The immune-microbiome axis in salt-sensitive hypertension: a focus on renal and neural mechanisms

Systemic arterial hypertension (SAH), characterized by a persistent elevation in blood pressure (BP), is a clinical condition that transcends the human species, affecting various mammalian species. Hypertension is the single largest risk factor for numerous diseases, including ischemic brain infarction, intracranial hemorrhage, myocardial infarction, renal diseases, and congestive heart failure (APA, 2020; WHO, 2012; Frame and Wainford, 2017). It has been widely documented that intrinsic factors like genetic background, sex and age (Nist et al., 2024; Kim et al., 2024; Demirci et al., 2025) as well as extrinsic factor like smoking (Groppelli et al., 1992), alcohol (Lima et al., 1999), sedentarism (Alvarez et al., 1999), and eating habits (Yamamoto-Kimura et al., 1996) are associated with the development of SAH. Among eating habits, salt intake plays a key role in the development of SAH (Grillo et al., 2019) and will be further discussed here.

High salt intake can fulfill physiological and homeostatic functions, particularly when the individual sodium balance is low and body sodium content must be replenished. Under this condition, the high salt intake is driven by an increase in sodium appetite, which results in a behavioral state in which the individual seeks and consumes higher than normal salt amounts, also called need-induced sodium appetite (Geerling and Loewy, 2008). Curiously, mammals also exhibit high sodium intake behavior which is not driven by physiological needs for body sodium replenishment but for what is understood as a hedonic stimulus termed need-free sodium appetite (Geerling and Loewy, 2008). For the purpose of this review, we will focus on the need-free sodium intake and its impact on the BP regulation and contributions to hypertension.

High salt intake has long been associated with "stiffen and harden pulse", a condition first described by Chinese physician Huang Di´s Neijing Swen, about 2500 BCE (Bailey and Dhaun, 2024; Ha, 2014). However, it was only in the beginning of the 20th century that the association between high salt intake and hypertension was established by Ambard and Beaujard using modern scientific methodology and standards (Ambard and Beaujard, 1904). Since then, several experimental and trial studies have supported these observations and provided evidence for the impact that high salt intake has on the pathophysiology of hypertension. In the 1940´s and 1950´s, studies by Kempner showed that the BP in 2 of the 6 patients under a strict rice fruit diet declined to normal levels and rose again after 20 g of sodium chloride was added daily (Grollman et al., 1945). In essence, this observation gave birth to the idea that would be later elaborated into the concept of the salt-sensitivity of BP (SSBP). The SSBP can be currently defined as a trait where the individual BP (animal or human) displays a change parallel to the changes in salt intake (Eli et al., 2016; Weinberger, 1996a; Weinberger, 1996b; Weinberger, 2006). The SSBP is a trait normally distributed in humans and is present in both the normotensive and hypertensive individuals. An important and influential American study showed that after salt depletion and following sodium load, 26% of the normotensive patients were ascribed as salt sensitive while 51% of the hypertensive patients were salt sensitive (Weinberger et al., 1986). Despite limitations (Bailey and Dhaun, 2024) this study established that hypertensive patients have higher probability of displaying a SSBP phenotype and launched the basis for the understanding that salt sensitivity is an important cardiovascular risk factor "independent of and as powerful as BP" by itself (Bailey and Dhaun, 2024; Eli et al., 2016).

Over the last 100 years scientific investigations have repeatedly demonstrated that renal pressure-natriuresis, hormonal hydroelectrolytic balance and neural sympathetic mediated events are key to the SSBP (Bie and Evans, 2017a; Bie and Evans, 2017b). These studies have revealed intricate interactions among different systems to sustain high BP and other detrimental outcomes of high salt intake. Of particular interest in this context is a growing body of evidence that has linked the immune cellular and signaling mechanisms not only to hypertension but also to the SSBP (Bailey and Dhaun, 2024; Mattson, 2014; Mattson, 2019; Rucker et al., 2018; Maaliki et al., 2022) and experimental and clinical studies led to the idea that hypertension may be an "inflammatory" disease (Boos and Lip, 2006; Solak et al., 2016). Although the immune events that take place along hypertension development and maintenance hold some characteristics of an "inflammatory state" such as heightened immune-related signaling molecules in end-organs linked to BP control and hypertension, it is crucial to acknowledge that this concept may deviate from the conventional definition of inflammation. Classically, inflammation is defined as a protective process by which the body's immune system responds to injury, infection, or harmful stimuli. The four typical signs of acute inflammation were first described by Celsus in ancient Rome (30–38 B.C.) (Chandrasoma and Taylor, 1998) and are defined as: Rubor (redness), Calor (heat), Tumor (swelling) and Dolor (pain). Those signs are not always present in end-organs associated with the development of hypertension and make one wonder whether "inflammation" truthy describes the role of the immune system in the development of hypertension. However, some authors have elaborated a new concept to describe a chronic, subclinical, sterile and systemic condition characterized by a persistent, mild elevation of inflammatory markers in the body (Minihane et al., 2015; Ronnback and Hansson, 2019; van de Vyver, 2023) that would better represent the role of the immune system in hypertension. This concept is termed "low-grade inflammation" (LGI) or "metabolic inflammation" or "metainflammation" (van de Vyver, 2023) and has been implicated in the pathogenesis of many non-communicable chronic diseases, including salt-sensitive hypertension (SSH) (Boos and Lip, 2006; Al-Nimer and Alhusseiny, 2016).

Based on the currently available experimental evidence, this review will explore some aspects of the intricate interplay between the immune system and its pro-inflammatory signaling molecules (PIM), the central nervous system (CNS) and the renal system in SSH.

The role of the immune system in BP regulation and hypertension development became evident with pharmacological studies in rodents showing that, under certain conditions, the inhibition or lacking of cyclooxygenase-1, a key enzyme in the prostanoids synthesis pathway, can lower the BP of Ang II-salt hypertensive rats (Asirvatham-Jeyaraj et al., 2013; Athirakul et al., 2001). In addition, a 2007 study by Guzik and cols. Showed that activation of immune cells contributed to the hypertension induced by angiotensin II (Ang II) infusion and deoxycorticosterone acetate (DOCA) plus high-salt diet in Rag1^−/− mutant mouse (Guzik et al., 2007). This particular study showed that the knockout mice for Rag1 lack mature T cells and B cells, which protected them from vascular dysfunction and remodeling in addition to reducing the hypertensive responses to Ang II and DOCA-salt (Guzik et al., 2007). Clinical studies also showed that patients with hypertension had a higher proportion of immunosenescent, proinflammatory, and cytotoxic CD8⁺ T cells in their blood. Furthermore, immunohistochemical assessment of renal biopsy specimens from patients with hypertensive nephrosclerosis revealed increased expression of the T-cell chemokine interferon (IFN)-inducible T-cell α chemoattractant in the proximal and distal tubules suggesting that T-cell-driven inflammation may also play a role in human hypertension, especially in the kidney (Youn et al., 2013).

One of the most important risk factors for hypertension, high salt intake, is found to alter the activation of inflammatory cells in both the innate and adaptive immune system (Afsar et al., 2018; Miyauchi et al., 2024; Li et al., 2022). Murine macrophages and T cells exposed to high salt have been found to express a pro-inflammatory state both, in vitro and in vivo (Binger et al., 2015; Jantsch et al., 2015; Kleinewietfeld et al., 2013; Wu et al., 2013; Zhang WC. et al., 2015). Additionally, a modest increase in extracellular salt concentration induces the serum glucocorticoid kinase 1 (SGK1) expression, a serine/threonine kinase 4 that promotes IL-23R expression by deactivating the transcription factor Forkhead box protein O1 (FOXO1) in mice. FOXO1 is a direct repressor of IL-23R expression and enhances the IL-17-producing T helper lymphocyte cells (T_H17) differentiation in vitro and in vivo through IL-23 mechanisms (Wu et al., 2013). The T_H17 polarization of naïve immune cells has been reported in both humans and mice (Miyauchi et al., 2024; Kleinewietfeld et al., 2013; Jorg et al., 2016; Wilck et al., 2017; Yakoub et al., 2024). Also, high salt concentrations in the medium can increase the production of PIM like TNF-α, IL-2 and granulocyte-macrophage colony-stimulating factor by cultured T_H17 cells (Kleinewietfeld et al., 2013). Moreover, the SGK1 activation has also been shown to stimulate the mineralocorticoid-mediated expression of epithelial sodium channels (ENaC) in the kidneys of mice (Wulff et al., 2002) what indicates that the SGK1 pathway is shared by inflammatory and sodium homeostasis mechanisms.

High salt also impacts macrophage core functions both in vitro and in vivo, especially because macrophages exhibit chemotactic migration in response to salt gradients in vitro (Muller et al., 2024). The incubation of bone marrow-derived macrophages with high concentrations of sodium chloride (NaCl) elicited a strong pro-inflammatory phenotype characterized by enhanced pro-inflammatory cytokines (PIC) production, increased expression of immune-stimulatory molecules, and an antigen-independent boost of T cell proliferation through pathways that may involve the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the mitogen-activated protein kinase (MAPK) signaling (Hucke et al., 2016). Additional evidence shows a direct action of NaCl in inducing pro-inflammatory phenotypes. Zhang and cols. Showed that a roughly 33% increase in medium NaCl concentration significantly induced interleukin 6 (IL-6) and MCP-1 (or CCL2) production by retinal pigment epithelium (ARPE-19) cells in culture (Zhang D. et al., 2015). This effect was not mediated by osmolarity, as an equivalent osmotic mannitol addition to the medium had no effect on IL-6 or MCP-1 production (Zhang D. et al., 2015). In addition to the NF-κB and MAPK pathways, evidence from humans and experimental animal studies have shown that myeloid-specific janus kinase 2 (JAK2) also contributes to LGI and SSH. The JAK2 signaling pathway plays crucial roles in many cellular processes and physiological functions such as cell growth and survival, hematopoiesis, immune regulation, inflammation, metabolism and gene transcription (Bader and Meyer, 2022). High salt upregulated gene expression of the JAK/STAT/SMAD pathway in human monocytes and the ablation of JAK2 signaling attenuated the SSH hypertension in mice (Saleem et al., 2024). The authors also found that JAK2 increased production of highly reactive isolevuglandins (IsoLG) and IL-6 by renal antigen presenting cells (APC). In addition, JAK2 also activates T cells and increases production of IL-6, interleukin 17A (IL-17A), and tumor necrosis factor-alpha (TNF-α) in mice (Saleem et al., 2024).

Although the evidence suggests that sodium can drive inflammation-related signaling pathways in immune cells, increased salt intake actually produces very small Cohen effect size in steady-state plasma sodium concentrations of certain models of SSH, such as the Dahl-salt-sensitive model (DSS) (Stocker, 2023; Nakamura and Cowley, 1989) or the HS12W model (Gomes et al., 2017). This poses some limitation to the general idea that high salt intake can affect immune cell physiology. It also may suggest that the activation of the immune system by high salt intake may include an indirect result of increased sodium "traffic" throughout the body. Indeed, assessment of serum sodium concentrations in humans showed only a modest (∼1.4%) increase in systemic serum sodium concentration after a high salt meal, lasting at least 2 h, and without changes in hormones involved with body fluid homeostasis or endothelial function, such as endothelin-1 (ET-1), vasopressin (AVP), and atrial natriuretic peptide (ANP) (Dickinson et al., 2014). One important question here yet to be answered is whether this transient increase in sodium concentration of the extracellular fluid could be enough to unleash important changes in immune cells phenotype toward a pro-inflammatory state and contribute to the LGI over time? Since sodium absorption by the intestine doesn´t distribute throughout body volume at once, the great gradient of sodium through the intestine wall could make these local immune cells more susceptible to sodium-driven changes in phenotype and cytokines profile production as described in in vitro studies. On the other hand, recent evidence has shown that high salt intake can result in non-osmotic sodium accumulation in the skin (Titze et al., 2003) and muscle tissue (Rossitto et al., 2020) pointing toward the possibility that immune cells in these regions could also be impacted by high sodium gradients and contribute to systemic LGI.

In addition to salt-induced immune cell differentiation and activation, sodium can enter into dendritic cells (DC) via the amiloride-sensitive epithelial sodium channel (ENaC) and activate the production of the PIM IL-1β and promote T cell production of IL-17A and IFN-γ (Barbaro et al., 2017). It has been proposed that higher sodium influx through ENaC in DC increases sodium/calcium exchange, thus activating phosphokinase C (PKC) and NADPH-oxidase (Barbaro et al., 2017). The increased reactive oxygen species production drives the production of IsoLG and the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome that activates caspase-1 and increases the production of IL-1β by the DC (Pitzer et al., 2022). Interesting, when such activated DC are adoptively transferred into naïve mice, they prime hypertension in response to a sub-pressor dose of Ang II (Barbaro et al., 2017). These experimental findings are further supported by a study showing that amiloride exerts anti-inflammatory effects by decreasing the PMI TNF and IL-6 plasma levels, but not IL-17A levels, in patients with resistant hypertension and type 2 diabetes (Thangaraj et al., 2024).

From a vascular perspective, transient high salt intake promotes T-cell-mediated hypertensive vascular injury in a mice model of high-salt intake drinking 1% NaCl solution (Yakoub et al., 2024). The authors showed that in transient high salt-treated hypertensive mice, the aortic injury was associated with increased inflammation, accumulation of neutrophils, monocytes, CD69⁺CD4⁺ T cells, as well as CD4⁺ and CD8⁺ memory T cells. Moreover, high salt intake sensitized the animals for angiotensin II-induced vascular lesions by increasing the expression of aortic RORγt as well as splenic CD4⁺T_H17 and CD8⁺TC1 T cells in Ang II-treated mice (Yakoub et al., 2024). The authors suggested that transient high salt intake induces a subclinical T-cell-mediated aortic immune response, which is enhanced by Ang II and contributes to the vascular lesion in these animals.

Collectively, these data strongly indicate that sodium can deeply affect the physiology of immune cells toward a LGI state, which strongly correlates with SSH. Certain pieces of evidence suggest that sodium-induced modifications of immune cells physiology have a causal relationship with hypertension and further studies are needed to fully understand the role of the immune signaling system in the pathophysiology of hypertension.

The central nervous system (CNS) plays a pivotal role in the BP regulation, both in normotension and hypertension (Guyenet, 2006) and this concept has been grounded on several findings in the literature showing that neurogenic mechanisms are important for heightened BP and, especially, for SSH (Eli et al., 2016; Maaliki et al., 2022; Adams et al., 2008). The major findings in this section are summarized in Table 1.

The reflex control of BP regulation has been widely recognized for its ability to short-term buffer large BP fluctuations and prevent potentially harmful sudden increases or decreases in systemic BP (Guyenet, 2006; Wehrwein and Joyner, 2013). In SSH, salt-dependent increases in BP are usually accompanied by reduced baroreflex sensitivity (Ozaykan et al., 2017; Rosa et al., 2020; Wang et al., 2005). In addition to salt-related baroreflex impairments, excessive salt intake also leads to impairment in the reflex response to cardiopulmonary reflex activation. These reflexes are volume/chemical sensing mechanisms that regulate sympathetic and parasympathetic outflow to the cardiovascular system in response to volume expansion and/or chemical activation with metabolic byproducts and neurochemicals (Vasquez et al., 1997; Vasquez, 1994). In Dahl salt rats, a high salt diet sensitized the cardiopulmonary reflex-driven sympathetic response to hypervolemia in Dahl salt resistant rats but not in Dahl salt sensitive rats (Victor et al., 1986). Interestingly, Dahl salt sensitive rats had a smaller sympathetic inhibition response when challenged with volume expansion compared to Dahl salt resistant rats, even under low-salt diet (Ferrari A. et al., 1984; Ferrari AU. et al., 1984). These findings suggest that the salt-sensitivity trait by itself includes a reduced sensitivity of the cardiopulmonary reflex in Dahl salt sensitive rats regardless of high salt intake. Since these studies were conducted in urethane-anesthetized rats, the full understanding of the cardiopulmonary reflex role in SSH regulation remains limited. However, it provides important evidence of changes in short-term BP regulation due to the salt-sensitive trait. The plasticity of the cardiopulmonary reflex has also been investigated in hypertensive humans and, consistent with experimental findings, the results revealed that high salt intake potentiates the cardiopulmonary reflex gain and atrial natriuretic factor response only in salt resistant hypertensive patients (Trimarco et al., 1991). Interestingly, the reflex response to carotid baroreceptor unloading was unaffected by salt loading in none of the groups (Trimarco et al., 1991) suggesting that cardiopulmonary reflexes are more sensitive than baroreflex to high salt intake in salt resistant hypertensive patients.

The paraventricular nucleus of the hypothalamus (PVN) is a hypothalamic nucleus that orchestrates neural and hormonal responses to changes in blood sodium concentration, osmolality and BP through two distinct cell subtypes: the parvocellular neurons, which comprise autonomic regulatory neurons (Ferguson et al., 2008; Osborn et al., 2007), and the magnocellular neurons, which include oxytocin and vasopressin producing/containing neurons (Antunes-Rodrigues et al., 2004). Therefore, the PVN is a key forebrain region that plays important roles in neurogenic hypertension (Osborn et al., 2007). While the majority of descending sympathetic-related projections originating from PVN parvocellular neurons connect to the rostral ventral lateral medulla (RVLM) in the brainstem or to the intermedial lateral column in the spinal cord (Guyenet, 2006; Dampney et al., 2018), the majority of the projections from magnocellular PVN neurons project to the neurohypophysis and release vasopressin and oxytocin to the pituitary portal system when activated (Antunes-Rodrigues et al., 2004). The outcome is a multifaceted role of the PVN in regulating BP levels and sodium excretion by the kidney which contributes to the pathophysiology of SSH.

The immune signaling mechanisms in hypothalamic and brainstem regions controlling BP have received considerable attention in the recent years and the evidence gathered so far point toward important immune influence on the functional role of these regions in the SSH. The blockade of microglia activation with minocycline, a selective CNS-acting non-steroidal anti-inflammatory drug, in Dahl salt-sensitive rats can inhibit the augmented local production of IL-1β, IL-6, TNF-α and the oxidative stress in the PVN. Likewise, minocycline infusion in the PVN also attenuated the high BP, the ratio between resting RSNA/MaxRSNA, central prostaglandin E₂ and plasm norepinephrine levels (Yu et al., 2022). The infusion of the IL-1β receptor inhibitor gevokizumab into the PVN of Dahl salt-sensitive rats also attenuated the BP, heart rate, and plasma norepinephrine levels (Qi et al., 2016) suggesting that this specific cytokine plays a role in the PVN-driven neurogenic pressor response. The authors also reported increased levels of NOX-2, NOX-4, IL-1β, NLRP3, Fra-LI and lower levels of IL-10 in Dahl salt-sensitive rats fed high salt diet and that gevokizumab restored the balance in the PVN (Qi et al., 2016). In addition, Jiang and cols. (2018) reported that Dahl salt-sensitive rats under high salt diet exhibited higher expression of PIC like TNF-α, IL-6, IL-1β and Fra1in the PVN and that intracerebroventricular infusion of highs sodium solution produced a marked increase in the expression of TNF-α, IL-6, IL-1β in Sprague-Dawley rats (Jiang et al., 2018). These studies highlight the role of high sodium concentrations in the PVN and its correlation to increased PIC production as well as the effect of the local anti-inflammatory agent minocycline or the IL-1β receptor inhibitor gevokizumab on SSH.

Although extensive research has advanced our understanding of immune signaling in the PVN regarding SSH, the role of immune signaling in the brainstem and its relationship to SSH is less advanced. It is known, however, that physiological reflex activation of the sympathetic circuit by bilateral carotid occlusion decreases the plasma levels of TNF and IL-1β, and increased the levels of IL-10 in endotoxemia induced by lipopolysaccharide in rats (Brognara et al., 2021a). Likewise, the activation of the Bezold-Jarisch reflex (the chemosensitive cardiopulmonary reflex) in endotoxemic rats reduced plasma levels of TNF and spleen levels of IL-6 (Brognara et al., 2021b). Although this evidence suggests that the autonomic activation of descending vagal pathways may influence peripheral PIM production, it does not provide further insights on how PIM can influence reflex regulation of the BP in the brainstem. On the other hand, toll-like receptor 4 and angiotensin II receptor 1 inhibition reduces BP as well as IL-6 and TNF-α protein density in the RVLM and nucleus tractus solitarius (NTS) of spontaneous hypertensive rats corroborating the idea that immune signaling in neuronal circuitries controlling BP is important for the hypertension development (Mowry et al., 2021).

Sodium balance is tightly regulated by kidneys under a wide range of sodium intake (Bagordo et al., 2024). Although recent evidence indicates that both human and rodents display nonosmolar sodium retention in skin and skeletal muscle under high salt intake (Thowsen et al., 2022; Titze, 2014), the kidneys still have a dominant role in the sodium handling by the body. The traditional view that high salt intake can lead to hypertension because of increased water intake followed by plasma volume expansion, increased cardiac output and autoregulatory vasoconstriction has been challenged by current evidence showing that plasma volume does not increase under high salt intake that mimics the human setting in a rodent model of SSH (Gomes et al., 2017; de Souza et al., 2021). The results of these studies suggest that hypertension is initially driven by neurogenic mechanisms with renal histological and functional disfunctions after the establishment of the hypertension (de Souza et al., 2021).

The accumulation of sodium in tissues has been demonstrated to contribute to systemic LGI (Sahinoz et al., 2021) which can impact renal functions through a variety of mechanisms (Frame and Wainford, 2017). For instance, the infiltration of immune cells in the kidneys has been shown to play an important role in the renal mechanisms that contribute to SSH in experimental models (Mattson, 2014). The genetic deletion of the recombination-activating gen 1 (Rag1) in Dahl-salt sensitive rats resulted in a significant reduction in T and B cells in the blood and spleen under normal salt diet (Mattson et al., 2013). Also, the exposure of these animals to high salt diet produced a blunted infiltration of T cells into the kidney that is typically found in wild type Dahl salt sensitive rats following high salt intake (Mattson et al., 2013). The reduction of T cells infiltration into the kidneys of Rag1-null Dahl salt sensitive rats was accompanied by a significant reduction in the SSH of these animals (Mattson et al., 2013). Furthermore, the infiltration of immune cells into the kidneys of Wistar rats under high salt diet following l-NAME administration was described as responsible for the impaired pressure natriuresis that contributes to SSH (Franco et al., 2013). The progression of renal injury in obese Dahl salt sensitive leptin mutant rats was associated with increased expression of the macrophage inflammatory protein 3-α (MIP3α) and, consequently, increased immune cell recruitment and infiltration in the renal tissue, thus producing renal low-grade inflammation (Ekperikpe et al., 2023). Interestingly, high salt, but not high BP, induces immune cell activation, renal infiltration, high expression of Na⁺/K⁺-ATPase and SSH in ovariectomized rats (Vlachovsky et al., 2024) showing that high salt intake has a more prominent effect on immune kidney system than high BP alone.

As immune cells infiltrate the kidneys, PIM drive important changes in the expression and activity of sodium channels in the nephron affecting sodium handling by kidney. This was be demonstrated in an AngII-driven hypertension mouse model in which i) RAS-mediated hypertension was accompanied by elevated levels of the macrophage cytokine IL-1 in the kidney (Crowley et al., 2010) and ii) the IL-1R deficiency or blockade limits BP elevation in this model by mitigating sodium reabsorption via the NKCC2 co-transporter in the nephron through a mechanism dependent on nitric oxide production by intra-renal macrophages (Zhang et al., 2016). The authors also showed that sodium balance in the IL-1R knockout mice became negative under Ang-II infusion while sodium balance in wild type mice increased, and that pre-treatment with furosemide abrogated the difference. Given that sodium balance is a reliable indicator of natriuresis relative to sodium intake, the findings indicate that IL-1R may contribute to the Ang-II-induced sodium retention, as proposed by the authors (Crowley et al., 2010). However, plasma sodium concentrations were not addressed in this work, leaving questions on whether IL-1 cytokine is actually influencing extracellular fluid concentration of sodium and/or affecting sodium retention in the skin and muscle (Titze, 2014), extra or intracellularly (Thowsen et al., 2022) following high sodium intake. Further evidence indicates that IL-1β plays a direct role in SSH and this is supported by findings that inflammasome components NLRP3, ASC, and caspase-1 were not only present in distal tubules and collecting ducts of Dahl-salt sensitive rats but also increased under high salt intake (Zhu et al., 2016). Additionally, the infusion of the caspase-1 inhibitor Ac-YVAD-cmk as well as the transplantation of mesenchymal stem cells into the renal medulla of Dahl-salt sensitive rats reduced the NLRP3 inflammasome activation and the salt-induced hypertension (Zhu et al., 2016), linking the inflammasome-derived mature IL-1β signaling system in the kidney to the SSH. Further supporting the role of IL-1β on renal sodium handling, diabetic db/db mice harboring an IL-1 receptor type 1 knockout bone marrow (db/db^IL1RKO) phenotype displayed lower expression and activity of epithelial sodium channel (ENaC) expression and activity compared with db/db transplanted with a wild-type bone marrow (Veiras et al., 2022). The db/db mice features high levels of kidney cortical IL-1β expression and, alongside with diabetes, have progressive increase in BP levels when exposed to high salt diet which involves an impaired downregulation of ENaC in the kidney epithelial cells in response to high sodium (Veiras et al., 2021). When exposed to high salt intake, the db/db^IL1RKO displayed a salt resistant BP as well as lower renal inflammation with reduced IL-1β-induced production of IL-6 by macrophages in the kidneys (Veiras et al., 2022). These findings indicate that kidney cortical IL-1β overproduction increases renal ENaC expression and activity through a mechanism that involves macrophages polarization toward a proinflammatory phenotype and renal IL-6 accumulation, with concurrent salt sensitivity of the BP (Veiras et al., 2022).

Chronic infusion of Ang II is well known for its ability to increase BP levels and significantly decrease natriuresis when experimental animals are challenged with saline solutions. Also, Ang II regulates the synthesis of pro-inflammatory cytokines and chemokines in the kidneys of female Wistar rats (Ruiz-Ortega et al., 2002) and can increase abundance of the phosphorylated forms of the Na-K-2Cl cotransporter (NKCC), Na-Cl cotransporter, Ste20/SPS-1-related proline-alanine-rich kinase in the distal tubule as well as ENaC expression in the collecting duct in mice (Kamat et al., 2015). Parallel to its direct effects on renal expression of sodium handling ion channels, Ang II, DOCA-salt and norepinephrine cause T cells and monocytes/macrophages to accumulate in the kidney and increase the local production of pro-inflammatory cytokines like INF-γ and IL-17 (Itani and Harrison, 2015). In this context, knockout mice for INF-γ (IFN-γ(−/−)) or IL-17A (IL-17A (−/−)) displayed a blunted response to Ang II-induced hypertension (Kamat et al., 2015) indicating that Ang II-driven hypertensin also involves downstream pathways activated by INF-γ and IL-17 cytokines. However, INF-γ(−/−) and IL-17 (−/−) did not affected the Ang II-induced increase in abundance of the phosphorylated forms of the Na-K-2Cl cotransporter, Na-Cl cotransporter, Ste20/SPS-1-related proline-alanine-rich kinase in the distal tubule but significantly decreased the abundance of Na/H-exchanger isoform 3, sodium phosphate transporter isoform 2 (NaPi2) and the motor myosin VI in the proximal tubule (Kamat et al., 2015). These findings suggest that both INF-γ and IL-17 can interfere with the renal sodium handling by altering the expression of sodium transporters within the initial portion of the nephron. Given the total amount of filtered sodium reabsorbed in the portion of the nephron, even small changes in ENaC expression could have a significant impact on sodium retention and its impact on BP.

The exposure of ENaC in M-1 cortical collecting duct cells to IL-6 increased the protein expression of α-ENaC, β-ENaC, γ-ENaC and prostasin as well as the amiloride-sensitive sodium current in a study by Li and cols. (2010) (Li et al., 2010). The SSBP is also strongly correlated with the T-lymphocytes levels of mRNA for IL-6 isolated from kidneys when compared to circulating T-lymphocytes in Dahl salt sensitive rats (Rudemiller et al., 2014). By treating these animals with an IL-6 neutralizing antibody, Hashmat and cols. (2016) showed that a decreased renal cortical level of IL-6 was correlated with reduced glomerular and tubular damaged as well as with BP levels in Dahl salt sensitive rats under high salt intake (Hashmat et al., 2016) suggesting the IL-6 may exacerbate may be involved in the salt sensitivity of Dahl salt sensitive rats.

The role of TNF-α in the renal changes that occur in response to high salt intake challenge are particularly interesting, especially because of the poor understanding of the exact mechanisms underlying the role of TNF-α in the SSH. While TNF-α antagonism has attenuates the hypertensive responses in many hypertensive animal models, contrasting findings demonstrate that the direct systemic administration of TNF-α usually induces hypotensive as well as natriuretic responses (Mehaffey and Majid, 2017) indicating that the solo increase in the circulating TNF-α levels may oppose the SSH. Such contrasting outcomes are speculated to result, at least in part, from differential activities of the two TNF-α cell surface receptors expressed in the kidney tissue. The TNFR1 is usually found in the proximal tubule, collecting duct, vascular endothelium and vascular smooth muscle while TNFR2 are usually found in the proximal tubule, collecting duct, vascular endothelium but not in the vascular smooth muscle (Mehaffey and Majid, 2017; Castillo et al., 2012). Studies conducted in TNFR1 knockout (TNFR1KO) and TNFR2 knockout (TNFR2KO) mice have elucidated the differential effects of both receptors on renal sodium handling and renal injury induced by TNF-α. The TNF-α infusion in mice triggers a surge in urinary volume output and fractional excretion of sodium, while the absence of TNFR1 attenuates this response (Castillo et al., 2012). Also, the TNF-α natriuretic activity is amiloride-sensitive suggesting that such effect may be mediated by ENaC activity (Majid, 2011; Shahid et al., 2008). Corroborating the role of TNFR1 role in renal sodium handling, recent findings showed that TNFR1 activity is downregulated in eNOSKO mice, which facilitates salt retention and contribute to SSH under high salt intake (Majid et al., 2024). On the other hand, mice lacking TNFR2 displayed less Ang II-induced fibrotic changes and macrophage extravasation indicating that TNF-α action on TNFR2 promotes renal tissue damage through proinflammatory pathway (Mehaffey and Majid, 2017; Singh et al., 2013). In summary, the actions of TNF-α in the kidney strongly depend on the receptor type it acts on and may oppose the sodium retention in mice under high-salt intake, probably counteracting its pro-hypertensive effects. That would strongly indicate that the role of TNF-α may depend on the production of other cytokines and chemokines in SSH.

The immune events that originate in the kidneys not only affect local renal functions but also influence immune events that occur in the brain. The renal and central nervous system signal each other through afferent (sensory) and efferent (motor) sympathetic autonomic nerves and recent findings suggest that signaling system has an important role in the SSH. Using the rat DOCA-salt model, Banek and cols. Showed that afferent renal nerve activity is augmented and that both, total and selective afferent renal nerves ablation, attenuated the DOCA-salt induced hypertension by about 50% (Banek et al., 2016). In addition, the authors also found that total, but not selective, afferent renal denervation attenuated the DOCA-salt induced renal inflammation assessed by CD3⁺, CD4⁺ and CD8⁺ cell counting and inflammatory markers (GRO/KC, MCP-1, IL-1β, IL-2, IL-6, IL-17a, and TNF-α) in the kidney (Banek et al., 2016). The findings suggest that while afferent renal nerves contribute to hypertension in the rat DOCA-salt model, the efferent renal nerves contribute to renal inflammation. The authors also proposed that renal inflammation may drive afferent renal activity to the central nervous system thus contribute to a positive feedback loop to the renal inflammation and to hypertension. Further studies on DOCA-salt model showed that the IL-1R activation is partially responsible for the increased afferents renal nerve activity and that IL-1β is increased in the kidneys and urine of DOCA-salt mice (Baumann et al., 2024). As in the DOCA-salt model of hypertension, both total renal denervation and afferent renal denervation attenuated the hypertension in the 2 kidneys, one clip (2K1C) model (Lauar et al., 2023). In addition to increased pro-inflammatory cytokines (TNF-α and IL-1β) in the clipped kidney and urine, the authors found increased expression of these cytokines in the hypothalamus of 2K1C rats. Curiously, both, total and afferent renal denervation decreased the levels of TNF-α, but only afferent renal denervation decreased the levels of IL-1β in the hypothalamus of 2K1C rats (Lauar et al., 2023), suggesting that renal inflammation can trigger an immune response in the central nervous system of this hypertension model. Together, the findings indicate a complex reinforcing interplay between the kidneys and the central nervous system to sustain SSH through immune-mediated mechanisms.

Aging is an inevitable ongoing process that is part of life and is also an important risk factor for cardiovascular disease (North and Sinclair, 2012). Despite its importance for cardiovascular diseases, the underlying mechanisms behind the processes that build up age-related impairments to the cardiovascular system are not fully understood. However, it is important to point out that the SSBP is a trait that becomes more pronounced as individuals age (Osanai et al., 1993) and, therefore, can be regarded as an additional risk factor for those carrying this trait. The association between age and SSBP has been documented and has been linked to vascular dysfunction and diminished kidney function. Factors as epigenetic modifications, diet, gut microbiome abundancy and diversity, intrinsic immune system setting, mitochondrial dysfunctions, increased levels of cortisol, immunosenescence and, regarding women, menopause are the prevailing elements that largely contribute to age-related cardiovascular disease (Demirci et al., 2025).

Recent experimental studies have shown that the aging process in Sprague-Dawley (SD) rats from 3 to 16 months is accompanied by increased BP, enhanced neurogenic pressor activity, BBB disruption, increased PIM (IL-6 and TNF-α) production, and microglia activation in the PVN of male Sprague-Dawley rats (Nist et al., 2024). These findings indicate that aging is associated with increased brain production of pro-inflammatory molecules in the PVN, a key brain region controlling sympathetic nerve activity and BP of male rats. The authors also found that treatment with losartan, an AT1R antagonist used as first-line treatment of hypertension, improved BP levels as well as reduced microglia activation and IL-6 and TNF-α production in the PVN of 16 months old male rats (Nist et al., 2024). Interestingly, females SD rats lack the increased BP and increased PIM production in the PVN during the same aging period indicating that female SD rats do not undergo the same cardiovascular issues that male SD rats due to aging. On the other hand, earlier studies showed that Dahl salt sensitive female rats, even under low-sodium diet, displayed an increase in BP over time, from the age of 3 months to the age of 12 months (Hinojosa-Laborde et al., 2004) indicating that the salt sensitive trait in these animals may overcome the protective effects of sexual hormones during the evaluated aging period. Ovariectomy accelerated the development of hypertension in Dahl salt rats, while the ovariectomy accompanied by estrogen replacement attenuated its development (Hinojosa-Laborde et al., 2004). These findings are aligned with results from studies showing an increase in salt sensitivity over the aging process is also reported in humans (Sander, 2002; Schulman et al., 2006) and further highlight the importance of the steroid hormones in the SSBP protection as salt-resistance women pre-menopause become salt-sensitive after menopause (Schulman et al., 2006).

A growing number of studies have showed that the decline in expression of the Klotho protein is linked to aging in humans and experimental animals (Abraham and Li, 2022). Klotho is a membrane/soluble protein expressed in the choroid plexus of the brain, a structure primarily linked to the CSF production, and the convoluted tubules in the kidney (Abraham and Li, 2022). The circulating levels of the soluble form of Klotho (α-Klotho) have been shown to directly correlate with glomerular filtration rate suggesting its diagnostic importance in kidney function decline, especially during aging (John et al., 2011). Interesting, the missense single nucleotide polymorphism in the Klotho gene, rs9536314, do humans is also associated with SSH (Citterio et al., 2020). In addition, experimental findings showed that high sodium intake led to SSH in mice Klotho heterozygous knockout mice as wells as in aged mice and that Klotho supplemented reversed SSH in these animals (Kawarazaki et al., 2020). Also, Klotho deficiency in heterozygous knockout mice is associated with renal damage and SSH through CCR2-mediated inflammation (Zhou et al., 2015), linking the Klotho deficiency with immune regulation of SSBP. Whether Klotho blood levels can function as a reliable marker of SSBP, especially in aged people, is yet to be determined.

The ongoing findings point toward the important role of immune signaling in key brain regions controlling autonomic regulation of BP in experimental models and may represent an important step for the understanding of its role in the human set of SSBP.

High salt intake is important risk factor for cardiovascular and kidney disease and yet reductions in salt intake have proved a challenging task to be achieved in the modern western society. Although the daily salt consumption has, indeed, reduced from the 18th century to current days (Ha, 2014), it still far from the recommendations by worldwide health authorities. Therefore, new strategies and approaches must be considered to mitigate the effects of the high salt intake, especially when considering the aging and longer lifespan our society conquer over the past century. The gut microbiota plays a crucial role in regulating BP and kidney function through its interaction with the immune and nervous systems. Therapeutic strategies such as dietary interventions, probiotics, prebiotics, symbiotic, and fecal microbiota transplantation have shown promise, under experimental and controlled conditions, in modulating gut microbiota to manage hypertension and chronic kidney disease (Al-Habsi et al., 2024; Baldi et al., 2021). These interventions aim to restore microbial balance, enhance gut barrier function, and reduce systemic inflammation, which are critical for lowering BP and protecting kidney and brain health. Targeting neural pathways that regulate immunity, and inflammation offers a novel approach to treating kidney diseases and hypertension. The use of anti-inflammatory agents that specifically target the CNS like minocycline or drugs with specific action on cytokine receptors like IL-1R and TNFR antagonists may be proven effective in counteract the pro-inflammatory effects of high salt intake and work alongside conventional anti-hypertensive therapies. SCFA, produced by gut microbiota, have anti-inflammatory effects and play a role in BP regulation. Enhancing SCFA production through dietary modifications or supplementation could be a therapeutic strategy to mitigate hypertension and its associated kidney damage.

However, further research is needed to elucidate the precise mechanisms by which the gut microbiota influences hypertension and kidney diseases. Understanding these pathways will aid in the development of targeted therapies that can more effectively modulate the neuron-immune-microbiome axis and may mitigate the detrimental effects of high salt intake on the cardiovascular and renal systems. As our understanding of the microbiome's role in hypertension and kidney diseases grows, there is potential for developing personalized treatment strategies. These could involve tailoring dietary interventions and microbiota-targeted therapies based on individual microbiome profiles. Conducting well-designed clinical trials to test the efficacy of microbiota-targeted interventions in humans is crucial. These trials will help validate the therapeutic potential of probiotics, prebiotics, and other microbiome-related strategies in managing hypertension and salt-related kidney diseases. In addition, utilizing metagenomics, metabolomics, and other omics technologies can provide comprehensive insights into the microbiome's role in disease pathogenesis. This integration will facilitate the identification of novel biomarkers and therapeutic targets.

In this review, we focused on key findings that substantiate the role of the immune signaling pathway in the pathophysiology of SSH, particularly emphasizing certain aspects of the neural and renal mechanisms. The salt-induced challenges that prompt the immune system to corroborate pro-hypertensive mechanisms also entail significant alterations in the gut microbiome. Consequently, the trafficking of large amounts of salt through the body not only impairs autonomic and volume-related regulation of the cardiovascular system, but also adversely affects the commensal bacterial community in the gut, which subsequently reverberates in the immune system, contributing to a low-grade, chronic inflammatory state associated with important neural and renal pathophysiological mechanisms. The multiplicity of signaling mechanisms involved and the overlapping effects of aging and sexual dimorphism underscore the complexity of SSH, necessitating novel approaches and further investigation in this field to develop effective management strategies for hypertension. A chart of our working hypothesis is summarized in Figure 1.