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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 1  |  Issue : 2  |  Page : 88-95

The Role of the Immune System in the Pathophysiology of Essential Hypertension


1 Department of Pediatric, Pediatric Respiratory Disease Research Center, National Research Institute of Tuberculosis and Lung Disease, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Social Determinants of Health Research Center, Semnan University of Medical Sciences, Semnan, Iran

Date of Submission23-Mar-2022
Date of Decision06-May-2022
Date of Acceptance27-May-2022
Date of Web Publication15-Jun-2022

Correspondence Address:
Dr. Parisa Honarpisheh
Department of Pediatric, Pediatric Respiratory Disease Research Center, National Research Institute of Tuberculosis and Lung Disease, Shahid Beheshti University of Medical Sciences, Masih Daneshvari Hospital, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpdtsm.jpdtsm_19_22

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  Abstract 


Hypertension (HTN) is a critical worldwide health issue and an imperative risk factor for the development of cardiovascular disease and kidney disease. There are many crevices in our knowledge about the pathophysiology of HTN. The mechanisms intervening in HTN are complex. In recent years, a large scale of evidence supports the role of various components of the innate and adaptive immune systems (such as immune cells subsets, cytokines, complement system, and toll-like receptors) as contributors to HTN and developed end-organ damage. The endpoint of all these pathways is to develop an inflammatory condition that leads to HTN and damage to the end organ. Despite the availability of different antihypertensive drugs, there are still many patients with persistent or uncontrolled HTN. Therefore, understanding these immune pathways and their effects on patients with resistant hypertension. In addition, finding the detailed immunopathogenesis may help us find more targeted therapeutic approaches and improve cardiovascular and renal function in this high-risk untreated population. This review article summarizes different conducted studies on immunity and HTN that indicate the basic role of the immune system in causing HTN.

Keywords: Adaptive immune system, hypertension, innate immune system


How to cite this article:
Rekabi M, Daneshmandi Z, Sadati E, Mirzendehdel M, Mahdaviani SA, Valinejadi A, Velayati AA, Honarpisheh P. The Role of the Immune System in the Pathophysiology of Essential Hypertension. J Prev Diagn Treat Strategies Med 2022;1:88-95

How to cite this URL:
Rekabi M, Daneshmandi Z, Sadati E, Mirzendehdel M, Mahdaviani SA, Valinejadi A, Velayati AA, Honarpisheh P. The Role of the Immune System in the Pathophysiology of Essential Hypertension. J Prev Diagn Treat Strategies Med [serial online] 2022 [cited 2022 Aug 19];1:88-95. Available from: http://www.jpdtsm.com/text.asp?2022/1/2/88/347542




  Introduction Top


Hypertension (HTN) is a major public health problem and an important cause of death and disability worldwide, and there is a strong link between HTN and the risk of kidney and cardiovascular disease (CVD). Therefore, understanding its pathogenesis is important to choose the appropriate treatment aimed at optimal control and prevention of developing end-organ damage. HTN is classified into two types: primary and secondary. When HTN is not the result of an identifiable cause, it is termed primary or essential, or idiopathic, accounting for 90% of all hypertensive cases.[1] The pathophysiology of essential HTN is multifactorial involving both genetic predisposition and environmental factors. Some of the major known pathophysiological mechanisms leading to hypertension include overactivation of the sympathetic nervous system, oxidative stress, inappropriate activation of hormones that regulate salt and water hemostasis such as angiotensinogen, impaired arterial baroreflex system and endothelial dysfunction. In addition, renal autoregulation maintains blood pressure within a narrow range and prevents excessively high systolic blood pressure and disturbances of renal autoregulation can be associated with arterial hypertension.[2],[3],[4] Endothelial dysfunction and impaired release of endothelial relaxation factors such as nitric oxide (NO) and increased release of endothelial constrictor factors such as endothelin (ET) and thromboxane cause an imbalance between vasodilator and vasoconstrictor factors and lead to HTN.[5] Recent evidence suggests that both the innate and adaptive immune systems contribute to the pathogenesis of HTN and end-organ damage. This study discusses the various components of the immune system involved in primary HTN. The discovery of these signaling pathways, receptors, interleukins, and their link to HTN can guide us to find novel treatments to control HTN by targeting them.


  The Innate Immune System Top


Various components of the innate immune system involved in HTN include cells (macrophages, natural killer cells, granulocytes, and dendritic cells), sentinel pattern recognition receptors (PRRs) (toll-like receptors [TLRs], nucleotide-binding oligomerization domain-like receptors), the complement system, and inflammatory cytokines.

Cells

Dendritic cells

Dendritic cells (DCs) play a fundamental role in HTN. Classical DCs are identified by the expression of Fms-like tyrosine kinase 3 (FLT3) and CD11c and major histocompatibility complex class II. One theory about the role of DCs in HTN is explained by the entry of sodium in DCs through the epithelial sodium channel (ENaC). Arvind et al. showed that serum/glucocorticoid kinase 1 in CD11c + cells may function as a sodium sensor and mediate salt-induced expression of the β and γ subunits of ENaC to mediate the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and NADPH oxidase-dependent lipid oxidation and the formation of isolevuglandin–protein adducts (IsoLG) and γ-ketoaldehydes or isoketals in DCs, leading to T-cell proliferation and the production of inflammatory cytokines and HTN.[6] DCs also contribute to angiotensin (Ang II)-induced arterial HTN. FLT3 ligand is a growth factor that stimulates the development and differentiation of DCs. DCs can activate renal T lymphocytes, and these activated T cells by promoting oxidative stress and sodium reabsorption, particularly in the distal nephron, can lead to HTN. In addition, DCs induce pro-hypertensive cytokines such as interleukin-1 (IL-1)-β and tumor necrosis factor-α (TNF-α) in the kidney. DCs also contribute to HTN by activating the oxidative stress pathway through NADPH oxidase (NOX2 and NOX4 isoforms) in the kidney.[7] Prohypertensive cytokines and oxidative stress affect renal sodium transporters.

Natural killer cells

Natural killer (NK) cells have an important role in angiotensin II (AT-II)-induced vascular dysfunction. This is mediated by the production of interferon-γ (INF-γ) and other cytokines, which causes oxidative stress in the vasculature and influx of inflammatory cells, leading to proinflammatory cytokines production.[8] In addition, NK cells exert a significant role in normal vascular remodeling and development of the placenta in pregnancy through the secretion of angiogenic factors and cytokines, and abnormal activation of these cells contributes to preeclampsia.[9]

Monocytes/macrophages

Macrophages contribute to ANG II-dependent HTN. RAS activation in the renal proximal tubules stimulates macrophages infiltration into the kidney and increases intrarenal cytokines such as IL-6, which can induce HTN through the activation of the JAK-STAT pathway and consequent angiotensinogen upregulation.[10] In contrast, the expression of the AT1 receptor on macrophages has a protective effect on intrinsic renal and vascular cells during HTN. In addition, reactive oxygen species (ROS) and TNF-α and IL-1β produced by macrophages lead to oxidative stress and impaired natriuresis and HTN. In contrast, dermal (vascular endothelial growth factor) VEGF-C-expressing macrophages can stimulate lymphangiogenesis, which facilitates sodium removal.[11]

Neutrophils

increased blood neutrophil count and neutrophil/lymphocyte ratio are found in hypertensive patients, nondipper hypertensive patients, and resistant forms of HTN.[12],[13],[14],[15] Molecules, enzymes, and neutrophils receptors involved in HTN include NADPH oxidase, myeloperoxidase (MPO), NF-E2-related factor-2 (Nrf-2), inducible NO synthase, neutrophil gelatinase-associated lipocalin (NGAL), S100a8/a9, ET adhesion molecules, neutrophil adhesion molecules, and adrenergic receptors. Adrenergic stimulation can cause the release of neutrophil-derived enzymes such as NADPH oxidase and MPO and the subsequent generation of ROS and reactive nitrogen species. This oxidative and nitrative stress can cause endothelial dysfunction. ROS play important role in HTN by promotion of sympathetic outflow, activation of proinflammatory factors such as Nrf-2, nuclear factor-kappa, and adaptor protein 1 (AP-1), induction of vasoconstriction in vessels, and water/sodium retention in the kidney[16],[17] [Figure 1]. In this sense, antioxidants can be an adjuvant therapy in hypertensive patients. On the other hand, activated neutrophils by the secretion of cytokines/chemokines, NGAL, and S100a8/a9 recruit macrophages and DCs, and these cells induce inflammation and remodeling processes, perpetuating HTN.[18] Similarly, the pro-oxidative milieu can induce the expression of neutrophil adhesion molecules and the rolling of neutrophils on the endothelial surface. ROS and S100a8/a9 secreted by neutrophils also promote the rolling process. Furthermore, the prohypertensive microenvironment induces ET-1 secretion by endothelial cells. By stimulating IL-8 production and adhesion molecules expression, ET1 can induce neutrophilic adrenergic receptors and adhesion processes, respectively, and enhance HTN.[18],[19]
Figure 1: The role of neutrophils in HTN; adrenergic stimulation can cause the release of neutrophil-derived enzymes such as NADPH oxidase and MPO and the subsequent generation of ROS and RNS. This oxidative and nitrative stress can cause endothelial dysfunction. ROS also active the proinflammatory factors such as Nrf-2, NFκB, and AP-1, which lead to proinflammatory cytokines production. These cytokines recruit dendritic cells and macrophages that play an important role in vessel remodeling, inflammation, and HTN. HTN: Hypertension, MPO: Myeloperoxidase, ROS: Reactive oxygen species, RNS: Reactive nitrogen species, NF-κB: Nuclear factor-kappa B, AP-1: Adaptor protein 1

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Toll-like receptors

TLRs belong to a family of PRRs, which play a crucial role to detect pathogens by the innate immune cells. They are present on macrophages, DCs, antigen-presenting cells, neutrophils, NK cells, T and B lymphocytes, vascular smooth muscle cells, and endothelial cells. Although TLRs are important in host defense, the loss of their downregulation is associated with inflammation.

Shear stress results in functional and structural vascular changes and remodeling, which is characterized by vessel stiffness. Vascular remodeling can lead to tissue hypoperfusion and cell injury/death. Tissue damage produces host-derived molecules called Damage-Associated Molecular Patterns (DAMPs). In addition, hypertensive stimuli such as high salt intake, stress, and AT-II can increase DAMPs in the circulation. TLRs can recognize DAMPs. TLRs activating proinflammatory signaling pathways such as NF-κB result in the synthesis of cytokines/chemokines/adhesion molecules and initiate an inflammatory response that leads to vascular remodeling. Short-term TLR activation restores hemostasis and has a protective effect and facilitates tissue repair, but sustained or excessive activation of TLRs can be detrimental and contribute to the proinflammatory state, chronic vascular inflammation, oxidative stress, vascular remodeling, and eventually overt HTN, especially in genetically predisposed individuals. In addition, NF-κB activation in rats has been shown to promote renal angiotensin II receptor (AT1R) expression and subsequent tubular sodium handling and increase blood pressure.[20]

The interaction between TLRs and DAMPs and the subsequent cytokine cascade may also trigger adaptive immune system responses and regulation and differentiation of T-cells as well as the development and establishment of HTN.[21] To date, several DAMPs, including AT-II, mitochondrial DNA (mtDNA), fibrinogen, heat shock protein 70, hyaluronan, uric acid, C-reactive protein, heparin sulfate, and fibronectin, are putative TLRs agonists and have been identified as potential contributors to HTN[22] and both extracellular TLRs 1, 2, 4, 5, 6 as well as endosomal TLRs 7, 8, 9 have been implicated to play a role in HTN.[21] There are two distinct TLR signaling pathways: the myeloid differentiation factor 88 (MyD88)-dependent pathways and the TLR domain-containing adaptor-inducing interferon (IFN)-β (TRIF)-dependent pathways that induce upregulation of proinflammatory mediators. TLRs 1, 2, 5, 6, 7, 8, 9 active NF-κB via the MyD88-dependent pathway and induce the production of inflammatory cytokines such as TNF-α, interleukins IL-1β, IL-6, IL-8, and IL-12, and monocyte chemotactic protein 1 (MCP-1). TLRs 7, 8, and 9 also provoke an inflammatory response and the production of type 1 INF through IRF7. The TRIF-dependent pathway activates interferon-regulatory factor 3 (IRF3) and the transcription factor NF-κB via TLR3 and 4. TLR4 also activates the MyD88 pathway NF-κB[23] [Figure 2]. The interaction between TLR-4 and TRIF appears to mediate ANG-II-induced HTN.[24] MyD88 and TRIF are known as adaptor proteins and may be important targets of therapeutic interventions for HTN. Overall, the aforementioned data underscore a substantial role of TLRs in the development of HTN and the potential therapeutic value of their inhibition. In addition, recent evidence suggests that TLR2 reduces NO, leading to endothelial dysfunction and atherosclerosis.[21] In vascular smooth muscle cells (VSMCs) of the pulmonary artery, TLR3 activation promotes the release of IL-8, CXCL10, and ET-1,[25] and in coronary VSMCs, TLR3 activation induces the release of IL-6 and MCP-1[26] and has a hypertensive effect. In contrast, it has been shown that after mechanical vascular injury, TLR3, through the expression of anti-inflammatory glycoproteins, has a protective effect on the vessel wall. The role of TLR4 in the development of HTN is exerted through aortic contraction and release of IL-6, but TLR activation by Gram-negative bacteria elevates NO and lowers blood pressure.[27] Flagellated microorganisms within the intestine cause TLR5 activation and stimulation of apolipoprotein A1 (ApoA1) production and high-density lipoprotein (HDL) in the liver, which is associated with a reduction in CVD. In this way, dysbiosis of gut microbiota through TLR5 suppression can decrease HDL and ApoA1 levels and lead to atherosclerosis and HTN.[28] Following cell injury, mtDNA is released into the circulation, leading to the activation of TLR9 in immune cells and endothelial cells and the production of proinflammatory cytokines through the MyD88-dependent pathway and increased endothelial permeability, respectively. These events lead to vascular dysfunction, vascular remodeling, and HTN. Prehypertensive stimuli such as excessive sodium diet, AT-II, and stress can activate TLR9.[21]
Figure 2: TLR signaling cascade. The myeloid differentiation factor 88 (MyD88)-dependent pathways and the TLR domain-containing adaptor-inducing IFNβ (TRIF)-dependent pathways: In the MyD88-dependent pathway, TLR signaling activates the inhibitor IKK complex, and IKK phosphorylates IκB (IκB/NF-κB complex) and leads to its ubiquitylation and degradation of IκB and its separation from NF-κB. Subsequently, NF-κB can be translocated from the cytoplasm to the nucleus and induce the transcription of inflammatory cytokine genes. Another signaling pathway related to My-88 is the stimulation of AP-1 transcription factor by the MAPK module. The MAPK module contains at least 3 protein kinases (ERK1/2, JNK/SAPK, and p38). Then AP-1 translocates to the cell nucleus and upregulates the expression of proinflammatory mediators. The TRIF-dependent pathway via TLR3 leads to the activation of IRF3, and IRF3 regulates the transcription of IFN-1. TLR: Toll-like receptor, IFNβ: Interferon β, IKK: I Kappa B Kinase, NF-κB: Nuclear factor-kappa B, MAPK: Mitogen-activated protein kinase, AP-1: Adaptor protein 1, IFN-1: Type 1 interferon

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Due to the fundamental role of the NF-κB signaling pathway, inhibition of this pathway (for example, with bortezomib) can be a promising candidate to control of HTN [Figure 3].
Figure 3: Different components related to the immune system involved in hypertension and proposed strategies to inhibit them

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Adaptor proteins

Adaptor proteins involved in HTN include myeloid differentiation primary response protein (MyD88), Toll-IL-1 receptor domain-containing adaptor protein (TIRAP)-inducing interferon-β (TRIF), and TRIF-related adaptor molecule (TRAM). TRAM and TIRAP recruit TRIF to TLR4 and MyD88 to TLR2 and TLR4, respectively, and ultimately induce inflammatory cytokines.[29] There are several MyD88-dependent signaling pathways. In one of them, TLR signaling activates the inhibitor I Kappa B Kinase (IKK) complex, and IKK phosphorylates IκB (IκB/NF-κB complex) and leads to its ubiquitylation and degradation of IκB and its separation from NF-κB. Subsequently, NF-κB can be translocated from the cytoplasm to the nucleus and induce the transcription of inflammatory cytokine genes. Another signaling pathway is the stimulation of AP-1 transcription factor by the mitogen-activated protein kinase (MAPK) module. The MAPK module contains at least 3 protein kinases (ERK1/2, JNK/SAPK, and p38) involved in HTN and vascular dysfunction. AP-1 then migrates to the cell nucleus and upregulates the expression of proinflammatory mediators.[30] Another transcription factor in the MyD88-dependent pathway is the interferon regulatory factor (IRF-7), which is only found downstream of TLR9,[29] and its contribution to HTN is not yet known.[21] The TRIF-dependent pathway via TLR3 and 4 leads to the IRF3 activation, and IRF3 regulates the transcription of IFN [Figure 2].

Interleukins

HTN is related to a persistent inflammatory state, and the levels of inflammatory cytokines such as IL-1β, IL-6, IL-8, IL-17, IL-23, TGFβ, and TNFα are higher in hypertensive patients. Innate immune cells produce inflammatory cytokines via different signaling pathways involved in HTN.

Interleukin-6

AT-II binding to the AT1 receptor stimulates the production of proinflammatory mediators such as IL-6. IL-6 through renal cortical phosphorylation of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) and subsequent tubular sodium reabsorption increases blood pressure.[31] Sterpetti et al. suggested that IL-6 can upregulate the vasoconstrictive effects of Ang II.[32] Moreover, IL-6 can be involved in the pathogenesis of HTN by stimulating collagen and fibrinogen synthesis in the arterial wall and therefore vascular stiffness.[32] In addition, IL-6 using STAT signaling enhances NADPH oxidase and endothelial NO synthase with a subsequent impact on superoxidase and NO levels, altering vascular permeability and causing vasoconstriction and vascular fibrosis.[33],[34] Moreover, IL-6 leads to the increased synthesis of inflammatory markers such as C-reactive protein and TNF-α in the liver, provoking vascular damage.[35] IL-6 induces the maturation of B cells and proliferation of INF-γ-secreting CD4+ T cells and it also influences the hypertensive response through the adaptive immune pathway.[36]

Interleukin-1

Both the IL-1α and IL-1β isoforms are involved in HTN through the IL-1 receptor type 1 (IL-1R1). RAS activation increases the expression of both IL-1 isoforms, and these isoforms reduce NO bioavailability through IL-1R1 signaling. NO suppresses Na-K-2Cl cotransporter (NKCC2) to facilitate natriuresis. In this regard, IL-1R1 signaling enhances NKCC2 cotransporter activity and therefore sodium retention and HTN.[37] IL-1 promotes the expression of adhesion molecules such as vascular cell adhesion protein 1, intercellular adhesion molecule 1, and E-selectin[38] and increases endothelial permeability and ultimately leading to endothelial dysfunction.[39]

Tumor necrosis factor-α

TNF-α has been implicated as a causative agent of both HTN and hypotension, and the cause of these paradoxical effects is unclear. Two surface receptors of TNF-α (TNFR1 and TNFR2) may explain these contradictory functions. TNF-α signaling through TNFR1 dampens intrarenal angiotensin formation, thus promoting the natriuretic response and controlling HTN. In contrast, TNF-α signaling via TNFR2 activates proinflammatory pathways and induces glomerulosclerosis and renal injury. Chronic high salt intake together with oxidative stress via reduced activity of TNFR1 and enhanced activity of TNFR2 lead to salt-sensitive HTN and renal injury, respectively.[40] Such discrepancies also may be explained by the TNF-α concentration. Moderate levels of TNF-α through diminished NO production and enhanced NaCl reabsorption are associated with HTN. In contrast, high levels of TNF-α cause inflammation and HTN.[41]

Due to the association between some of the inflammatory cytokines (such as IL-1, IL-6, TNFα,…) and HTN, measuring the serum levels of these cytokines and using their inhibitor drugs (such as tocilizumab: anti-IL-6 or adalimumab or infliximab: anti-TNFα) may attenuate HTN [Figure 3].

Complement system

complement activation may lead to HTN through its impact on the vasculature and both innate and adaptive immune responses. All three complement pathways (classic, alternative, lectin) are involved in HTN. Ang II leads to macrophage recruitment and C1q secretion. C1q induces classic pathway signaling that promotes hypertensive vascular remodeling.[42] The alternative pathway amplifies complement inflammatory responses and seems to play a role in hypertensive end-organ damage.[43] The lectin pathway is activated by DAMPs that have been released from damaged cells due to shear stress.[44] Complement activation produces the anaphylatoxins C3a and C5a. C3a causes vasoconstriction and HTN through thromboxane prostanoid and cyclooxygenase 1 (COX1).[45] C5a causes the production of ROS through intracellular binding to its receptor (C5aR1) and induces activation of T helper 1 (Th1). After Th1 activation, the C3a-C3rR complex is transported to the cell surface and induces a Th1 response.[42] T cells induce endothelial dysfunction and HTN through the production of inflammatory cytokines, such as IFN-γ, TNF-α, and IL-17A.[46]


  Adaptive Immune System Top


Components of the adaptive immune system involved in arterial HTN include B cells and their antibodies (Ab), T cells, and their proinflammatory cytokines.

B cells

Dingwell et al. confirmed that B cells increase vasopressin receptor 2 (V2R) expression within the medulla of the kidney. Antidiuretic hormone after binding to V2R can affect blood pressure through the handling of salt and water in the distal nephron.[47] Several research has confirmed the role of autoantibodies in HTN. There was an increase in antibodies against heat shock protein 65 and 70 (Hsp65, Hsp70), AT-II receptor type 1 (AT1), α1 adrenergic receptor (α1AR), and vascular L-type Ca2+ channel in hypertensive patients. Furthermore, an increased level of anti-AT1 and anti-α1AR was found in patients with refractory HTN and malignant HTN.[46]

Cytokines

T-cell-derived cytokines such as IL-17, IFN-γ, and TNF-α are implicated in essential HTN and end-organ damage. IL-17 produced by T helper 17 (Th17) causes endothelial dysfunction, decreased NO-dependent vasodilatation, and expression of inflammatory cytokine genes in aortic smooth muscle cells[46] and induces TNF-α and IL-6 production.[48] IL-17 also plays a crucial role in maintaining Ang II-induced HTN.[49] Nordlohne et al. showed that IL-17 induces atherogenesis and that numerous factors such as hyperlipidemia, diabetes mellitus, AT-II, chronic kidney disease, and excess sodium intake can stimulate IL-17A production in Th17 cells.[50]

T-cell subtypes

Both cytotoxic T cells (CD8+) and T helper cells (CD4+) are implicated in the development of HTN and hypertensive nephrosclerosis.[51] TNF-α and IFN-γ are produced by CD8 + and T helper type 1 cells, and IL-17 is produced by T helper type 17 cells. IFN-γ and TNF-α regulate renal sodium transporters during Ang II-dependent HTN. Ang II actives cortical Na-K-2Cl cotransporter (NKCC), Na-Cl cotransporter, and ENaC and inactivates proximal transporters Na/H exchanger isoform 3, Na-phosphate transporter isoform 2 [NaPi2], and medullary NKCC that result in a significant decrease of FENa in distal tubules and eventually HTN.[52] Marvar et al. demonstrated that AT-II can stimulate central mechanisms and sympathetic outflow, particularly in the circumventricular organ, which results in circulating T-cell activation and vascular inflammation.[53] Regulated upon activation, normal T-cell expressed and presumably secreted chemokine (RANTES) is also necessary for chemotaxis of T cells expressing the RANTES receptors CCR1, CCR3, and CCR5 in perivascular fat tissue in Ang II-induced HTN.[54] Foxp33+ regulatory T cells (Treg cells) have an antihypertensive effect due to their important role in coronary vessels relaxation. Moreover, Treg cells suppress activated monocytes and macrophages. These Treg cells release IL-10, and this cytokine decreases NADPH oxidase activity, which is associated with better endothelial function in hypertensive cases.[55] Therefore, a decreased proportion of Treg cells contributes to the induction of HTN.[56] A similar result was found during mineralocorticoid receptor (MR) activation. MR activation alters the Th17/Treg ratio in peripheral tissue, heart, and kidney and causes vascular remodeling and HTN.[57] It has been demonstrated that gender affects the Th17/Treg ratio and males revealed a higher rate of disproportionate T-cell ratio and therefore they have a higher prevalence of T-cell mediated hypertension, renal disease, and end-organ damage(2).[46]

Due to the role of different subtypes of T cells in HTN, increased proportion of Treg cells and decreased CD4+ and CD8+ T cells can be a therapeutic option in hypertensive patients [Figure 3].

One of the major challenges among nephrologists and cardiologists is patients who still have uncontrolled HTN despite receiving several antihypertensive drugs. Therefore, it seems that other unidentified mechanisms play an important role to drive HTN. This study provides insight into the fundamental role of both innate and adaptive immune systems in the development of inflammation, vascular remodeling, fibrosis, HTN, and end-organ damage, and HTN should be considered an inflammatory disease. Advancement in the understanding of different immune pathways and uncovering mechanisms responsible for activation of immune response results in pharmacologic modulation of these pathways and more targeted therapeutic approaches to overcome them and increase the percentage of patients who achieve their blood pressure goal.

Acknowledgment

The authors would like to thank the Pediatric Respiratory Disease Research Center for editorial assistance.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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