivity from general hypertension, sodium-induced tissue injury, and broader inflammatory signaling.

3. Role of the Renal System in SSBP

Morgan and colleagues (1990) provided important evidence for a renal contribution to SSBP by demonstrating that transplantation of kidneys from Dahl SS rats into SR recipients resulted in the development of hypertension after exposure to HSD (10, 38). Similarly, Curtis et al. (1983) demonstrated that hypertensive patients became normotensive when the kidneys from normotensive donors were transplanted into them and vice versa (10, 39). Collectively, these findings support a central and causal role for the kidney in long-term blood pressure regulation (10, 38, 39). In healthy SR individuals, increased dietary sodium activates several compensatory mechanisms that prevent substantial increases in blood pressure. These include suppression of systemic RAAS, enhanced pressure natriuresis, nitric oxide (NO)-mediated vasodilation, activation of natriuretic peptide pathways, and increased renal sodium excretion. SSBP may develop when one or more of these adaptive responses are impaired or insufficient (40-44). For example, Limas and colleagues reported that Dahl SS rats exhibit reduced renal prostaglandin production and increased prostaglandin degradation compared with Dahl SR and Sprague-Dawley rats. Reduced renal prostaglandin availability may impair the renal adaptive response to HSD, thereby increasing susceptibility to SSBP (45).

In the same way, Hall et al. (2012) reported that elevated arterial pressure can increase renal perfusion and promote sodium and water excretion. This response facilitates restoration of sodium and fluid balance and contributes to normalization of arterial pressure. This autoregulatory mechanism, termed “pressure natriuresis,” is impaired in many forms of hypertension and is considered a central mechanism linking renal sodium handling to long-term blood pressure regulation (40, 41, 46). Supporting this evidence, S-P467L mice, a PPARγ mutant knock-in model used to investigate SSBP, fail to appropriately vasodilate the renal vasculature following HSD. This response is associated with increased renal vascular resistance and reduced renal blood flow compared with normotensive controls, owing to impaired NO synthesis. Consequently, impaired renal perfusion and sodium excretion may promote Na⁺ and water retention, renal injury, and ultimately the development of SSBP (42). Reinforcing this concept, studies have shown that SS individuals retain substantially more sodium than SR individuals during HSD, supporting the classical volume-expansion and renal dysfunction framework of SSBP (3, 10, 41). This may occur because sodium-retaining pathways, including the RAAS, mineralocorticoid signaling, and renal tubular sodium transporters, fail to appropriately downregulate their activity during HSD. Conversely, endogenous mechanisms that promote sodium excretion, including natriuretic peptides, NO, and renal eicosanoids, may be impaired. Consequently, renal sodium excretion is reduced, leading to extracellular fluid expansion and increased blood pressure (3, 5, 41, 47, 48).

Despite suppression of the systemic RAAS during high-salt conditions, intrarenal Ang II and aldosterone/MR signaling may remain inappropriately activated in SS models. This aberrant intrarenal signaling can promote vasoconstriction and increase vascular resistance. At the same time, impaired glomerular filtration, reduced renal blood flow, and blunted pressure natriuresis limit the kidney’s capacity to excrete excess sodium. Together, these abnormalities increase vascular tone and promote renal tubular sodium reabsorption (8, 48-50). Moreover, HSD upregulates the NADPH oxidase subunits p22^phox and p47^phox and downregulates endothelial NO synthase (eNOS) in Dahl SS rats via the Ang II type 1 receptor (AT1R). This results in increased ROS production, diminished NO levels, and impaired natriuresis, all of which ultimately contribute to SSBP (50-52). This paradoxical activation of the intrarenal RAAS despite HSD may result from genetic predisposition or acquired renal damage in SSBP (53). In addition to the classical RAAS pathway, research has identified tissue-specific RAAS in organs such as the brain and vasculature, which may lead to salt sensitivity independently of the systemic RAAS (54). However, central inhibition of RAAS components has been shown to attenuate or prevent the salt-induced increase in blood pressure in Dahl SS rats (55, 56). These findings suggest that RAAS signaling within the central nervous system plays an important role in regulating cardiovascular responses to HSD in SS models.

Under high-salt conditions, dysregulation of several intracellular signaling pathways can enhance renal sodium reabsorption. Among these, two important pathways implicated in SSBP are the Rac1/mineralocorticoid receptor (MR)/serum- and glucocorticoid-regulated kinase 1 (SGK1) pathway and the β2-adrenergic receptor/glucocorticoid receptor/WNK4 pathway (57-59), as shown in Figure 1. Mechanistically, intrarenal Ang II activates Rac1, a member of the Rho family of small GTPases, which can enhance MR activation even when circulating aldosterone levels are low. Thus, salt sensitivity may reflect not only altered ligand availability but also increased tissue responsiveness to Ang II or aldosterone/MR signaling. Activated MR signaling increases SGK1 expression and activity, which promotes phosphorylation and inhibition of neural precursor cell-expressed developmentally downregulated protein 4-2 (NEDD4-2), an E3 ubiquitin ligase that normally facilitates ENaC ubiquitination and degradation. Inhibition of NEDD4-2 consequently increases ENaC abundance at the apical membrane, enhancing sodium reabsorption and contributing to elevated blood pressure (58, 59, 60, 61-65). Rac1 activation also induces the production of NADPH oxidase-derived ROS and activates nuclear factor-κB (NF-κB) signaling, leading to renal inflammation, fibrosis, and increased pendrin expression. In addition, increased pendrin expression enhances chloride reabsorption in the distal nephron, thereby facilitating coupled NaCl reabsorption and contributing to extracellular fluid expansion and elevated blood pressure (58, 61, 66, 67). Notably, WNK kinases, a family of serine/threonine kinases, function as intracellular chloride-sensitive regulators of renal electrolyte transport. In experimental models relevant to SSBP, Ang II can activate WNK kinases, which subsequently phosphorylate STE20/SPS1-related proline-alanine-rich kinase (SPAK) and oxidative stress-responsive kinase 1 (OSR1). These kinases regulate major renal sodium transporters, including the NCC in the DCT and the Na⁺-K⁺-2Cl⁻ cotransporter 2 (NKCC2) in the thick ascending limb (TAL), thereby promoting renal sodium reabsorption and contributing to elevated blood pressure (42, 57, 68-72).

Figure 1.

Proposed mechanisms by which renal signaling pathways contribute to salt sensitivity of blood pressure (SSBP). A high-salt environment can dysregulate the Rac1/MR/SGK1 and WNK-SPAK/OSR1 signaling pathways in the kidney, as demonstrated in experimental models of SSBP and Ang II-associated hypertension. Activation of these pathways increases the activity of renal sodium transporters, including the epithelial sodium channel (ENaC) in the collecting duct, the Na⁺-Cl⁻ cotransporter (NCC) in the distal convoluted tubule (DCT), and the Na⁺-K⁺-2Cl⁻ cotransporter 2 (NKCC2) in the thick ascending limb (TAL) (58, 62, 72). Enhanced renal sodium reabsorption promotes extracellular fluid expansion and contributes to the development of SSBP. This figure was created using BioRender.com.

In addition, cellular and tissue injury may occur following sodium exposure independently of changes in blood pressure. For instance, enhanced sodium reabsorption imposes a substantial metabolic demand on renal tubular cells. A substantial proportion of renal oxygen consumption is devoted to sodium reabsorption, largely to support Na⁺/K⁺-ATPase activity (73). Increased sodium reabsorption during HSD increases the energetic demand on renal tubular cells, requiring greater mitochondrial ATP production to sustain ion transport (73, 74). Consistent with these findings, Z. Wang et al. (2017) reported that HSD impaired mitochondrial enzyme activity in the kidneys of Dahl SS rats. This mitochondrial dysfunction was associated with reduced cellular metabolism and ATP production, accompanied by the accumulation of metabolites within renal cells (75, 76). In addition, high dietary salt exposure has been shown to increase mitochondrial ROS (mROS) production in renal-derived cells, contributing to activation of the tonicity-responsive enhancer-binding protein (TonEBP/OREBP) and suggesting that mitochondrial redox signaling is an early cellular response to hypertonic stress (77). Similarly, in Dahl SS rats, high-salt exposure is also associated with increased renal oxidative stress, with p67^phox-dependent NADPH oxidase activity contributing to altered mitochondrial redox status in the renal medulla. Notably, genetic disruption of p67^phox reduced renal oxidative stress, renal injury, and SSBP (78-80). These findings should, however, be interpreted in the context of the distinction between direct sodium-induced cellular injury and mechanisms that have been shown to contribute specifically to blood pressure elevation in SS models.

4. Role of Vascular Dysfunction in SSBP

Cardiac output (CO) and systemic vascular resistance (SVR) are major determinants of arterial blood pressure, which can be approximated by the relationship BP = CO × SVR (42). In normal SR individuals and Dahl SR rats, increased dietary sodium intake may cause a modest increase in sodium and water retention, resulting in transient increases in extracellular fluid volume and cardiac output. However, this response is normally counterbalanced by compensatory mechanisms, including endothelial NO production. NO promotes vascular relaxation, reduces vascular resistance, and facilitates renal sodium excretion, thereby limiting the increase in blood pressure, as observed in Dahl SR rats (42, 81-83). Miyoshi et al. (1997) proposed that, in SS individuals, high salt intake impairs endothelial function, thereby contributing to the excessive increase in blood pressure (84). Consistent with this concept, both SS humans and experimental models, including S-P467L mice, exhibit impaired endothelium-dependent vasorelaxation following high-salt exposure, accompanied in some settings by enhanced vasoconstrictor responses and elevated blood pressure (42, 43, 81, 82, 85). These findings support impaired endothelial adaptation as an important component of SSBP. In contrast, spontaneously hypertensive rats (SHR) are primarily a model of genetically driven hypertension rather than intrinsic salt sensitivity. Although high-salt exposure can further impair vascular relaxation and exacerbate blood pressure elevation in SHR, these findings should be interpreted as evidence of salt-associated worsening of pre-existing hypertension rather than as direct evidence of mechanisms specific to SSBP (42, 43, 81, 82, 85). This vascular dysfunction may result from increased activity of vasoconstrictor pathways (such as thromboxane A₂ and endothelin-1), reduced activity of vasodilator pathways (such as NO, endothelium-derived hyperpolarizing factor, and prostacyclin), or a combination of both (44, 86). This concept is referred to as the “vasodysfunction theory”. Early experimental studies in Dahl SS rats demonstrated that the relatively small difference in blood volume between SR and SS mice suggests that vascular dysfunction and structural alterations in the vasculature may contribute substantially to elevated blood pressure, rather than impaired natriuresis alone (82, 83, 86), as shown in Figure 2. Consistent with these observations, plasma volume in Dahl SS rats returned toward baseline after one week of HSD, whereas elevated vascular tone and blood pressure persisted (81). HSD can also interfere with neural regulation of cardiovascular function in SSBP. For example, high salt intake may blunt the normal suppression of sympathetic nervous system activity, impair parasympathetic regulation, and reduce baroreflex sensitivity. Collectively, these alterations may increase vascular tone and contribute to elevated blood pressure in SS individuals (87).

Figure 2.

Renal and vascular responses to increased dietary sodium in salt-resistant (SR) and salt-sensitive (SS) states. SR responses involve appropriate vascular adaptation and effective renal sodium excretion, thereby maintaining sodium balance and limiting increases in blood pressure. However, in Dahl SS rats, impaired vascular adaptation and/or renal sodium excretion can increase vascular resistance and promote sodium retention, potentially resulting in extracellular fluid expansion, increased cardiac output, and elevated blood pressure. The pressure-natriuresis relationship is blunted or shifted in salt sensitivity, such that a greater increase in blood pressure may be required to achieve adequate sodium excretion and restore sodium balance, as observed in Dahl SS rats (82, 83,). This figure was created with BioRender.com.

In Dahl SS rats, endogenous NO normally contributes to the regulation of microvascular tone; however, Boegehold (1992) reported that this protective influence is progressively diminished during the development of SSBP (88). Subsequent studies showed that chronic treatment with cicletanine restored endothelial function and reduced blood pressure in Dahl SS rats. These effects were attributed to increased production of NO and vasodilatory prostaglandins, which may limit vascular and renal injury (89). Consistent with these experimental findings, Bragulat et al. (2001) reported that, compared with SR individuals, SS hypertensive patients exhibited impaired endothelium-dependent vasodilation despite preserved endothelium-independent vasodilation. These findings further support a role for impaired NO signaling in endothelial dysfunction and abnormal vascular reactivity in SS individuals (90). Potential mechanisms contributing to reduce NO bioavailability include decreased availability of essential eNOS cofactors, increased oxidative stress, and accumulation of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase activity (42, 82, 91). Greaney et al. (2012) demonstrated that short-term HSD increases superoxide production in resistance arteries, primarily through NADPH oxidase and xanthine oxidase activity, independently of an increase in blood pressure. Increased superoxide can, in turn, reduce NO bioavailability, impair endothelial function, and limit vascular relaxation (92-94). In eNOS knockout mice, HSD-induced hypertension and elevated superoxide activity were attenuated by antioxidant treatment and NADPH oxidase inhibition (95). Moreover, Ang II can disrupt endothelial mitochondrial function by increasing oxidative stress. Ang II increases mitochondrial ROS (mROS) levels, reduces glutathione availability, and impairs mitochondrial respiration and membrane potential, in part through activation of NADPH oxidase (96). Complementary evidence from other experimental models suggests that similar alterations in vascular reactivity can occur in salt-associated hypertensive states. For example, White and colleagues (1996) reported that DOCA-salt hypertensive rats exhibited altered vasoconstrictor sensitivity in the carotid and mesenteric arteries following L-NAME administration compared with control animals (97). However, because DOCA-salt hypertension results from mineralocorticoid exposure combined with HSD, rather than an intrinsic differential blood pressure response to dietary sodium, this model should not be considered equivalent to classical SSBP.

The initial studies of SSBP focused primarily on impaired NO-dependent vasodilation. However, d’Uscio et al. subsequently demonstrated that increased endothelin-1 signaling in Dahl SS rats also contributes to endothelial dysfunction, vascular remodeling, and hypertension. Selective endothelin receptor A antagonism reduced blood pressure and attenuated these vascular abnormalities (98-100). Similarly, Majane et al. demonstrated that the vasodilatory effects mediated by the endothelin B (ETB) receptor in Dahl SS rats are largely dependent on NO. Using the selective ETB receptor antagonist BQ-788 and the NO synthase inhibitor L-NAME, the authors found that ETB receptor blockade produced little additional effect on blood pressure when NO production was already inhibited. These findings support an important role for NO in ETB receptor-mediated vascular regulation in SSBP (101).

Recent work has also highlighted a direct role for sodium-sensitive ion channels in disrupting vascular function. Vogt et al. (2023) reported that excess sodium can accumulate in tissues such as the skin, muscles, and endothelial glycocalyx. This tissue sodium accumulation has been associated with salt sensitivity and hypertension (102). At the cellular level, studies using cultured endothelial, immune, and renal cells exposed to elevated extracellular sodium provide important insights into the direct effects of sodium loading or hypertonicity on cellular signaling and function. However, these findings should be interpreted cautiously because demonstration of a sodium-responsive pathway under experimentally elevated extracellular sodium concentrations does not, by itself, establish that the pathway contributes causally to SSBP in vivo. In this context, even under physiological aldosterone levels, an increase in extracellular sodium can stimulate Na⁺/K⁺-ATPase activity and substantially increase ENaC expression in endothelial cells, with some studies reporting nearly a twofold increase. These responses may initially represent a compensatory mechanism that helps endothelial cells adapt to changes in sodium availability and maintain sodium homeostasis (62, 103, 104). However, persistent activation or dysregulation of these pathways may lead to endothelial stiffening, glycocalyx damage, reduced NO production, and impaired vasodilation, as demonstrated in bovine aortic endothelial GM7373 cells (62, 104-107).

Further supporting this mechanism, Korte et al. (2014) demonstrated that increased ENaC activity and endothelial stiffening were associated with endogenous aldosterone synthase (CYP11B2) expression and MR signaling in endothelial cells under high-sodium conditions (106). Moreover, in ex vivo human umbilical artery endothelial cells (HUAECs), elevated sodium concentrations compromised endothelial layer integrity by approximately 50%, increased endothelial cell stiffness by 130%, and reduced protective glycocalyx components such as heparan sulfate by approximately 68%. These alterations were associated with increased vascular permeability and sodium uptake into the vessel wall (108). Brown (2023) proposed that dietary sodium-related fluid retention may interact with phosphate-associated vascular calcification and arterial stiffening, potentially contributing to blood pressure elevation. As blood vessels become calcified and stiff, their ability to expand in response to changes in blood volume is reduced, which may increase vascular resistance and contribute to elevated blood pressure (109). This distinction between physiological sodium sensing and maladaptive responses to chronic sodium excess is particularly important for understanding how sodium-sensitive vascular mechanisms may contribute to SSBP.

Vinaiphat et al. (2023) reported that HSD can disrupt the endothelial glycocalyx and endothelial cell proteins, contributing to vascular inflammation and dysfunction. These alterations may also affect the surrounding vessel wall by promoting immune-cell infiltration and compromising vascular integrity over time. Thus, persistent high-salt intake may contribute to vascular injury across multiple organs and increase the risk of hypertension and cardiovascular disease (110), as illustrated in Figure 3. Similarly, Nickenig and Harrison (2002) described how RAAS activation can influence vascular tone while promoting oxidative stress and inflammatory signaling, thereby contributing to progressive endothelial dysfunction (111). Overall, SSBP involves an imbalance between renal sodium handling and vascular adaptation to increased sodium intake, with endothelial dysfunction, oxidative stress, and inflammatory signaling contributing to sustained increases in vascular resistance and blood pressure. Growing evidence further suggests that the effects of HSD extend beyond the kidneys and vasculature, with other organs potentially contributing to the metabolic and inflammatory processes associated with cardiovascular dysfunction (20, 112).

Figure 3.

Proposed vascular mechanisms contributing to salt sensitivity of blood pressure (SSBP). High-salt intake can disrupt the endothelial glycocalyx and activate vascular inflammatory and oxidative stress pathways. Increased epithelial sodium channel (ENaC) activity and NADPH oxidase (NOX) activation may reduce nitric oxide (NO) bioavailability and impair vasodilation, as demonstrated in in vitro endothelial cell models (62, 106, 108). Moreover, evidence from Dahl SS rats further suggests that HSD also promotes immune-cell infiltration and inflammatory signaling, contributing to vascular inflammation and endothelial dysfunction (52, 113). Collectively, these mechanisms may contribute to the development and maintenance of SSBP. This figure summarizes mechanistic evidence derived from diverse experimental studies and models; the pathways shown should therefore not be considered directly comparable or interpreted as representing a single integrated causal mechanism. Figure created using BioRender.com.

5. Role of Immune Cells and Inflammation in SSBP

Kidney transplantation studies have provided strong evidence for a causal role of the kidney in blood pressure regulation (10, 38). However, subsequent findings indicate that renal mechanisms alone do not fully account for SSBP and that extra-renal factors, including vascular and immune mechanisms, also contribute to its development (114). Supporting a role for immune mechanisms, Bataillard et al. (1989) and subsequent studies reported that immunosuppression attenuated the development of hypertension in genetically predisposed rat models (115-117). Similarly, later studies showed that treatment with the immunosuppressive agent mycophenolate mofetil reduced blood pressure, an effect associated with reduced renal inflammation and improved vascular function, including increased NO bioavailability and reduced vasoconstrictor activity (118, 119). Although several experimental studies have demonstrated that immunomodulatory interventions can attenuate inflammation and reduce blood pressure in models relevant to SSBP, these findings should not be generalized to all immunosuppressive therapies. The effects of immunomodulatory agents on blood pressure depend on their specific mechanisms of action, dose, and clinical context. For example, hypercortisolism in Cushing syndrome is associated with hypertension despite the anti-inflammatory and immunosuppressive effects of glucocorticoids, while calcineurin inhibitors such as cyclosporine and tacrolimus can induce hypertension through mechanisms that include renal vasoconstriction, increased sodium retention, and sympathetic activation (120, 121).

Previous studies have demonstrated that immune and lymphatic mechanisms contribute to fluid homeostasis and blood pressure regulation during high-salt intake, and that disruption of these pathways can promote hypertension (23, 114). Supporting this evidence, Takahashi et al. showed that HSD rapidly increases leukocyte adhesion and renal inflammatory signaling in young Dahl SS rats, even before the development of marked hypertension. Blocking leukocyte adhesion reduced subsequent kidney injury, suggesting that early immune activation may play a role in salt-induced renal damage (113). Extending these findings, Chandramohan et al. demonstrated that HSD in Dahl SS rats promotes intrarenal angiotensin II/AT₁ signaling, NADPH oxidase-mediated oxidative stress, NF-κB-dependent inflammation, and profibrotic responses, accompanied by immune-cell infiltration, hypertension, and proteinuria, whereas these responses were markedly attenuated in SR rats (52). In this setting, infiltrating immune cells may further promote oxidative and inflammatory injury, while the resulting cytokine production facilitates additional immune-cell recruitment, creating a feed-forward inflammatory cycle that can exacerbate renal injury and contribute to SSBP elevation (122, 123). Under healthy conditions, NO helps maintain vascular homeostasis partly by limiting leukocyte and platelet adhesion through regulation of endothelial adhesion molecules, including ICAM-1 and VCAM-1 (124-126). However, reduced availability of vasodilators such as NO and prostacyclin, together with increased production of vasoconstrictors such as thromboxane A₂, can enhance the expression of adhesion molecules, thereby promoting leukocyte adhesion, tissue infiltration, and vascular inflammation (113, 127). Consistent with this, the L-NAME/high-salt model represents an experimentally induced state of NO deficiency and salt-associated hypertension rather than an intrinsic model of dietary salt sensitivity. In this model, HSD promoted a pro-inflammatory macrophage phenotype in the kidney and gonads, characterized by increased pro-inflammatory markers and reduced markers of alternative activation (128). These findings suggest that immune activation can accompany and potentially amplify salt-associated hypertensive injury, although they do not by themselves establish that macrophage polarization is a primary determinant of SSBP.

Although macrophages have traditionally been classified using the simplified M1/M2 framework, this binary model does not adequately capture the diversity and plasticity of macrophage states observed in vivo. Current nomenclature therefore emphasizes the cellular source, activating stimuli, and functional characteristics rather than assigning macrophages to rigid M1 or M2 categories (129). In the context of high-salt exposure, elevated extracellular NaCl can induce a distinct macrophage activation state termed M(Na). Zhang et al. demonstrated that high salt exposure increased the expression of proinflammatory genes while suppressing anti-inflammatory and pro-endocytic genes in both human monocyte-derived macrophages and murine macrophages, as shown in Figure 4. Importantly, the resulting phenotype was distinguishable from conventional LPS- or IFN-γ-induced macrophage activation, supporting the concept that sodium can act as an independent environmental stimulus that shapes macrophage function rather than simply inducing a conventional M1 phenotype (130). HSD also potentiated LPS-induced inflammatory activation while suppressing IL-4-induced alternative activation, further demonstrating that sodium modifies macrophage responses in a stimulus-dependent manner (130). In addition, HSD-activated macrophages can release pro-fibrotic mediators, including TGF-β and PAI-1, which have been implicated in cardiac and renal fibrosis in Dahl SS rats (8, 131, 132).

Figure 4.

Proposed framework illustrating the interplay between innate and adaptive immune responses and renal and vascular mechanisms involved in salt sensitivity of blood pressure (SSBP) following increased dietary salt intake. Increased sodium availability and tissue sodium accumulation may promote immune activation, including pro-inflammatory macrophage activation, reduced anti-inflammatory signaling, Th17-cell activation with increased IL-17A production, and CD8⁺ T-cell activation with increased IFN-γ production. These immune responses may interact with renal and vascular pathways, contributing to impaired vasodilation, increased vascular resistance, altered renal sodium handling, and sodium retention. Collectively, these mechanisms may contribute to the development and maintenance of elevated blood pressure and SSBP. The figure integrates evidence from Dahl salt-sensitive rats and related experimental models, including Ang II and DOCA-salt models, to illustrate salt-associated immune activation, renal inflammation, endothelial dysfunction, and blood pressure elevation (52, 130, 133). This figure was created using BioRender.com.

The effects of sodium on macrophages also depend on tissue context. In the skin, sodium accumulation generates a hypertonic microenvironment that can activate macrophages through NFAT5- and p38/MAPK-dependent mechanisms and enhance antimicrobial responses (136). In contrast, high-salt and DOCA-salt models of hypertension are associated with macrophage accumulation and inflammatory activation in the kidney, where macrophages can contribute to renal injury and blood pressure elevation (137). Vascular macrophage recruitment is also increased during DOCA-salt hypertension and is associated with CCR2-dependent inflammatory signaling (138). Thus, macrophage activation in the kidney, vasculature, skin, or circulation should not automatically be interpreted as a uniform systemic M1 phenotype.

Macrophage metabolism is closely linked to functional state and can be altered by high-salt exposure. For example, HSD can suppress glycolytic and mitochondrial metabolic responses during IL-4/IL-13-induced macrophage activation, whereas other studies have demonstrated direct inhibition of mitochondrial respiration in both murine and human mononuclear phagocytes following high-salt exposure (139, 140). However, sodium-induced metabolic responses should be considered dynamic and context-dependent rather than interpreted as a uniform metabolic switch from oxidative phosphorylation to glycolysis (139, 140). Sodium-induced macrophage responses can additionally involve inflammatory and stress-response pathways, including p38/MAPK-c-Fos/AP-1, ERK1/2-c-Fos/AP-1, NFAT5, and inflammasome signaling. Hypertonic conditions have been shown to activate NLRP3- and NLRC4-associated inflammatory responses in macrophages, while sodium-dependent NFAT5 activation can promote macrophage effector functions under tissue hypertonicity (130, 136, 141). Further evidence suggests that activation of NLRP3 and NLRC4 inflammasomes in macrophages in SS models can promote calcium overload, caspase-1 activation, and subsequent IL-1β release, potentially contributing to vascular dysfunction, vascular remodeling, and hypertension (142-144). IL-1β produced in the renal microenvironment can also influence macrophage activation and cytokine production, including IL-6, which may promote downstream T-cell responses such as Th17 differentiation (141, 143). Similarly, high-salt exposure activated NLRP3-associated inflammatory signaling and increased oxidative stress in cultured endothelial cells, providing mechanistic evidence for a potential role of this pathway in sodium-associated vascular dysfunction (145, 146). In addition, Krishnan et al. (2019) demonstrated that blocking the NLRP3 inflammasome with MCC950 reduced blood pressure, renal inflammation, and fibrosis in the DOCA-salt model, supporting a role for NLRP3 signaling in this model of salt-associated experimental hypertension; however, this model does not by itself establish SSBP (147).

Classical dendritic cells contribute to Ang II-induced hypertension, which shares several mechanisms with SSBP, by promoting immune activation in the kidney and thereby increasing inflammation, sodium retention, and blood pressure (148). Characterizing the cellular mechanisms underlying these responses may provide insight into the pathogenesis of SSBP. Sodium uptake through ENaC, particularly the α- and γ-subunits, in dendritic cells triggers Ca²⁺-dependent activation of protein kinase C and SGK (149, 150). This signaling cascade activates NADPH oxidase subunits, including p47^phox, leading to increased ROS generation and lipid peroxidation. Consequently, immunogenic lipid peroxidation products, including isolevuglandin (IsoLG; also known as γ-ketoaldehydes or isoketals), accumulate in dendritic cells and promote T-cell activation through the production of inflammatory cytokines, including IL-6, IL-1β, and IL-23 (151), as shown in Figure 5. In addition, depletion of antigen-presenting cells (APCs) has been shown to prevent hypertension, improve natriuresis, and reduce cardiac and renal injury in experimental models of salt-associated hypertension (152). Activated T cells can subsequently infiltrate the kidneys and contribute to renal injury, sodium retention, and fibrosis through the release of cytokines such as IFN-γ, IL-17A, and TNF-α, as demonstrated in both Ang II-treated and L-NAME/high-salt models (150, 151). Supporting these findings, another study showed that A20, an anti-inflammatory ubiquitin-editing protein expressed in dendritic cells, protects against Ang II-induced hypertension by suppressing T-cell activation, inflammation, and renal sodium retention (153). However, because Ang II infusion represents a model of Ang II-driven hypertension rather than isolated salt sensitivity, these findings should be interpreted as mechanistic evidence for dendritic-cell-T-cell interactions in hypertension rather than direct evidence that this pathway specifically mediates SSBP.

Figure 5.

This figure summarizes a proposed pathway linking high-salt exposure, dendritic-cell activation, and downstream renal and vascular inflammatory responses that may contribute to salt sensitivity of blood pressure (SSBP). Excess ENaC-mediated Na⁺ uptake promotes Ca²⁺ influx, protein kinase C (PKC) and NADPH oxidase activation, and increased ROS production. This can drive IsoLG-protein adduct formation and activate NF-κB/NLRP3 signaling, promoting pro-inflammatory cytokine production and Th17 responses that contribute to vascular dysfunction, renal inflammation, and fibrosis, as demonstrated in Ang II-treated and L-NAME/high-salt models (149-151). However, IL-17A can exert context-dependent effects, and protective actions have also been reported in certain renal conditions. Thus, its role should not be considered uniformly pathogenic across renal and cardiovascular diseases (134, 135). This figure was created using BioRender.com.

Studies have shown that high-salt exposure promotes the expansion of pro-inflammatory Th17 cells through p38/mitogen-activated protein kinase (MAPK), nuclear factor of activated T cells 5 (NFAT5), and SGK1/Forkhead box O1 (FoxO1) signaling pathways (73, 130, 154, 155). In parallel, in L-NAME/high-salt models, sodium loading promotes a pro-inflammatory T-cell phenotype through SGK1 and IL-23 signaling. These findings support a mechanistic link between sodium exposure, immune activation, and hypertension (156, 157). Interestingly, salt-induced SGK1 can further amplify inflammatory responses by increasing NKCC1 activity in T cells, particularly Th17 cells. This, in turn, further increases SGK1 and IL-23 receptor expression, creating a positive-feedback loop that amplifies inflammation (156, 158, 159). T-cell-specific SGK1 deficiency attenuates immune activation, limits salt-induced blood pressure elevation, and reduces vascular dysfunction, highlighting an important role for T-cell SGK1 signaling in experimental salt-associated hypertension (159). In addition, accumulating evidence indicates that targeting sodium transport pathways may exert anti-inflammatory and tissue-protective effects. Pharmacological inhibition of ENaC, NHE1, and NKCC1 using agents such as amiloride and bumetanide has been shown to reduce oxidative stress, vascular inflammation, macrophage activation, and tissue injury. Collectively, these findings highlight the potential of sodium transport pathways as therapeutic targets in inflammation-associated cardiovascular and systemic diseases (149, 160, 161). However, because much of the current evidence is derived from experimental models, further translational and clinical studies are required before these approaches can be considered for the management of SSBP.

Guzik et al. demonstrated that T cells contribute directly to Ang II-induced hypertension and vascular dysfunction, with Ang II promoting T-cell activation and vascular recruitment through AT₁ receptor/NADPH oxidase-dependent mechanisms, leading to TNF-α production, increased vascular oxidative stress, and impaired vascular function (162, 163). Inhibition of T-cell activity or TNF-α signaling can reduce inflammation, protect blood vessels, and lower blood pressure in both Ang II-infused and DOCA-salt models (162, 164). Similarly, lymphocyte deficiency attenuates Ang II-induced hypertension and cardiac and renal injury in SCID mice, suggesting that adaptive immune responses contribute to hypertension, in part by promoting renal sodium retention (165). However, these findings should be interpreted as evidence of immune mechanisms contributing to salt-associated or Ang II-driven hypertension rather than as direct evidence of mechanisms specific to SSBP. Activated T cells may contribute to sodium retention through the release of pro-inflammatory cytokines, particularly IL-17A and IFN-γ (166). These cytokines increase the activity of several renal sodium transporters, including NKCC2, NCC, sodium-hydrogen exchanger 3 (NHE3), and ENaC, thereby promoting sodium and water reabsorption. Furthermore, IL-17A activates p38 MAPK signaling in fibroblasts, increases collagen production, and promotes renal fibrosis (156, 167-169). Consequently, renal sodium excretion is impaired, contributing to sustained elevation of blood pressure (170, 171). At the same time, IL-17 can disrupt vascular function by reducing eNOS activity, activating the RhoA/Rho kinase pathway, increasing vascular tone, and contributing to vascular stiffness and hypertension (172, 173). Mice deficient in these cytokines exhibited lower blood pressure and preserved sodium and water excretion (166). However, conflicting evidence exists in some settings; IL-17A deficiency accelerates albuminuria and hypertensive renal disease, suggesting that IL-17A may exert protective effects under certain conditions (134). Similarly, low-dose IL-17A has been shown to attenuate diabetic kidney disease in both type 1 and type 2 diabetes models by reducing signal transducer and activator of transcription 3 (STAT3)-driven fibrosis and increasing expression of the anti-inflammatory protein whey acidic protein (WAP) through AMP-activated protein kinase (AMPK) activation (135). Overall, these findings indicate that IL-17A has context-dependent effects, with its biological actions influenced by disease setting, concentration, and duration of exposure. Thus, therapeutic strategies targeting immune-cell signaling may need to selectively modulate rather than broadly suppress immune responses according to disease context. Liu et al. demonstrated in DOCA-salt mice that renal CD8⁺ T cells promote salt-associated hypertension by stimulating NCC activity in the distal convoluted tubule (DCT) through redox- and kinase-dependent signaling, thereby enhancing renal sodium retention (133, 174). Moreover, cytokines released by activated T cells, particularly TNF-α, can suppress eNOS expression in endothelial cells, thereby contributing to endothelial dysfunction (175, 176), and promote oxidative stress, hypertension, and cardiac hypertrophy in hypertensive mice following Ang II infusion (177, 178).

On the other hand, regulatory T (Treg) cells are a specialized subset of T lymphocytes that suppress excessive immune activation. They express high levels of FoxO1 and FoxP3, which contribute to their regulatory functions and help protect the vasculature and kidneys against RAAS-mediated injury (179-181). However, in SSBP, these protective effects may be weakened by high-salt exposure, contributing to endothelial dysfunction, reduced NO bioavailability, and elevated blood pressure (182-184). Mechanistic studies of T cells suggest that elevated sodium can promote SGK1-dependent Th17 differentiation. Studies using cultured mouse T cells and experimental autoimmune models have shown that increased NaCl exposure enhances SGK1 expression, promotes phosphorylation and cytoplasmic sequestration of FoxO1 and FoxO3, and favors pathogenic Th17-cell responses through an IL-23-dependent mechanism (73, 157, 185, 186), as shown in Figure 6. Although these findings were not obtained in SSBP models, they provide mechanistic support for a potential role of the SGK1-Th17 axis in linking high-salt exposure to immune activation. In contrast, adoptive transfer of Treg cells has been shown to protect against Ang II-induced hypertension. This protection is associated with reduced inflammation, oxidative stress, and immune-cell infiltration in the vasculature, thereby preserving endothelial function and limiting vascular injury (187). Similarly, expansion of Treg cells in mice using an IL-2/anti-IL-2 antibody complex increased Treg-cell numbers approximately fivefold, reduced aortic collagen remodeling, suppressed inflammatory Th17/IL-17 responses, and protected against Ang II-induced vascular stiffening (188). Moreover, Treg cells release cytokines such as IL-10, which protect blood vessels against Ang II-induced endothelial dysfunction by limiting oxidative stress both in vitro and in vivo (189).

Figure 6.

This figure integrates mechanistic findings from different experimental studies and models; therefore, the depicted pathways should not be interpreted as equivalent in strength of evidence or as a single unified causal pathway. High-salt exposure may enhance SGK1-dependent signaling, which can suppress FoxP3 expression, weaken Treg-cell immunosuppressive function, and alter T-cell differentiation toward Th1- and Th17-associated inflammatory responses, based on mechanistic evidence from T-cell studies and relevant experimental models (73, 157, 185, 186). Increased signaling through IL-17A, IFN-γ, and TNF-α may contribute to vascular dysfunction, renal inflammation, sodium retention, and tissue remodeling, thereby promoting elevated blood pressure, as observed in Ang II-induced hypertensive models (187, 189). However, the effects of IL-17A are context-dependent, and protective roles have also been reported in certain renal disease settings (134, 135). Figure created using BioRender.com.

Collectively, these findings indicate that renal, vascular, and immune mechanisms in SSBP do not operate independently but form a dynamic, bidirectional network. Immune activation can impair renal sodium handling and promote vascular dysfunction, whereas renal sodium retention, hypertension, and vascular injury can further stimulate inflammatory signaling (19, 128, 190). For example, cytokines produced by activated immune cells can increase renal sodium transporter activity and impair endothelial NO signaling, thereby linking inflammation to both sodium retention and increased vascular resistance. Conversely, hypertension-induced mechanical and oxidative stress can promote leukocyte activation and vascular and renal inflammation, establishing a self-reinforcing cycle that sustains SSBP and target-organ injury (19, 173). Thus, the contribution of individual immune-cell populations should be interpreted within the broader renal-vascular-immune network rather than as isolated inflammatory events. Potential diagnostic and therapeutic targets are being investigated to address this complex condition. Among these, transcription factors that regulate immune activation and cytokine production have gained increasing attention, as discussed in the following section.

6. Transcriptional Regulators as a Therapeutic Target in SSBP

Accumulating evidence suggests that dysregulation of several transcriptional regulators, including hypoxia-inducible factor-1α (HIF-1α), MR, STAT3, and NF-κB, may contribute to the pathogenesis of SSBP. HIF-1α, a transcription factor that is highly expressed in the renal medulla, plays an important role in protecting against salt-induced increases in blood pressure. HIF-1α exerts these effects, in part, by regulating genes such as nitric oxide synthase (NOS), cyclooxygenase-2 (COX-2), and heme oxygenase-1 (HO-1), which support renal blood flow and promote sodium excretion. Inhibition of HIF-1α reduces the expression of these protective genes, impairs renal sodium handling, and promotes the development of SSBP (191, 192). HIF-1α stability is regulated by prolyl hydroxylase domain-containing protein 2 (PHD2), which hydroxylates HIF-1α and promotes its subsequent degradation through the von Hippel–Lindau (VHL)-dependent pathway. Increased PHD2 activity can therefore reduce HIF-1α availability and its protective effects, contributing to SSBP in rats fed an HSD (193). In Dahl SS rats, HSD fails to adequately suppress PHD2 activity in the renal medulla, in contrast to normotensive rats. Consequently, HIF-1α activation in the renal medulla remains blunted during HSD, contributing to impaired sodium excretion and elevated blood pressure (194). Further studies demonstrated that renal medullary PHD2 knockdown in Dahl SS rats increased HIF-1α and its target genes, including NOS, HO-1, and COX-2, thereby enhancing sodium excretion and pressure natriuresis and attenuating SSBP (195). Similarly, restoration of HIF-1α signaling through gene delivery, cobalt chloride treatment, or pharmacological stabilization with roxadustat enhanced natriuresis, attenuated salt-induced hypertension, and reduced vascular, cardiac, and renal injury in experimental models (192, 196). However, recent evidence indicates that the cardiovascular effects of HIF-PHD inhibitors are complex and remain incompletely understood. Although experimental studies have shown that HIF stabilization can improve renal oxygenation, enhance pressure natriuresis, and lower blood pressure, both preclinical and clinical studies have also reported an increased risk of hypertension with certain PHD inhibitors under specific conditions (197). These findings suggest that HIF-PHD signaling has pleiotropic effects and that therapeutic modulation of this pathway requires careful consideration of the specific agent, dose, and disease context.

Unlike the predominantly protective effects of HIF-1α in the renal medulla, pro-inflammatory transcriptional pathways may contribute to SSBP. Recent studies have identified STAT3-dependent immune activation as a potential mechanism in this process. Saleem et al. reported that HSD activates JAK2 (Janus kinase 2) signaling in CD11c⁺ cells and promotes STAT3 and SMAD3 activation. This response increases the production of reactive isolevuglandins (IsoLGs) and the inflammatory cytokine IL-6 by renal APCs, which subsequently promote T-cell activation and contribute to SSBP (198). These findings further emphasize the potential role of transcriptional regulation within immune cells in promoting inflammatory responses associated with SSBP.

The transcriptional regulators implicated in SSBP comprise mechanistically distinct classes rather than a single family of transcription factors. For example, the MR is a ligand-activated nuclear receptor that functions as a transcription factor and plays an important role in SSBP and its associated cardiovascular and renal complications (199). Under physiological conditions, MR regulates the expression of proteins involved in renal sodium transport, including ENaC and Na⁺/K⁺-ATPase, thereby promoting Na⁺ and water reabsorption in the collecting duct (200). However, excessive or inappropriate MR activation under pathological conditions contributes to renal and cardiovascular injury. For example, Shibata et al. (2007) showed that HSD activates MR in podocytes of Dahl SS rats, resulting in increased ROS generation and SGK1 expression and ultimately contributing to podocyte injury, proteinuria, and hypertensive nephropathy (201). Consistent with these observations, MR blockade suppressed albuminuria and renal injury in Arhgdia⁻/⁻ mice (63). MR signaling also contributes to vascular and cardiac injury in settings that are not necessarily equivalent to SSBP. In vascular smooth muscle cells, MR signaling contributes to aldosterone-induced arterial stiffness, even in the absence of major structural changes in the vessel wall (202). Because aldosterone/DOCA-salt models combine mineralocorticoid excess with sodium loading, findings from these models are best interpreted as evidence of MR-dependent salt-associated hypertension and organ injury. For example, activation of endothelial MR contributes to vascular dysfunction, inflammation, and cardiac fibrosis in response to aldosterone and DOCA/salt treatment. MR deletion reduced macrophage infiltration, inflammatory gene expression, and cardiac fibrosis but did not prevent the increase in systolic blood pressure (203, 204). Similarly, aldosterone combined with salt loading increased blood pressure, macrophage infiltration, M1-associated markers such as iNOS and IFN-γ, and renal fibrosis, as indicated by increased collagen, fibronectin, connective tissue growth factor (CTGF), and collagen type I (Col I) expression. These effects were attenuated by spironolactone, supporting an MR-dependent mechanism (132). These findings suggest that MR contributes to cardiovascular and renal inflammation and fibrosis through mechanisms that may be partly independent of its effects on blood pressure. Beyond its effects on renal and vascular tissues, MR has also emerged as a regulator of adaptive immune responses. At the molecular level, MR interacts with nuclear factor of activated T cells 1 (NFAT1) and AP-1 in T cells, thereby promoting the accumulation of IFN-γ-producing T cells, particularly CD8⁺ T cells, in the kidneys and vasculature. These effects are enhanced following Ang II infusion and are associated with increases in both systolic and diastolic blood pressure. Notably, flow cytometry studies showed that either T-cell-specific MR deletion, as in TMRKO mice, or treatment with the MR antagonist eplerenone markedly reduced T-cell accumulation and attenuated the associated increase in blood pressure (205).

MR activation and immune-cell-mediated inflammation converge, in part, on NF-κB, a central regulator of inflammatory gene expression (206). Ang II-induced ROS can activate NF-κB signaling in Dahl SS rats, increasing the expression of inflammatory mediators such as MCP-1, TNF-α, NLRP3, and pro-IL-1β. These responses may contribute to vascular injury and renal and vascular inflammation associated with SSBP (142, 207). In addition to its classical inflammatory functions, NF-κB can also influence sodium transport pathways. For example, Ang II induces NF-κB nuclear translocation and increases NF-κB binding to the promoters of WNK1/2/4, SPAK, OSR1, and NKCC1 genes, providing a potential mechanistic link between inflammatory signaling and ion transport regulation (208). Table 1 summarizes comparative evidence for the major transcriptional and signaling pathways implicated in SSBP.

Table 1.

Comparative evidence supporting major pathways involved in salt sensitivity of blood pressure (SSBP). Importantly, evidence from animal models should be interpreted according to whether the model directly demonstrates salt sensitivity, represents hypertension occurring during salt loading, or examines sodium-induced cellular injury without a blood-pressure phenotype; these categories should not be considered equivalent to human SSBP. AP-1, activator protein-1; Ang II, angiotensin II; APCs, APCs; AT₁, angiotensin II type 1 receptor; BP, blood pressure; CCD, cortical collecting duct; CNT, connecting tubule; COX-2, cyclooxygenase-2; DCT, distal convoluted tubule; DCs, dendritic cells; DOCA, deoxycorticosterone acetate; DSS, Dahl salt-sensitive; ENaC, epithelial sodium channel; eNOS, endothelial NO synthase; GFR, glomerular filtration rate; HIF-1α, hypoxia-inducible factor-1α; HO, heme oxygenase; HO-1, heme oxygenase-1; iNOS, inducible NO synthase; IsoLGs, isolevuglandin adducts; JAK2, Janus kinase 2; MR, mineralocorticoid receptor; NCC, sodium-chloride cotransporter; NEDD4-2, neural precursor cell expressed developmentally downregulated protein 4-2; NKCC2, sodium-potassium-chloride cotransporter 2; NLRP3, NOD-, LRR-, and pyrin domain-containing protein 3; NO, NO; OSR1, oxidative stress-responsive kinase 1; PBMCs, peripheral blood mononuclear cells; PHD2, prolyl hydroxylase domain protein 2; RAAS, renin–angiotensin–aldosterone system; SGK1, serum/glucocorticoid-regulated kinase 1; SPAK, STE20/SPS1-related proline-alanine-rich protein kinase; STAT3, signal transducer and activator of transcription 3; TAL, thick ascending limb; WNK, with-no-lysine [K] kinase.

Major pathway	Representative model	Salt/BP context	Target tissue/cell	Intervention /experimental approach	Principal finding	Evidence type / level	Direct SSBP evidence	References
Pressure–natriuresis	Dahl SS vs. Dahl SR rats; renal medullary studies	HSD; blunted pressure-natriuresis in Dahl SS	Kidney, particularly renal medulla	Renal perfusion pressure manipulation; renal medullary gene manipulation	Dahl SS rats exhibit impaired pressure-natriuresis, resulting in sodium retention and a rightward shift of the pressure–natriuresis relationship. Restoration of renal medullary HIF-1α markedly enhanced pressure-natriuresis and attenuated salt-induced BP elevation.	In vivo physiological + mechanistic animal evidence	Yes — strong/direct	(192, 209)
Systemic / intrarenal RAAS	Dahl SS rats; renal/cardiac/CNS tissue RAAS studies	HSD suppresses circulating RAAS but paradoxically maintains/increases tissue RAAS	Kidney, CNS, heart	ACE inhibition; measurement of plasma and tissue Ang II/ACE; renal Ang II studies	Persistent/inappropriately elevated intrarenal Ang II signaling may promote renal vasoconstriction and sodium reabsorption despite suppression of circulating RAAS. ACE inhibition attenuates SSBP and renal injury.	In vivo mechanistic animal evidence	Yes — strong/direct	(118, 210, 211)
Rac1–MR	Dahl SS vs. Dahl SR rats	HSD with suppression of circulating aldosterone	Distal nephron, DCT2/CNT/CCD	Rac1 inhibitor NSC23766; MR antagonist eplerenone; genetic models	HSD activates renal Rac1 selectively in SS animals, producing ligand-independent MR activation, enhanced distal Na+ reabsorption and hypertension. Rac1 inhibition suppresses MR activation and attenuates BP elevation.	In vivo genetic/pharmacological mechanistic evidence	Yes — very strong/direct	(58, 66)
MR–SGK1–ENaC/NEDD4-2	Nedd4-2-null mice; Dahl SS/aldosterone models	High salt / mineralocorticoid-sensitive hypertension	Connecting tubule and collecting duct	Nedd4-2 knockout; amiloride; MR/SGK1 manipulation	SGK1 phosphorylates and inhibits NEDD4-2, reducing ENaC ubiquitination and degradation. Loss of NEDD4-2 increases ENaC abundance/activity and produces SSBP that is markedly reduced by amiloride.	Genetic + pharmacological in vivo evidence	Yes — strong/direct	(212-214)
WNK–SPAK/OSR1–NCC	Dahl SS/Dahl SR rats; sympathetic/NCC studies	High salt; NCC dysregulation is strongly associated with the Dahl SS phenotype	Distal convoluted tubule	High-salt feeding; α1-adrenergic antagonism; NCC phosphorylation analysis	Salt-resistant animals suppress WNK/SPAK/OSR1 signaling and NCC with HSD, whereas Dahl SS rats fail to appropriately suppress SPAK/OSR1 and NCC, promoting NaCl retention.	In vivo mechanistic animal evidence	Yes — strong/direct	(215, 216)
SPAK/OSR1–NKCC2	Isolated TALs from Dahl SS vs. Dahl SR rats	Normal/high salt; SSBP	Thick ascending limb	NKCC2 phosphorylation/transport studies; SPAK manipulation	Dahl SS rats exhibit enhanced NKCC2 activity and phosphorylation, with increased surface NKCC2 during HSD. Abnormal TAL NaCl reabsorption contributes to the renal defect underlying SSBP.	Cellular + ex vivo + animal evidence	Yes — moderate-to-strong/Direct	(217-219)
NO/eNOS/iNOS	Dahl SS vs. Dahl SR rats; high-salt studies	High Na+; salt-induced hypertension	Renal medulla; vascular endothelium	L-arginine supplementation; aminoguanidine/iNOS inhibition; NOS activity measurements	In Dahl SS rats, reduced renal medullary NO bioavailability impairs pressure-natriuresis and contributes to SSBP; complementary endothelial-cell studies show that elevated extracellular sodium can directly impair eNOS/NO signaling	In vivo + ex vivo mechanistic evidence	Yes — strong/direct for renal NO; indirect for endothelial-cell sodium effects	(105, 220-222)
Macrophage–dendritic cell–T-cell immune axis	Dahl SS, DOCA-salt and high-salt immune models	High salt; renal inflammation and SSBP	Kidney, APCs/DCs, macrophages, T cells	Immunosuppression; immune-cell depletion/adoptive transfer; ENaC/SGK1 manipulation	HSD promotes ENaC-dependent DC activation, IsoLG formation, T-cell activation, and renal inflammation	Mechanistic; genetic/cell-depletion; pharmacological; replicated	Moderate-to-strong, model-dependent	(143, 149, 151, 223)
NF-κB	Dahl SS and DOCA-salt hypertension models	High salt / mineralocorticoid-salt hypertension	Kidney, heart, vascular tissue, immune cells	NF-κB inhibition; antioxidant/HO-1 induction	High salt/mineralocorticoid hypertension increases NF-κB activation, promoting inflammatory gene expression. NF-κB inhibition or suppression reduces inflammatory injury and improves BP/end-organ damage in experimental hypertension. NF-κB also provides the priming signal for NLRP3 activation.	Mechanistic animal evidence; pathway-level evidence	Moderate / model-dependent	(142, 224)
NLRP3 inflammasome	DOCA-salt mice; NLRP3-deficient mice; SS human monocytes	High sodium / DOCA-salt SSBP	Dendritic cells/APCs, kidney, cardiovascular tissues	NLRP3 knockout; MCC950; ENaC inhibition; IsoLG scavenging; adoptive DC transfer	HSD activates ENaC-dependent ROS/IsoLG formation and NLRP3 inflammasome activation in APCs. NLRP3 deficiency blunts salt-induced hypertension, while pharmacological inhibition reduces BP, renal inflammation and fibrosis.	Genetic + pharmacological + mechanistic; human translational support	Yes — strong preclinical/direct experimental evidence; human causal evidence limited	(142, 143, 149)
JAK/STAT	Ang II hypertension; emerging high-salt/immune studies	Ang II hypertension; high-salt inflammatory setting	Kidney, vascular tissue, myeloid/APC compartment	JAK2 inhibitor AG-490; genetic myeloid JAK2 manipulation	Ang II activates renal JAK2/STAT3, with JAK2 inhibition reducing renal Na+ retention, GFR reduction and hypertension. More recent work links myeloid JAK2 to high-salt-induced inflammatory signaling, IsoLG and IL-6 production	Mechanistic; pharmacological; cell-specific genetic; emerging direct SSBP evidence	Limited-to-moderate / emerging	(225, 226)
HIF-1α–PHD2	Dahl SS rats	High salt; impaired renal medullary adaptation	Renal medulla	HIF-1α overexpression; CoCl2; PHD2 shRNA	HSD normally suppresses PHD2 and stabilizes HIF-1α, inducing protective genes such as HO-1 and COX-2. This response is blunted in Dahl SS rats. HIF-1α overexpression or PHD2 silencing restores pressure-natriuresis, increases Na+ excretion and attenuates SSBP	Genetic/interventional; mechanistic	Yes — moderate-to-strong, direct preclinical	(192, 195)
AP-1	DSS rats; DOCA-salt rats; human monocytes/PBMCs with SSBP phenotype	High-salt-induced SSBP; mineralocorticoid + high-salt hypertension	Renal glomeruli; renal/cardiovascular tissues; APCs (APCs)/monocytes	AT1 receptor blockade (TCV-116); HO-system induction (hemin/heme-arginate); assessment of AP-1 DNA-binding activity, c-Fos/c-Jun and FOS/JUN-family expression; high-salt exposure in APCs/monocytes	High-salt feeding in DSS rats increased glomerular AP-1 activity, while AT1 receptor blockade suppressed AP-1 activity despite limited BP effects, supporting an Ang II–AP-1 link in SS renal injury. In DOCA-salt hypertension, AP-1/c-Jun activation accompanied oxidative stress, inflammation, and fibrosis, whereas HO-system induction suppressed AP-1 and attenuated tissue injury	Experimental animal and emerging human immune-cell evidence; includes a classical DSS model of SSBP and mineralocorticoid-salt hypertension models	Limited/emerging; mainly associative/mechanistic AP-1 activation is demonstrated in SSBP-related models, but direct causal evidence from AP-1-specific inhibition or genetic manipulation remains limited	(224, 227, 228)

7. Human Evidence and Clinical Translation

Although human studies support the existence and clinical importance of salt sensitivity, the human evidence remains more limited and less mechanistically defined than the extensive evidence derived from animal models and cultured cells. In humans, salt sensitivity is typically assessed by comparing blood pressure during controlled periods of high- and low-sodium intake, although other approaches, including acute sodium loading followed by sodium depletion or diuretic-induced sodium depletion, have also been used. However, protocols vary considerably in terms of sodium dose, duration of dietary intervention, dietary composition, washout periods, blood-pressure measurement methods, and the criteria used to classify individuals as SS (5, 31, 229-231). Twenty-four-hour urinary sodium excretion provides an objective estimate of sodium intake and can help assess dietary adherence, but it should not be regarded as a direct measure of salt sensitivity. Salt sensitivity is defined by the blood-pressure response to a change in sodium intake rather than by sodium excretion alone (231, 232). In addition, classification of the SS phenotype may vary between testing protocols, with some studies reporting only moderate reproducibility of 53-60% over a 6-month interval (233).

Differences in blood-pressure assessment add another layer of variability. Casual or single office measurements are susceptible to measurement error and white-coat effects, whereas ambulatory blood-pressure monitoring (ABPM) provides repeated measurements throughout the 24-h period and allows both daytime and nighttime responses to dietary sodium to be evaluated (231, 234). Indeed, ABPM has been used to characterize salt sensitivity in hypertensive individuals by assessing changes in 24-h, awake, and asleep blood pressure during low- and high-sodium intake (234). Dietary intake of other electrolytes may also influence the observed response to sodium. Potassium can modify renal and vascular responses to sodium and therefore contributes to the relationship between dietary electrolyte balance and SSBP (5, 235). Chloride may also have effects that are not simply attributable to sodium, as intracellular chloride regulates WNK kinase activity and thereby influences the WNK-SPAK/OSR1-NCC pathway involved in renal electrolyte transport and blood-pressure regulation (236, 237). Antihypertensive medications represent another potential source of variation because they can alter renal sodium handling, RAAS activity, vascular tone, and other pathways involved in sodium-dependent blood-pressure regulation. Nevertheless, a recent crossover trial showed that reducing dietary sodium lowered 24-h ambulatory blood pressure in individuals both receiving and not receiving antihypertensive therapy, indicating that pharmacological treatment does not necessarily eliminate the blood-pressure response to dietary sodium (238).

Several clinical characteristics can further influence salt sensitivity. The prevalence of salt sensitivity increases with age and is higher in individuals with conditions such as CKD, hypertension, diabetes, and metabolic dysfunction (5, 31). Obesity and metabolic abnormalities may also affect renal sodium handling, sympathetic activity, oxidative stress, and vascular responses to sodium loading (5). Sex is another important factor, with women generally showing greater salt sensitivity than men in several human studies, although the magnitude of this difference varies among populations and experimental protocols (5, 31). Changes in sex-hormone signaling after menopause may further influence the pressure-natriuresis relationship and contribute to altered sodium sensitivity in some postmenopausal women (239). These sources of heterogeneity are important to consider when translating mechanistic findings from highly controlled experimental models to the more diverse human population.

Recent translational studies examining myeloid ENaC signaling and IsoLG formation provide an important link between experimental immune mechanisms and SSBP in humans. Preclinical studies indicate that increased sodium entry into APCs through ENaC can promote oxidative stress and IsoLG formation, leading to IsoLG-protein adduct formation, activation of APCs, and subsequent adaptive immune responses (151). Importantly, a recent mechanistic clinical study involving 19 hypertensive individuals found that IsoLG-positive APCs were associated with the salt-sensitivity index and that IsoLG accumulation in these cells changed in response to salt loading and depletion specifically in SS individuals. The investigators also detected expression of the ENaC δ-subunit and SGK1 in human APCs and identified an association between renal 14,15-epoxyeicosatrienoic acid (14,15-EET) and the IsoLG response to dietary sodium (240). Together, these findings provide important human evidence linking myeloid ENaC/IsoLG signaling to the blood-pressure response to dietary sodium in human SSBP. Nevertheless, the available human evidence remains limited and primarily mechanistic. Thus, although these findings support the translational relevance of the pathway, they do not yet establish a causal role for myeloid ENaC/IsoLG signaling in human SSBP or demonstrate that its magnitude and downstream effects are identical to those observed in experimental models (240).

8. AP-1 as an Emerging Therapeutic Candidate in SSBP

AP-1 comprises a family of transcription factor complexes formed primarily by members of the Fos (c-Fos, Fra-1, Fra-2, and FosB) and Jun (c-Jun, JunB, and JunD) protein families. As a redox-sensitive transcription factor complex, AP-1 binds to DNA and regulates the expression of genes involved in inflammation, cell migration, differentiation, adhesion, cytokine production, and extracellular matrix remodeling (227). Evidence from multiple inflammatory and autoimmune settings provides additional mechanistic insight into the broader role of AP-1 in regulating vascular and immune responses (241, 242). For example, AP-1 contributes to the polarization and functional differentiation of T cells and promotes the expression of inflammatory cytokines (241). Multiple studies further indicate cooperative crosstalk between NF-κB and AP-1 signaling pathways, which may amplify downstream gene expression. Fujioka et al. demonstrated that NF-κB regulates the expression of Elk-1 (ETS-like protein 1), a transcription factor involved in c-Fos induction. Inhibition of NF-κB activity reduced Elk-1 and c-Fos expression and consequently attenuated AP-1 activation and the expression of downstream target genes (243). In parallel, the NF-κB p65 subunit can interact with AP-1 components, including c-Fos and c-Jun, thereby enhancing the transcriptional activity of both NF-κB- and AP-1-responsive genes and establishing a cooperative regulatory network that may sustain inflammatory gene expression (244). Although NF-κB is a major regulator of inflammasome priming, AP-1 can also cooperate in the transcriptional regulation of pro-inflammatory genes, including pro-interleukin-1β, and may facilitate inflammasome activation (245). Moreover, oxidative stress has been shown to activate AP-1 and reduce endothelial PPARγ expression, suggesting a potential link between redox-sensitive AP-1 signaling and endothelial dysfunction. Curcumin, which has been reported to suppress AP-1 signaling, also blocked the downregulation of PPARγ induced by oxidative stress and reduced the inflammation of in vitro human umbilical vein endothelial cells (HUVECs) (246). However, because these findings were obtained in an in vitro endothelial model, they demonstrate a direct cellular response to oxidative stress rather than establishing AP-1 as a mediator of SSBP.

Furthermore, AP-1 has also been associated with autoinflammatory disorders, such as psoriasis and rheumatoid arthritis (247, 248). Hannemann et al. (2017), for instance, identified c-Jun as a regulator of macrophage behavior in rheumatoid arthritis, showing that c-Jun increased cyclooxygenase-2 expression while suppressing arginase-1, an enzyme associated with limiting inflammatory activation (242). In addition, genetic and pharmacological studies provide compelling evidence for the central role of AP-1 in regulating inflammatory responses. Loss of Jun/AP-1 expression reduces cytokine production, while selective inhibition of c-Fos/AP-1 with T-5224 suppresses pro-inflammatory cytokines and matrix-degrading enzymes, thereby protecting against tissue injury in multiple preclinical models, including acute kidney injury, osteoarthritis, and intervertebral disc degeneration (249-252). These studies collectively establish the broader inflammatory and tissue-injury functions of AP-1 but should be regarded as mechanistic context rather than direct evidence for its role in SSBP. Importantly, high-salt exposure promotes a proinflammatory phenotype in mouse bone-marrow-derived macrophages and human monocyte-derived macrophages by increasing the expression of proinflammatory molecules while suppressing anti-inflammatory and pro-endocytic responses. Mechanistically, this effect involves activation of the p38/c-Fos/AP-1 and ERK1/2/c-Fos pathways and inhibition of the ERK1/2/STAT6 pathway (130). Consistent with these findings, c-Fos mRNA expression and AP-1 activity are increased in the glomeruli of SS rats following HSD and are associated with MAPK activation (227). In support of this, Pitzer et al. (2022) reported dynamic changes in Fos and Jun expression in response to alterations in dietary sodium in SS models (143). Thus, evidence from unrelated inflammatory disorders is used here to establish the biological plausibility of AP-1 as a regulator of oxidative, inflammatory, and fibrotic signaling, while its proposed role as a therapeutic target in SSBP is based primarily on evidence obtained from SSBP and related experimental models. Recently, Ahmad et al. (2026) demonstrated that high-salt exposure activates AP-1 signaling in myeloid APCs, with increased expression of FOS/JUN family members associated with SSBP responses in human and mouse models (253). These findings further support AP-1 as a potential regulator of SSBP, while highlighting the need to delineate the specific AP-1 complexes and cellular compartments mediating these effects.

Although AP-1 represents an attractive therapeutic candidate because of its important role in inflammatory signaling, several challenges remain (254, 255). AP-1 is composed of multiple Fos- and Jun-family proteins that form distinct homo- and heterodimers with cell- and context-specific functions (254, 256). Consequently, indiscriminate inhibition of activator protein-1 (AP-1) may suppress not only pathological inflammatory signaling but also physiological processes involved in tissue homeostasis, cellular differentiation, tissue repair, and cardiovascular and renal function. These diverse functions highlight the need for tissue-specific and context-dependent therapeutic strategies (251, 257). However, selective pharmacological inhibition of AP-1 has shown therapeutic benefit in preclinical cardiovascular disease models (258). Although these studies were not performed in SSBP models, they demonstrate conserved AP-1-dependent inflammatory mechanisms that may also be relevant to SSBP. Moreover, the specific AP-1 dimers responsible for disease progression remain incompletely characterized. Cell-specific genetic approaches targeting individual AP-1 components in renal tubular, endothelial, vascular smooth muscle, macrophage, dendritic, and T cells will be particularly important for determining whether AP-1 activation in specific cellular compartments is necessary for SSBP. These considerations suggest that future therapeutic strategies should focus on identifying pathogenic AP-1 complexes, defining their cell-specific functions in SSBP, and developing selective approaches that preserve adaptive AP-1 signaling while inhibiting disease-promoting pathways. Hence, additional mechanistic and translational studies are required before AP-1 can be considered a clinically viable therapeutic target.

9. Conclusion and Future Directions

SSBP is a complex disorder involving coordinated dysfunction of the kidneys, blood vessels, and immune system in response to high-salt intake. Beyond plasma volume expansion, excess sodium can impair endothelial function, NO bioavailability, ROS regulation, renal mitochondrial activity, and immune homeostasis. Interactions between dietary sodium and immune responses contribute to tissue injury and sustain elevated blood pressure. A more complete understanding of the molecular communication among these systems is therefore essential for developing targeted therapeutic strategies. AP-1 integrates several redox-sensitive and inflammatory pathways implicated in salt-induced renal, vascular, and immune dysfunction. Recent evidence, including our findings, supports a role for AP-1 signaling in SSBP; however, AP-1 is not yet a fully validated therapeutic target. Several limitations should be considered when interpreting the current evidence. Much of the available evidence derives from animal and in vitro studies, with limited human validation due to heterogeneous definitions of salt sensitivity, short-term dietary interventions, medication and comorbidity-related confounding, and variability in blood-pressure and sodium measurements. Therefore, mechanisms established in experimental models should not automatically be considered clinically validated in human SSBP. Future studies should use cell-specific genetic approaches, selective pharmacological interventions, rigorous blood-pressure phenotyping, and well-characterized human salt-sensitive populations to establish the causal contribution and therapeutic potential of AP-1. Further work should also identify disease-promoting AP-1 complexes, determine the safety and specificity of selective inhibition, and assess whether AP-1 modulation improves sodium handling and blood pressure without disrupting physiological adaptive responses. These studies will determine whether AP-1 can progress from an emerging mechanistic target to a clinically actionable therapeutic strategy in SSBP.

Abbreviation

ACE

Angiotensin-converting enzyme

Ang II

Angiotensin II

AP-1

Activator protein-1

AT1R

Angiotensin II type 1 receptor

BP

Blood pressure

CCR2

C-C chemokine receptor 2

CKD

Chronic kidney disease

DAMPs

Damage-associated molecular patterns

DCs

Dendritic cells

DCT

Distal convoluted tubule

DOCA

Deoxycorticosterone acetate

ENaC

Epithelial sodium channel

eNOS

Endothelial NO synthase

ERK1/2

Extracellular signal-regulated kinase 1/2

FGF

Fibroblast growth factor

FoxO

Forkhead box O

FoxO1

Forkhead box O1

FoxO3

Forkhead box O3

FoxP3

Forkhead box P3

HIF-1α

Hypoxia-inducible factor-1α

HIF

Hypoxia-inducible factor

HSD

High-sodium diet

ICAM-1

Intercellular adhesion molecule-1

ICAM-2

Intercellular adhesion molecule-2

IFN-γ

Interferon-γ

IgG

Immunoglobulin G

IL-1β

Interleukin-1β

IL-6

Interleukin-6

IL-10

Interleukin-10

IL-17A

Interleukin-17A

IL-18

Interleukin-18

IL-23

Interleukin-23

IL-33

Interleukin-33

IsoLG

Isolevuglandin

JAK

Janus kinase

L-NAME

Nω-nitro-L-arginine methyl ester

MAPK

Mitogen-activated protein kinase

MCP-1

Monocyte chemoattractant protein-1

MR

Mineralocorticoid receptor

Na⁺

Sodium ion

NCC

Sodium-chloride cotransporter

NCX

Sodium-calcium exchanger

NFAT5

Nuclear factor of activated T cells 5

NF-κB

Nuclear factor κB

NHE3

Sodium-hydrogen exchanger 3

NKCC1

Sodium-potassium-chloride cotransporter 1

NKCC2

Sodium-potassium-chloride cotransporter 2

NLRP3

NLR family pyrin domain-containing 3

NLRC4

NLR family CARD domain-containing 4

NO

NO

NOS

NO synthase

OSR1

Oxidative stress-responsive 1

PAI-1

Plasminogen activator inhibitor-1

PHD2

Prolyl hydroxylase domain protein 2

PKC

Protein kinase C

PPARγ

Peroxisome proliferator-activated receptor-γ

RAAS

Renin-angiotensin-aldosterone system

ROS

Reactive oxygen species

SGK

Serum/glucocorticoid-regulated kinase

SGK1

Serum/glucocorticoid-regulated kinase 1

SPAK

STE20/SPS1-related proline-alanine-rich kinase

SSBP

Salt sensitivity of blood pressure

STAT3

Signal transducer and activator of transcription 3

TGF-β

Transforming growth factor-β

Th1

T helper 1

Th17

T helper 17

TNF-α

Tumor necrosis factor-α

Treg

Regulatory T cell

VCAM-1

Vascular cell adhesion molecule-1

WAP

Whey acidic protein

WNK

With-no-lysine kinase

Data Availability

No datasets were generated or analyzed during the current study.