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Immune Cells as Central Coordinators of Cardiorenal Crosstalk in Hypertension: Mechanisms, Pathways, and Therapeutic Implications

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12 August 2026

Posted:

13 August 2026

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Abstract
Hypertension remains the leading preventable cause of cardiovascular disease and premature death worldwide. In the hypertensive state, renal and cardiovascular dysfunctions become entrenched in a self-perpetuating feedback loop, with immune cells emerging as central coordinators of this pathological crosstalk. This review examines the mechanisms by which immune cells integrate signals from high salt, the renin-angiotensin-aldosterone system (RAAS), and the sympathetic nervous system (SNS) to drive chronic inflammation and end-organ damage. We highlight the salt-dendritic cell-isolevuglandin (IsoLG)-T cell axis as a critical pathway linking dietary sodium to immune activation and hypertension. We also explore bidirectional interactions between immune cells and RAAS components, as well as neuro-immune crosstalk that amplifies sympathetic outflow. Counter-regulatory mechanisms, including the ACE2/Ang-(1-7)/Mas axis, the kallikrein-kinin system, Urodilatin, Klotho, and renalase, provide endogenous braking signals that limit inflammation. Finally, we discuss emerging immunomodulatory therapeutic strategies and identify key unanswered questions for future research. Understanding immune cells as central coordinators of cardiorenal communication offers new opportunities for precision medicine approaches to hypertension.
Keywords: 
hypertension
;  
immune cells
;  
cardiorenal inflammation
Subject: 
Medicine and Pharmacology  -   Cardiac and Cardiovascular Systems

1. Introduction

Hypertension, affecting approximately one-third of adults (more than1.3 billion people) worldwide, is the most common risk factor contributing to the global burden of cardiovascular morbidity and mortality.[1] Effectively managing hypertension significantly could avert millions of cardiovascular disease-related deaths annually.[2] The Kidney and heart work together intimately to maintain blood pressure stability and their dysfunctions play inextricable roles in the development of hypertension. [3,4]
Cardiovascular dysfunction and renal dysfunction are deeply interconnected. Impairment in one organ quickly creates a cascading negative impact on the other, often referred to as Cardiorenal Syndrome or Cardiovascular-Kidney-Metabolic (CKM) Syndrome. [3,5] Renal dysfunction is highly prevalent in cardiovascular disease (CVD), affecting approximately half of patients with cardiac condition.[6] Cardiac dysfunction is highly prevalent in patients with kidney disease. About half of all patients with chronic kidney disease (CKD) stage 4/5 experiencing cardiovascular disease, and cardiovascular complication is the leading cause of death for CKD patients. [7,8] Cardiovascular and renal dysfunctions trigger chronic systemic high blood pressure through a self-perpetuating spiral of damage. Beyond hemodynamic factors, the Renin-Angiotensin-Aldosterone System (RAAS) and Sympathetic Nervous System (SNS) play central roles in the cardiorenal connections underlying hypertension.
A large body of evidence demonstrated that hypertension is a state of chronic immune activation and low-grade systemic inflammation.[9] Immune cells interact closely with RAAS and SNS, forming a self-amplifying cycle that drives hypertension, chronic inflammation, tissue fibrosis, and progressive cardiorenal organ damage. Despite extensive research into the complex pathology of hypertension and the development of numerous effective medications, more than half of patients still have poorly controlled blood pressure.[10] Exploring the precise interconnected immune cells pathway in the cardiorenal axis is critically needed for developing better diagnostics and targeted therapies.
In this review we focus on the cardiorenal connections in hypertension and the central coordinator role of immune cells in this process (Figure 1). We provide a comprehensive synthesis of how immune cells sense hypertensive stimuli, integrate signals from RAAS and SNS, and amplify inflammation and tissue injury. We also highlight the emerging concept of neuro-immune circuits that link the brain, kidney, and cardiovascular system. Finally, we discuss the translational potential of immunomodulatory strategies and identify key unresolved questions that should guide future research.

2. Pathophysiology of Cardiorenal Connections in Hypertension

Blood pressure is fundamentally determined by the product of cardiac output (CO) and systemic vascular resistance (SVR). The kidneys regulate systemic blood pressure by dynamically controlling blood volume and vascular tone, primarily through the renin–angiotensin–aldosterone system (RAAS) and the sympathetic nervous system (SNS). [11,12,13] In turn, the heart provides hormonal signals, including atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), as well as neural inputs that regulate blood pressure by modulating vascular tone and renal sodium handling. [14,15,16]
High dietary salt intake is one of the most common factors that directly increases blood volume, thereby elevating CO.[17] Elevated blood pressure increases glomerular hydrostatic pressure, resulting in a transient increase in the glomerular filtration rate (GFR).[18] Increased renal blood flow suppresses the activity of sodium transporters, including the Na⁺/K⁺-ATPase and Na⁺/H⁺ exchangers, along the renal tubules.[19] Under physiological conditions, elevated systemic blood pressure suppresses SNS activity and renin release while stimulating the production of renal vasodilators through multiple counter-regulatory mechanisms. [20,21,22] In hypertension, however, this finely coordinated feedback system becomes disrupted because of renal and/or cardiovascular dysfunction, resulting in persistent elevation of blood pressure.
Endothelial dysfunction, vascular remodeling, and fibrosis are the major pathological processes responsible for vascular lumen narrowing and increased arterial stiffness, both of which elevate systemic blood pressure.[23] Endothelial dysfunction is characterized by impaired endothelial function, with reduced bioavailability of vasodilators, including nitric oxide, prostaglandins, and kinins, together with increased production of vasoconstrictors such as endothelin-1, vasopressin, and angiotensin II.[24] Nitric oxide is the principal endogenous vasodilator and promotes vascular smooth muscle relaxation through the cyclic guanosine monophosphate (cGMP) signaling pathway.[20] Oxidative stress and inflammatory cytokines are the primary drivers of impaired nitric oxide bioavailability.[25] Endothelin-1, which is produced by the kidney and vascular endothelium, is among the most potent endogenous vasoconstrictors. [26,27] Binding of endothelin-1 to receptors on vascular smooth muscle cells triggers intracellular calcium influx, producing sustained vasoconstriction and increasing systemic vascular resistance. [28,29,30]
In hypertension, renal and cardiovascular dysfunction establish a self-perpetuating vicious cycle that further increases CO and/or SVR. Prolonged systemic hypertension causes hypertensive nephropathy by damaging the glomerular microvasculature. Impaired renal filtration promotes sodium retention, fluid overload, and chronic inflammation, all of which contribute to sustained elevations in blood pressure.[12] Injured kidneys also release vasoactive mediators that promote vasoconstriction, vascular remodeling, and arterial stiffening, further exacerbating hypertension.[31] Sustained hypertension imposes chronic pressure overload on the heart, ultimately leading to adverse cardiovascular remodeling, including left ventricular hypertrophy (LVH), arterial injury, and eventually heart failure. [32,33] As cardiac function declines, reduced cardiac output diminishes renal perfusion and lowers effective arterial pressure.[34] The resulting renal hypoperfusion activates the RAAS, further increasing blood pressure and accelerating progressive injury to both the heart and kidneys.[3,35,36,37] In addition, impaired cardiac function elevates central venous pressure, causing renal venous congestion that further compromises renal function and perpetuates cardiorenal injury.[38]

3. The Inflammatory Paradigm in Hypertension

Hypertension is increasingly recognized as a chronic systemic inflammatory condition. Excess sodium accumulation in tissues, hormones like angiotensin II (Ang II) and aldosterone, overactive SNS are the most common factors stimulating immune cell activation and infiltration into the heart, blood vessels, and kidneys. [39,89] Circulating monocytes and recruited T cells and macrophages infiltrate into the vessel walls, creating a chronic inflammatory cycle that accelerates arterial stiffening and vascular dysfunction. [40,41] The inflammatory immune cells accumulated in kidney produce pro-inflammatory cytokines and ROS, causing kidney injury, driving sodium retention and blood volume expansion. [39,42] On the other hand, once the blood pressure is elevated, immune cells can sense the mechanical stretch and amplify the inflammatory cycle. Mechanical stretch from high blood pressure triggers the bone marrow to release more inflammatory monocytes into the bloodstream.[43] High blood pressure physically stretches the endothelial cells, triggering the release of pro-inflammatory cytokines and reactive oxygen species, which recruits immune cells into the walls of blood vessels.[44] Mechanical stretching of high blood pressure triggers neutrophils to release Reactive Oxygen Species (ROS) and Neutrophil Extracellular Traps (NETs) through influx of calcium by activation of TRPV4 and PIEZO1 channels. [45,46]
The immune cells integrate signals from high salt, the RAAS, and the SNS to drive chronic inflammation and cardiorenal system end-organ damage. As shown in Figure 2, immune cells play a central coordinator’s role in the cardiorenal crosstalk, in which the blood pressure states were determined, remain healthy or develop hypertension.

4. Renin-Angiotensin-Aldosterone System (RAAS) and Immune Cells Interactions

Overview of RAAS in Hypertension

Renin-Angiotensin-Aldosterone System (RAAS) is a central hormone system that regulates blood pressure initiated in the kidney. Chronic activation of the RAAS causes excessive vasoconstriction and sodium retention, leading to hypertension.[95] The RAAS cascade elevates blood pressure through multiple mechanisms. Renin is produced by the juxtaglomerular cells in the kidneys, in response to low pressure, low sodium or stimulation from the sympathetic nervous. Renin acts upon angiotensinogen, converting it into Angiotensin I (Ang I). Angiotensin-converting enzyme (ACE) converts Ang I into Ang II, which is primary effector peptide acting on the AT1 receptor (AT1R) to narrow arterioles. Ang II triggers the adrenal glands to release aldosterone, which activates ENaC and SGK1, prompting the kidneys to retain sodium. Ang II signals the pituitary gland to release antidiuretic hormone (ADH), which further increases water reabsorption in the kidneys. While circulating, Ang II is also produced locally in the renal tubules, activating the AT1R, causing increased renal sodium reabsorption and tightening blood vessels. [13,96] In addition, both Ang II and aldosterone act on the brain to increase the sensation of thirst and the desire for salt, further expanding the total blood volume.[97]
Although RAAS is crucial survival mechanism in evolutional history and remains functional in specific situations in modern ages, such as severe trauma and dehydration.[98] In modern populations RAAS often remains overactive due to modern high-sodium diets and lifestyles, resulting in a continuous cycle of vasoconstriction, oxidative stress, and inflammation. Inflammation triggers RAAS directly and multiple components of the RAAS signaling pathway have been shown to directly affect immune cell activation and function (Figure 4).[99]

Bidirectional Communication Between Immune Cells and RAAS

Pro-inflammatory cytokines secreted from immune cells bind to receptors on juxtaglomerular cells, altering intracellular cyclic AMP (cAMP) levels driving renin gene transcription and releasing of stored renin. [100,101] Oh et al demonstrated that renal macrophages can directly promote juxtaglomerular cells to secrete renin, through their increased release of miR-106b-5p.[102] On the other hand, renin triggers inflammatory pathways in immune cells. Renin activates (pro)renin receptor expressed in monocytes and T cells, triggering intracellular ERK1/2 phosphorylation, enhancing the secretion of cytokines like IL-6, TNF-α, and inflammatory mediators like cyclooxygenase-2. [103,104,105]
Pro-inflammatory cytokines stimulate hepatocytes and renal cells to upregulate angiotensinogen (AGT) production, accelerating Ang II formation. [106,107] A study by Lai et al demonstrated that cytokine IL-6 drives angiotensinogen expression in liver through activation of JAK/STAT3 and JAK/p38/NF-kB signaling pathways.[108] While systemic AGT is primarily synthesized in the liver, localized renal inflammation triggers intrarenal AGT production, leading to localized Ang II spikes, promoting vasoconstriction, ROS production, and fibrosis.[109] In kidney, IL-6 acts directly on renal proximal tubules to initiate angiotensinogen (AGT) transcription through the NF-κB and JAK-STAT pathways. [110,111]
Ang II behaves as an inflammatory mediator, activating the Ang II receptors expressed in immune cells, such as T lymphocytes, dendritic cells, macrophages, and neutrophils.[112] At the same time, inflammatory conditions upregulate the angiotensin receptors (particularly the AT₁R subtype), increasing the immune cell’s sensitivity to Ang II.[113] Ang II binds to AT1Rs on native Cd4+ T cells, activating naive CD4+ T cells to pro-inflammatory Th1/Th17 cells while suppressing the master regulator of regulatory T cells (Tregs). [114,115]
Activation of AT1Rs on T cells activates the PKA-proteasome pathway, promoting the degradation of IkBa and MKP-1. Degradation of these inhibitory proteins upregulates NF-kB and STAT1, triggering the production of Th1 cytokines such as IFN-γ and TNF-α, suppressing FoxP3 expression. [114,115,116,117] AT1R activation enhances T cell responsiveness to inflammatory cytokines (like IL-6 and IL-12), activating STAT3 and RORgt, driving naïve T cells to differentiate into the Th17. [114,115,118] With the presence of Ang II, TGF-β signaling act to disrupt immune tolerance by shifting the differentiation of naïve T-cells diverted away from the Treg pathway and into the pro-inflammatory Th17 pathway. [115,119] The accumulation of activated Th1/Th17 T cells in kidneys and blood vessels secrete cytokines that increase inflammation, contributes significantly to high blood pressure and vascular remodeling. [57,114,120,121] Moreover, Ang II acts as a co-stimulatory molecule binding to AT1R on CD8+ T cells to synergize with the T cell receptor (TCR) and enhance T cell proliferation and differentiation.[113] NK cells are also fully equipped with RAAS elements. They produce and delivery Ang II to localized sites of inflammation, which triggers the maturation of other innate immune cells, like dendritic cells and macrophages. [118,122]
Type 1 angiotensin receptors expressed on CD11c+ dendritic cells act as an immune-regulatory brake. They suppress dendritic cell maturation and constrain T cell activation, limiting pro-inflammatory cytokine release and fluid retention.[123] Ang II causes vascular smooth muscle cells, endothelial cells, and macrophages to release Monocyte Chemoattractant Protein-1 (MCP-1). [124,125,126] Ang II binds to the AT1R, stimulates NADPH oxidase, resulting in a rapid increase in intracellular ROS. The ROS production and G protein signaling activate several mitogen-activated protein kinase (MAPK) pathways, specifically ERK1/2 and p38 MAPK. The activated MAPKs, alongside calcium signaling, stimulate the translocation of the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factor to the nucleus, promoting the MCP-1 gene expression. [126,127,128] MCP-1 binds to CCR2 on monocytes, drawing them into the arterial wall, heart and kidneys where they turn into macrophages and contribute to hypertension. [129,130,131] The activation of NF-κ B also upregulates adhesion molecules gene expression on endothelial cell, such as ICAM-1, VCAM-1, and E-selectin, which promotes the infiltration of immune cells including T cells, macrophages, and neutrophils into vessel walls and kidneys. [40,124,132] Ang II prompts endothelial cells to release inflammatory chemokines (such as IL-8), which rapidly recruit neutrophils to sites of injury.[133] Similarly, Ang II stimulates neutrophils to produce high amounts of ROS.[134] Ang II triggers neutrophils to release neutrophil extracellular traps (NETs) that can cause blood clots and vascular inflammation.[135] While Ang II stimulates neutrophils, activated neutrophils can also release proteases (such as cathepsin G) that convert Ang I directly into Ang II, sustaining local inflammation. [133,136] Ang II stimulates B cells differentiate into plasma cells that secrete large amounts of Immunoglobulin G (IgG). These antibodies accumulate in the walls of blood vessels, promoting structural remodeling and stiffness. The deposition of IgG triggers the recruitment of pro-inflammatory macrophages and T cells to the vascular wall, which worsens endothelial dysfunction and increases oxidative stress. [60,137] All the pro-inflammatory cells (including T cells, macrophages, neutrophils, B cells) recruitment and infiltration in kidney, heart and blood vessel, promoting atherosclerosis, left ventricular hypertrophy, and vascular remodeling. [99,105] Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs) exert direct immunomodulatory effects by blocking pro-inflammatory AT1Rs. This suppresses leukocyte recruitment, reduces the secretion of pro-inflammatory cytokines, and mitigates long-term tissue damage. [99,107,114]

Aldosterone and Mineralocorticoid Receptor Signaling

Aldosterone also actively drives inflammation by activation of mineralocorticoid receptors (MR) on dendritic cells, T cells and macrophages. Aldosterone activates dendritic cells, triggering the release of pro-inflammatory cytokines like IL-6 and TGF-β, downregulates programmed death-ligand 1 (PD-L1). [138,139] Through dendritic cell interactions, aldosterone polarizes CD4⁺ T cells toward a Th17 phenotype and activates CD8⁺ cytotoxic T cells.[140] MR signaling alters the distribution of T cells, reducing circulating naive T cell counts in the blood while upregulating migration markers like CXCR4, causing them to accumulate in kidneys and aorta.[141] Once MR is activated by aldosterone, T cells are differentiated into subsets Th1 and Th17 phenotypes while suppressing anti-inflammatory regulatory T cells (Tregs).[142] MR activation regulates CD8⁺ and CD4⁺ T cells, driving the secretion of IFN-γ, a cytokine that promotes superoxide generation and inflammation. [143,144] Aldosterone triggers monocytes and macrophages to release inflammatory cytokines like IL-6 and TGF-β1, promoting migration into vascular walls, leading to tissue remodeling, plaque instability, and fibrosis. [138,145] Mineralocorticoid receptor antagonists (MRAs), like spironolactone and finerenon, have been shown to reduce the polarization of inflammatory Th17 cells by monocyte-derived dendritic cells. [146,147]

Counter-Regulatory Mechanisms of RAAS

Multiple intrinsic counter-regulatory pathways are employed to mitigate hyperactivation of RAAS and maintain blood pressure homeostasis (Figure 4). Renin is the initiating and rate-limiting enzyme of RAAS. Live-tissue mapping showed that high Ang II triggers rapid calcium oscillations across neighboring juxtaglomerular cells. This calcium surge acts as a physical biological brake to shut down renin overproduction. [148,149] Urodilatin, synthesized in the distal tubules of the kidney, inhibits renin secretion and blocks aldosterone releasing.[150] In addition, urodilatin binds to Natriuretic Peptide Receptor A (NPR-A) receptors in the renal medullary collecting ducts, increasing cyclic GMP (cGMP). Elevated cGMP activates protein kinase G (PKG) and inhibits sodium (Na+) entry via apical amiloride-sensitive sodium channels and suppresses water reabsorption.[150] Urodilatin also exhibits anti-inflammatory effects by modulating the function of immune cells, including neutrophils and macrophages, and inhibited the generation ROS, suppressing pro-inflammatory cytokines like TNF-α, IL-6. [151,152]
The ACE2/Ang-(1-7)/Mas receptor axis is “counter-regulatory” arm of the RAAS. Angiotensin-converting enzyme 2 (ACE2) breaks down the Ang II into Angiotensin-(1-7).[153] Ang-(1-7) binds to the Mas G protein-coupled receptor to trigger cellular responses, such as promotion of nitric oxide synthesis, inhibition of pro-inflammatory cytokines, suppress of fibrogenesis, and prevention of oxidative stress and NLRP3 inflammasome.[154] Activation of the Mas receptor promotes the expansion of regulatory T cells (Tregs) and the transition of macrophages from the pro-inflammatory M1 state to the anti-inflammatory and tissue-repairing M2 phenotype. [114,155,156]
The kallikrein-kinin system (KKS) is an important hormonal system that counteracts RAAS and lowers blood pressure. [157,158] The enzyme kallikrein acts on kininogens to generate kinins (mainly bradykinin), which bind to the B₂ receptor on kidneys and blood vessels, promoting sodium excretion, stimulating the release of vasodilators (like nitric oxide and prostaglandins). [159,160] Bradykinin dampens Type I Interferon (IFN) responses by inhibiting the phosphorylation of STAT2, preventing excessive inflammation.[161] Experimental approaches involve delivering the human tissue kallikrein gene were developed to combat hypertension. ACE Inhibitors not only reduce the production of the Ang II, but also prevent the breakdown of bradykinin simultaneously. [157,160] Angiotensin Receptor Blockers (ARBs) block the angiotensin type 1 receptors directly. Blocking AT1, the excess Ang II is diverted to act on AT2 receptors. AT2 receptors stimulation activates the tyrosine phosphatase SHP-1, which subsequently upregulates prolylcarboxypeptidase (PRCP). PRCP acts as a catalyst that converts plasma prekallikrein into active plasma kallikrein, activating KKS. [162,163]

The FGF23-Klotho Axis in Hypertension

The FGF23-Klotho axis is another important hormonal pathway interconnected with RAAS to manage blood pressure.[164] Fibroblast Growth Factor 23 (FGF23) is a hormone secreted primarily by osteocytes in response to rising phosphate levels or active vitamin D (1,25-dihydroxyvitamin D). FGF23 is massively elevated in hypertension patients with CKD. FGF23 suppresses the synthesis of active vitamin D in the kidneys by downregulating the expression of the enzyme 1α-hydroxylase (CYP27B1). Simultaneously, it stimulates the enzyme 24-hydroxylase (CYP24A1), which breaks down active vitamin D into inactive metabolites.[165] Vitamin D is a potent inhibitor of renin, its deficiency leads to increased renin biosynthesis, effectively upregulating RAAS.[166] in addition, FGF23 promotes sodium reabsorption by upregulating the sodium/chloride co-transporter (NCC) on the distal convoluted tubule of the kidney through ERK1/2 and SGK1 pathway.[167] FGF23 promotes sympathetic overactivity by activating FGFR4-calcineurin signaling. [168,169] Ang II directly stimulates FGF-23 production in osteocytes and FGF-23 suppresses Ace2 in the kidney, preventing the breakdown of Ang II. [170,171] Aldosterone interacts with mineralocorticoid receptors (MRs) in osteoblasts and osteocytes, stimulating the expression of the FGF23 gene.[172] Ang II and aldosterone upregulate FGF23 production but act directly to reduce renal expression of Klotho on renal tubules.[164]
Klotho, a crucial anti-aging protein highly expressed in all major tubular segments of kidneys, functions as an obligatory co-receptor of FGF23 to regulate the production of active vitamin D and signal the kidneys to excrete excess phosphate.[173] In CKD patients, their kidneys lose the ability to produce the Klotho protein. Klotho suppresses RAAS activity through Wnt/β-catenin signaling pathway.[174] The Wnt/β-catenin pathway positively regulates the transcription of multiple RAS genes.[175] Klotho binds directly to Wnt proteins (such as Wnt1, Wnt4, and Wnt7a), blocking β-catenin activation and its entry into the cell nucleus.[174] Klotho inhibits Vascular Smooth Muscle Cells (VSMCs) from transforming into osteoblast-like cells, directly stopping arterial stiffening.[176] Klotho shields cardiomyocytes from structural remodeling, preventing left ventricular hypertrophy (LVH) by reducing systemic oxidative stress and limiting abnormal cellular signaling (such as the p38 and ERK pathways). [177,178]
During periods of severe systemic inflammation, activated macrophages produce FGF23 locally. The locally produced FGF23 interacts with FGFRs to directly stimulate the expression of pro-inflammatory cytokines like TNF-α and inhibit anti-inflammatory like Arginase-1. [179,180] High circulating levels of FGF23 bind to FGFR2 on neutrophils impairing the ability to navigate to sites of inflammation.[181] FGF23 acts to suppress active vitamin D production in the kidneys, which exaggerate inflammatory responses and impaired infection clearance. [179,182] Research suggests that elevated FGF23 could be a novel marker for identifying individuals at higher risk for developing high blood pressure.[183]
The Klotho protein acts as a systemic anti-inflammatory factor by suppressing pathways such as NF-kB and the NLRP3 inflammasome, ultimately reducing the production of active inflammatory cytokines.[184] Klotho directly limits the production of pro-inflammatory cytokines like IFN-γ, TNF-α, and IL-6 from T cells, suppressing the differentiation of Th1 and Th17 cells while promoting the activity of Tregs. [182,185] Klotho protects monocytes from DNA damage and stress-induced senescence, reducing the secretion of pro-inflammatory cytokines while boosting anti-inflammatory markers like IL-10.[186] It actively shifts macrophages away from the pro-inflammatory M1 type and toward the anti-inflammatory M2 type.[182] Preclinical studies indicate that restoring Klotho levels can stop further increases in blood pressure and mitigate end-organ damages in cardiorenal system. [164,178,187]

5. Sympathetic Nervous System (SNS) and Immune Interactions

SNS Overactivation in Hypertension

The sympathetic nervous system (SNS) drives short-term blood pressure elevation was a crucial, life-saving mechanism to survive acute physical threats.[188] In modern environments, constant mental stress, sedentary lifestyles, high salt diets and obesity over activate the SNS, causing hypertension. Chronic overactivation of SNS continuously releases norepinephrine, which binds to b1 adrenergic receptors in the heart. This accelerates heart rate and increases myocardial contractility. It acts on vascular a1 receptors to constrict blood vessels and increase arterial stiffness, which elevates systemic blood pressure and increases the heart’s workload.[189] In kidney, sympathetic signals constrict the renal arteries, reducing renal blood flow and the Glomerular Filtration Rate (GFR), which limits the kidney’s ability to excrete sodium and water properly.[190] Increased SNS releases norepinephrine, which binds to a-adrenergic and b-adrenergic receptors on the basolateral membranes of tubular cells, stimulating Na, K-ATPase activity, directly driving the proximal tubule to absorb more sodium and water.[191]
Norepinephrine released from renal sympathetic nerves binds directly to b1-adrenoceptors on juxtaglomerular (JG) granular cells, activating cAMP pathway. Elevated intracellular cAMP levels activate Protein Kinase A (PKA), triggering the phosphorylation and exocytosis of renin into the bloodstream.[192] On the other hand, sustained sympathetic overactivity leads to cardiac hypertrophy and renal disfunction, which in turn triggers sensory afferent nerves that signal the brain and central sympathetic outflow. [193,194,195]

Neuro-Immune Crosstalk

The SNS directly innervates primary and secondary lymphoid organs, including bone marrow, thymus, spleen, and lymph nodes.[196] For example, sympathetic nerve activation significantly drives the mobilization and release of hematopoietic stem and progenitor cells (HSPCs) from the bone marrow into the peripheral circulation, thereby influencing the systemic immune repertoire.[197] As shown in Figure 5, SNS overactivation stimulates immune cells (such as T cells, macrophages, and neutrophils) to release pro-inflammatory cytokines, causing arterial stiffening, endothelial dysfunction, and fluid retention. Research by Marvar et al demonstrated that noradrenaline can activate T-cell and promote their infiltration into blood vessel walls, leading to peripheral vascular inflammation.[198] Increasing evidence showed that elevated norepinephrine from nerve terminals activates adrenergic receptors on T-cells, promoting their accumulation in kidney and blood vessel and creating a feedforward mechanism that raises blood pressure. [199,200,201,202] Catecholamines (noradrenaline and adrenaline) activate α and β adrenergic receptors expressed on macrophages, creating antagonistic effects.[203] When catecholamines bind to α1 adrenergic receptors on macrophages, massively increases the secretion of proinflammatory mediators, such IL-1β, by the Protein Kinase C (PKC) and p38 Mitogen-Activated Protein Kinase (p38 MAPK) pathways.[204] β2AR is generally expressed at higher levels than the other subtypes on macrophages. When NE binds to β₂-ARs, it activates adenylate cyclase, increasing intracellular cyclic AMP (cAMP) levels. Elevated cAMP activates PKA, which prevents the pro-inflammatory transcription factor NF-κB from entering the cell nucleus. By blocking NF-κB, NE inhibits the transcription and release of pro-inflammatory cytokines like TNF-α, IL-6, and IL-8, while promoting the production of anti-inflammatory IL-10, which drives fibrosis instead of inflammation. [205,206] NE decreases the expression of the CCR2 chemokine receptor, which reduces the ability of macrophages to migrate out of the bloodstream and into inflamed tissues.[207] Renal nerves contribute to the migration of CD161a+/CD68+ macrophages to the renal medulla, where they contribute to increased renal expression of NKCC2, promoting water and sodium reabsorption. [208,209]
SNS directly affect immune cell behaviors. In return, active immune cells release pro-inflammatory cytokines (such as IL-1b, IL-6, and TNF-α) that communicate back to the brain, activate microglia in the hypothalamus and brainstem, further amplifying SNS output (Figure 5).[210] Sympathetic ganglia contain resident macrophages that directly interact with neuronal cell bodies, modulating neurotransmitter release and neuronal excitability. [211] This neuro-immune crosstalk creates a powerful, self-sustaining bio-loop, amplifying the chronic inflammation condition. [212,213] Spiral catheter technology disrupts overactive nerves lining the kidney arteries, which effectively reduces blood pressure in experimental models and humans.[214] Renal denervation has been shown to decrease the activation of monocytes, dendritic cells and T-cells.[199,215,216,217]

Purinergic Signaling and Immune Activation

When the SNS is activated in hypertension, it releases ATP alongside norepinephrine from nerve terminals into the kidneys. [218,219] As a sympathetic cotransmitter, ATP binds to P2 receptors (such as P2X1) on vascular smooth muscle cells, triggering an influx of calcium, causing blood vessels to constrict and increasing peripheral vascular resistance.[220] Disruption of some P2 receptors (such as P2Y2, P2X4) can impair sodium excretion, leading to salt-resistant arterial hypertension. [221,222] Recently P2 receptors are increasingly recognized as a vital communication bridge between the immune system and the development of hypertension. [223,224,225] A recent study by Shokoples et al demonstrated that elevated extracellular ATP acts as a damage-associated molecular patterns (DAMPs) in hypertension.[226] Excess ATP binds to P2X7 receptors on immune cells, activating the NLRP3 inflammasome, amplify Ca2+ influx during T cell activation, which triggers the release of potent pro-inflammatory cytokines like IL-1β and IL-18. [227,228,229] Disruption of P2RX7 could reduce the infiltration of activated T cells, and blunt Ang II-induced BP elevation.[226] When the P2RX7 receptor is activated by excess ATP on Tregs, it promotes a significant loss of FOXP3 and drives their conversion into pro-inflammatory Th17-like cells.[230]
Renalase: A Counter-Regulatory Hormone
Renalase is a kidney-secreted hormone that decreases sympathetic nerve activity by metabolizing circulating adrenaline, noradrenaline and their precursors. Deficiency in renalase, often in CKD patients, is strongly associated with increased sympathetic activity and high blood pressure. [231,232] Renalase deficiency promotes a systemic and local proinflammatory state by triggering a significant upregulation of cytokines like TNF-α and MCP-1.[233] Renalase functions as a cytokine that activates PI3K/AKT, JAK/STAT, and the MAPK pathways, driving the differentiation of macrophages toward the anti-inflammatory M2 phenotype. Exposure of activated M1 macrophages to renalase blocks inflammasome activation and production of IL6, IL1β.[234] Proper renalase has been shown to protect kidney and heart from ischaemic injuries, fibrosis by suppressing oxidative stress. [235,236] Exogenous renalase could potentially be developed as a new treatment for managing hypertension by dampening severe inflammation, especially in CKD patients. [233,235,237]

6. Therapeutic Implications and Future Perspectives

Current Pharmacological Approaches

Because the heart and kidneys operate in a continuous, intertwined loop in hypertension, hypertension should be treated as a disorder of dysregulated cardiorenal communication. Effectively managing hypertension requires a coordinated approach that addresses both organs. Recent years, a combination of SGLT2 inhibitors and GLP-1 receptor agonists was developed as foundational treatments for cardiovascular-kidney diseases as well as hypertension.[238] SGLT2 Inhibitors lower blood sugar and blood pressure by causing the kidneys to excrete excess glucose and sodium, reducing sympathetic tone.[239] GLP-1 receptor agonists significantly reduce appetite and promote substantial weight loss. They reduce systemic inflammation and oxidative stress, protecting the kidney function and lowering the risk of major adverse cardiovascular events.[240] When taken together, SGLT2 inhibitors and GLP-1 receptor agonists provide synergistic, complementary benefits.[239] To reduce the adverse renal outcomes, ERAs and RAAS inhibitors are increasingly combined with SGLT2 inhibitors to maximally protect kidney function while managing hypertension.[241]

Emerging Immunomodulatory Strategies

Interventions targeting immune processes show potential in reducing cardiorenal damage and mitigating hypertension.[242] Some studies are looking at the use of anti-inflammatory agents like colchicine and methotrexate to curb hypertension-induced inflammation. [242,243] Drugs have been investigated for their ability to neutralize inflammatory cytokines (IL-17A, IL-1B, TNF-α) that contribute to hypertension.[41] Pre-clinical models showed specific IsoLG scavengers like 2-hydroxybenzylamine (2-HOBA) intercept and neutralize highly reactive IsoLGs, protecting immune cells from dysfunction and significantly lowering blood pressure. [244,245] NLRP3 inhibitors are being studied for their potential to treat hypertension and its associated organ damage. [246,247] SGK1 inhibitors are an emerging class of experimental therapeutics being investigated for salt-sensitive hypertension and metabolic syndrome. [72,248,249] Regulatory T cells (Tregs) help suppress immune responses and reduce inflammation, acting to protect the vascular system and lower blood pressure. [250,251] Because of this crucial connection, modulating the immune response and balancing T cell subtypes are active areas of clinical research for novel, immune-regulatory treatments for hypertension.[252] For example, Srinivas et al block the destructive calcium signaling by Treg-specific deletion of the STIM1 gene restores redox balance and protect against hypertension-induced cardiovascular complications.[253]
Future Directions and Unanswered Questions
Immune cells play a central coordinator role in dysregulated cardiorenal communication in hypertension. Immune cells sense hypertensive stimuli, like high salt, Ang II, aldosterone, sympathetic neurotransmitters, integrate with signals from RAAS, SNS, cardiovascular and renal system, amplify the inflammation and tissue injury, driving persistent hypertension. Although significant work has been done, some questions remain poorly understood. Which immune cell subtypes and pathways are the best targets for hypertension treatment which benefits the whole cardiorenal system? Discrete neuro-immune circuits that link the brain, kidney, and cardiovascular system in hypertension have been identified. However, the complexity of these circuits and the potential for off-target effects require careful preclinical and clinical evaluation. These interconnected circuits provide multiple nodes for therapeutic intervention. Targeting brain-immune interactions, for example, with drugs that cross the blood-brain barrier or with vagal nerve stimulation, represents a promising frontier in hypertension management. The clinical translation of microbiome-targeted interventions remains in early stages, and the causal relationships between specific microbial taxa and BP regulation require further elucidation. The etiology and pathogenesis of hypertension are highly heterogeneous, especially immune cells. With the unprecedented advances of high-throughput molecular technologies, including single-cell RNA sequencing, spatial transcriptomics, proteomics, and metabolomics, coupled with artificial intelligence, new opportunities are created to develop personalized interventions to better prevent hypertension and improve patient-specific cardiovascular outcomes. [1,254,255,256]

Funding

This work was funded by grants from the National Institutes of Health (NIH) grant R01HL144941 (AK).

Conflicts of Interest

The authors declare no conflict of interest. The figures were created with BioRender.com.

References

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Figure 1. Immune cells act as central coordinators of cardiorenal crosstalk in hypertension. Immune cells integrate signals from hemodynamic stress, high salt, the renin-angiotensin-aldosterone system (RAAS), and the sympathetic nervous system (SNS) to disrupt the normal cardiorenal communication in blood pressure management. The dysregulated cardiorenal communication drives chronic inflammation, fibrosis and end-organ damage in cardiorenal system, causing progressive hypertension.
Figure 1. Immune cells act as central coordinators of cardiorenal crosstalk in hypertension. Immune cells integrate signals from hemodynamic stress, high salt, the renin-angiotensin-aldosterone system (RAAS), and the sympathetic nervous system (SNS) to disrupt the normal cardiorenal communication in blood pressure management. The dysregulated cardiorenal communication drives chronic inflammation, fibrosis and end-organ damage in cardiorenal system, causing progressive hypertension.
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Figure 2. The balance of pro-inflammatory and anti-inflammatory immune cells controls the health status of blood pressure. Healthy cardiorenal communication maintains stable blood pressure through multiple counter-regulatory mechanisms limiting inflammation. Uncontrolled pro-inflammatory immune cells promote a self-perpetuating feedback loop causing renal dysfunction, cardiovascular dysfunction and cardiac remodeling. Sustained sodium retention and vascular stiffening leads to hypertension.
Figure 2. The balance of pro-inflammatory and anti-inflammatory immune cells controls the health status of blood pressure. Healthy cardiorenal communication maintains stable blood pressure through multiple counter-regulatory mechanisms limiting inflammation. Uncontrolled pro-inflammatory immune cells promote a self-perpetuating feedback loop causing renal dysfunction, cardiovascular dysfunction and cardiac remodeling. Sustained sodium retention and vascular stiffening leads to hypertension.
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Figure 3. High-salt diet drives immune activation and salt-sensitive hypertension. Salt accumulation increases intracellar Na+ in dendritic cells, leading to the production of ROS. ROS increases the isolevuglandin (IsoLG)-protein adducts. The IsoLG-protein adducts act as antigen driving naïve T cell differentiated to pro-inflammatory T17 cells, producing IL-17A, IFN-γ, and TNF-α. At the same time, high salt suppresses Treg cells. High salt concentrations trigger macrophages by shifting them into M1 phenotype while suppressing their M2 phenotype. Pro-inflammatory Th17 cells and M1 macrophages drive vascular dysfunction and kidney injury, leading to the development of SSBP.
Figure 3. High-salt diet drives immune activation and salt-sensitive hypertension. Salt accumulation increases intracellar Na+ in dendritic cells, leading to the production of ROS. ROS increases the isolevuglandin (IsoLG)-protein adducts. The IsoLG-protein adducts act as antigen driving naïve T cell differentiated to pro-inflammatory T17 cells, producing IL-17A, IFN-γ, and TNF-α. At the same time, high salt suppresses Treg cells. High salt concentrations trigger macrophages by shifting them into M1 phenotype while suppressing their M2 phenotype. Pro-inflammatory Th17 cells and M1 macrophages drive vascular dysfunction and kidney injury, leading to the development of SSBP.
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Figure 4. Communication between immune cells and renin-angiotensin-aldosterone system (RAAS). The major RAAS components, including renin, Ang II and aldosterone, are bidirectional communicated with immune cells. They may activate pro-inflammatory immune cells, which elevate the blood pressure. In healthy conditions, ACE2, kallikrein-kinin system (KSS), and kidney released Urodilatin and Klotho act as counter-regulatory mechanisms to provide endogenous braking signals that limit inflammation. Impaired counter-regulatory mechanisms fail to balance the inflammation signals in immune cells, leading to hypertension.
Figure 4. Communication between immune cells and renin-angiotensin-aldosterone system (RAAS). The major RAAS components, including renin, Ang II and aldosterone, are bidirectional communicated with immune cells. They may activate pro-inflammatory immune cells, which elevate the blood pressure. In healthy conditions, ACE2, kallikrein-kinin system (KSS), and kidney released Urodilatin and Klotho act as counter-regulatory mechanisms to provide endogenous braking signals that limit inflammation. Impaired counter-regulatory mechanisms fail to balance the inflammation signals in immune cells, leading to hypertension.
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Figure 5. Sympathetic overactivation drives hypertension through neuro-renal-immune amplification. Chronic stress, high salt and obesity et al cause sympathetic nervous system (SNS) overactivation. Sympathetic nervous system (SNS) nerve terminals release norepinephrine (NE) and ATP. NE stimulates immune cells (such as T cells, macrophages, and neutrophils) to release pro-inflammatory cytokines (such as IL-6, IL-1β, TNF-α), causing inflammation, arterial stiffening, cardiorenal damage and hypertension. As a sympathetic cotransmitter, ATP binds to P2X7 receptors on immune cells, triggering the release of potent pro-inflammatory cytokines. In return, pro-inflammatory cytokines communicate back to the brain, further amplifying SNS output.
Figure 5. Sympathetic overactivation drives hypertension through neuro-renal-immune amplification. Chronic stress, high salt and obesity et al cause sympathetic nervous system (SNS) overactivation. Sympathetic nervous system (SNS) nerve terminals release norepinephrine (NE) and ATP. NE stimulates immune cells (such as T cells, macrophages, and neutrophils) to release pro-inflammatory cytokines (such as IL-6, IL-1β, TNF-α), causing inflammation, arterial stiffening, cardiorenal damage and hypertension. As a sympathetic cotransmitter, ATP binds to P2X7 receptors on immune cells, triggering the release of potent pro-inflammatory cytokines. In return, pro-inflammatory cytokines communicate back to the brain, further amplifying SNS output.
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