Hypertension and immune system disorders -
Accordingly, inflammation and immune system activation cause derangement in kidneys, arteries, brain, and heart functions that consequently promote hypertension and end-organ damage [ 57 ].
In support of the above mentioned hypothesis, current studies indicated that known stimuli that raise blood pressure such as high-salt diet, Ang II, and DOCA-salt directly and indirectly activate immune system cells.
Elevated blood pressure can stress tissue cells to the level that DAMPs released by tissues. Moreover, hypertensive stimuli can directly activate immune cells and also cause formation of neoantigens in the tissues. As a result of released DAMPs, neoantigens, and direct immune cells activation by hypertension stimuli, activated immune cells are formed, target organs infiltrated by activated immune cells, and diverse inflammatory cytokines are released by the activated immune cells.
Eventually, the affected target organs, mainly the kidney, blood vessels, and sympathetic nervous system function are perturbed and this leads to further elevated blood pressure level and finally to hypertension. Immune cells such as monocytes, macrophages, and dendritic cells DCs release pro-hypertensive cytokines that promote the BP elevation via actions in the vasculature augmenting vascular dysfunction , kidney increasing sodium retention , and stimulating sympathetic nervous system outflow [ 58 ].
Many studies implicated that in the kidney, inflammatory cells and their products contribute to blood pressure elevation at least in part by increasing renal sodium transport [ 59 ]. Genetic deletion of IL-6 in mice results in blunted hypertension in response to angiotensin II infusion [ 60 ].
Taken together, these studies suggest that IL-6 enhances renal tubule sodium reabsorption and elevates BP at least in part through up regulation of renal tubule ENaC. IL-1 is a pro-inflammatory cytokine that plays a central role in both acute and chronic inflammation, acting as a primary inducer of the innate immune response.
Studies indicated that type 1 IL-1 receptor IL-1R1 stimulation by IL-1 potentiates blood pressure elevation by suppressing nitric oxide NO -dependent sodium excretion in the kidney. Nitric oxide is a potent driver of sodium excretion in the kidney that acts via cyclic guanosine monophosphate cGMP and phosphodiesterase two to limit Na-K-2Cl cotransporter NKCC2 activity in the medullary thick ascending limb.
Thus, by relieving NO inhibitory effect on NKCC2, IL-1 enhances reabsorption of electrolytes by medullary thick ascending limb and enhances retention of sodium and water by kidney [ 39 ]. Interferon gamma IFN-γ is a proinflammatory cytokine produced by innate and adaptive immune cells, and T cell production of IFN-γ is increased in Ang II-induced hypertension and mice deficient in IFN-γ have a blunted blood pressure response to Ang II infusion.
Experimental studies indicate that IFN-γ positively regulates sodium hydrogen exchanger 3 NHE3 in the proximal tubule, NKCC2 in medullary thick ascending limb, and NCC in the distal tubule. Whether IFN-γ directly modulates these sodium transporters or acts through downstream mediators is unknown [ 62 ].
Mice model experimental studies and cell culture model studies showed that interleukin 17A up regulates NHE3 in proximal segment , NCC and ENaC in distal segment of renal tubules. Moreover, studies implicated that interleukin 17A regulates renal sodium transporters through a serum and glucocorticoid regulated kinase 1 SGK1 dependent pathway [ 63 ].
Serum and glucocorticoid regulated kinase1 is an important mediator of salt and water retention in the kidney through inhibition of neural precursor cell expressed developmentally down-regulated Nedd mediated ubiquitination and degradation of NHE3, NCC, and ENaC in the renal tubule, thereby enhancing the expression of these transporters on the cell surface [ 64 ].
Besides its effect on electrolyte and water homeostasis regulation function of kidney, sustained inflammation results in renal fibrosis, oxidative stress, glomerular injury, and chronic kidney disease [ 59 ].
Blood vessels are other organs that are affected by activated immune system and chronic low grade inflammation associated with hypertension. Elevated blood pressure has an impact on the vasculature as a consequence of both the mechanical effects of blood pressure and shear stress [ 65 ].
Inflammation can impair blood vessels in two ways. Inflammation can cause functional arterial stiffening by impairing the functional relaxation capability of arteries. The other mechanism is structural remodeling of arteries due to hypertension-associated inflammation [ 66 ].
Likewise, many experimental studies confirmed involvement of immune cells and inflammatory cytokines in vascular dysfunction associated with experimental hypertension. An experimental study done on mice showed that Ang II infusion in mice increased immune cell content T cells, macrophages, and dendritic cells in perivascular adipose tissue and adventitia [ 67 ].
Endothelial cell culture study showed that inflammatory marker, C-reactive protein CRP , caused a marked down regulation of endothelial nitric oxide synthase eNOS mRNA and protein expression [ 68 ]. Similarly, TNF-α mediated inhibition of eNOS expression was observed in endothelial cell culture [ 69 ].
Acute treatment of endothelial cells with IL caused a significant increase in phosphorylation of the inhibitory eNOS residue threonine eNOS Thr [ 70 ].
All these studies indicate that inflammation decreases bioavailability of endothelial NO and thus impairs vascular smooth muscle relaxation and subsequent vasodilatations. Moreover, involvement of immune cells and inflammatory cytokines in hypertensive vascular remodeling is implicated by many studies.
These studies implicated that immune cells and inflammatory cytokines play roles in vascular fibrosis, remodeling of small and large vessels, and vascular rarefaction in hypertension.
Nonetheless, this remains to be further investigated. Other important organ both in development of hypertension and as an end-organ target of hypertension is the brain.
Regulation of short-term blood pressure level by sympathetic nervous system SNS is well established. SNS stimulation is associated with constriction of blood vessels, increased cardiac output, and augmented sodium and fluid retention by the kidneys [ 72 ]. Moreover, SNS serves as an integrative interface between the brain and the immune system.
Mounting evidence implicate that many forms of essential hypertension are initiated and maintained by an elevated sympathetic tone [ 73 ].
The elevated sympathetic activity can be initiated by several factors including humoral factors such as angiotensin II and by environmental factors such as stress and high salt intake. Observations such as increased splenic sympathetic nerve discharge SND and consequent increase in splenic cytokine gene expression IL-1β, IL-6, IL-2, and IL due to central Ang II administration the effect which was abrogated by splenic sympathetic denervation , and others led to the hypothesis that central stimuli such as angiotensin II cause modest elevations of blood pressure, which leads to activation of immune system.
Subsequently, the activated immune system leads to severe hypertension [ 76 ]. This hypothesis proposed a mechanism that occurs in a two-phase feed forward fashion. The initial phase brings a modest elevation in blood pressure i. In the second phase, the activated immune system generates cytokines and other inflammatory mediators which work in concert with the direct effects of hypertensive stimuli such as angiotensin II, catecholamines, and salt to cause vascular and renal dysfunction, promote vasoconstriction, vascular remodeling, a shift in the pressure-natriuresis curve and sodium retention, and ultimately causes sustained hypertension [ 74 ].
Hypertension is a widely prevalent public health problem of world adult population. It is a major risk factor of cardiovascular diseases, chronic kidney disease, and dementia. This indicates lack of efficacy of existing hypertension treatment strategies and existence of additional drivers of hypertension that must be identified and may be targeted.
One of the proposed pathophysiologic mechanisms that contribute for elevated BP and target organ damage among hypertensive patients is activation of the immune system and chronic low grade systemic inflammation.
In kidneys, inflammatory cells and their products contribute to blood pressure elevation by increasing renal sodium retention and by causing renal fibrosis, oxidative stress, and glomerular injury. IL-1, IL-6, IFN-γ, and IL are among pro-inflammatory cytokines that enhance sodium retention by renal tubules.
Activated immune cells and pro-inflammatory cytokines may contribute to functional arterial stiffening and structural remodeling of arteries that consequently cause elevated blood pressure in hypertension.
C-reactive protein, TNF-α, and IL may hamper synthesis of or inhibit nitric oxide NO synthase. Inflammatory cells that infiltrate blood vessels such as macrophages and lymphocytes and their pro-inflammatory products may also contribute for vascular remodeling.
Perturbed immune system and chronic low grade systemic inflammation also enhance SNS activity which in turn contributes to elevated blood pressure by its effect on blood vessels tone vasoconstriction , on the kidneys sodium and water retention, RAAS activation and on immune system activation of immune system and enhanced production pro-inflammatory cytokines.
Thus, unraveling the detail pathophysiological mechanisms by which activated immune system and inflammation contribute to hypertension paves a way to identify target, and to design and develop therapeutic intervention for hypertension. Even though currently there is no anti-inflammatory drug to treat hypertension, anti-inflammatory agents that target specific inflammatory pathway without compromising general immune system of an individual are possible future hypertension treatment drugs.
Author does not have any conflict of interest whatsoever with regard to content or opinions expressed above. Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Edited by Naofumi Shiomi. Open access peer-reviewed chapter Immune System and Inflammation in Hypertension Written By Mohammed Ibrahim Sadik.
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Chapter metrics overview Chapter Downloads View Full Metrics. Impact of this chapter. Abstract Hypertension is a widely prevalent and a major modifiable risk factor for cardiovascular diseases. Keywords hypertension immune system inflammation. References 1.
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Ryan reports grants from Veterans Affairs, grants from NIH, grants from AHA, during the conduct of the study. Wolf declares no conflicts of interest relevant to this manuscript.
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Download PDF. Abstract Purpose of Review To highlight important new findings on the topic of autoimmune disease-associated hypertension. Recent Findings Autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis are associated with an increased risk for hypertension and cardiovascular disease.
Summary This review examines the prevalent hypertension in autoimmune disease with a focus on the impact of immune system dysfunction on vascular dysfunction and renal hemodynamics as primary mediators with oxidative stress as a main contributor. Diagnosis and management of autoimmune diseases in the ICU Article 19 December The Different Therapeutic Choices with ARBs.
Which One to Give? Article Open access 03 March Renal Disease and Systemic Sclerosis: an Update on Scleroderma Renal Crisis Article Open access 01 June Use our pre-submission checklist Avoid common mistakes on your manuscript. Hypertension Is Prevalent in Patients with Autoimmune Disease Clinical evidence shows that there is a strong association between autoimmune diseases like SLE and RA with hypertension [ 16 ].
Risk Factors for Autoimmune Disease and Hypertension Both SLE and hypertension are multifactorial diseases. Genetic Factors Numerous susceptibility genes have been identified in the pathogenesis of autoimmune diseases.
Sex-Specific Factors The idea that the immune system can impact blood pressure in a sex-dependent manner is supported by numerous studies summarized in these recent reviews [ 48 , 49 , 50 ]. Metabolic Factors Autoimmune diseases like SLE are commonly associated with metabolic changes including insulin resistance and dyslipidemia [ 55 ].
Immune System Dysfunction: The Role of B and T Cells Recent studies from our laboratory demonstrated a key mechanistic role of immune system dysfunction in hypertension associated with autoimmunity in the NZBWF1 female mouse model of SLE [ 10 , 11 , 60 ].
Vascular Dysfunction Numerous studies reported that patients with SLE or RA exhibit impaired vascular function as measured by endothelial dependent, flow-mediated dilatation [ 78 , 79 ]. Renal Hemodynamics Body salt and fluid homeostasis and are essential for normal blood pressure control, and renal hemodynamic changes that lead to increased sodium and water reabsorption and extracellular fluid volume underlie the development of hypertension.
Alterations in Glomerular Filtration Rate and Renal Blood Flow Surprisingly, little is known about how the immunological changes that occur in patients with autoimmune disease directly impact renal hemodynamic function and increase the risk of developing hypertension.
Renin-Angiotensin System The renin-angiotensin system RAS is widely recognized for its role in blood pressure control and is also recognized for its role as a proinflammatory mediator.
Oxidative Stress Reactive oxygen species ROS , such as superoxide anion, hydrogen peroxide, and hydroxyl anion, are known to play a major role in the tissue damage associated with autoimmune disease and in the development of hypertension [ 98 , 99 ].
Neutrophils Neutrophils are specialized phagocytic cells of the innate immune system that play a key role in the release of ROS during an autoimmune inflammatory response [ ]. Mitochondrial Dysfunction Apoptosis and NETosis are both energy-consuming processes that require mitochondria as an energy source, and mitochondria are a major cellular source of intracellular ROS generation [ ].
Conclusions The management of high blood pressure in patients with autoimmune disease should be considered a major aspect of their treatment plan. Article PubMed Google Scholar Barbour KE, Helmick CG, Boring M, Brady TJ.
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Increasing idsorders indicates that Wnd and hypertensive end-organ damage are not only mediated by hemodynamic injury. Inflammation also diworders an important role in Hypertension and immune system disorders pathophysiology and contributes to the deleterious syztem of this disease. Moreover, convincing evidence shows that T and B Fueling for long-distance events from the adaptive immune system are involved in hypertension and hypertensive end-organ damage. Sodium intake is undoubtedly indispensable for normal body function but can be detrimental when taken in excess of dietary requirements. Some of these effects are mediated by changes in the microbiome and metabolome that can be found after high salt intake. Modulation of the immune response can reduce severity of blood pressure elevation and hypertensive end-organ damage in several animal models. The purpose of this review is to briefly summarize recent advances in immunity and hypertension as well as hypertensive end-organ damage. Hypertension is the primary cause of cardiovascular disease, Hhpertension is a leading Hypdrtension worldwide. Current Support healthy aging process options focus Continuous blood glucose monitoring on Hypertension and immune system disorders Hyertension pressure through Hjpertension peripheral resistance or reducing fluid Hypertensin, but Hyperrension than half of Hypertensiob patients can reach Continuous blood glucose monitoring pressure control. Hence, identifying unknown mechanisms causing essential hypertension and designing new treatment Hypwrtension are critically needed for improving public health. In recent years, the immune system has been increasingly implicated in contributing to a plethora of cardiovascular diseases. Many studies have demonstrated the critical role of the immune system in the pathogenesis of hypertension, particularly through pro-inflammatory mechanisms within the kidney and heart, which, eventually, drive a myriad of renal and cardiovascular diseases. However, the precise mechanisms and potential therapeutic targets remain largely unknown. Therefore, identifying which immune players are contributing to local inflammation and characterizing pro-inflammatory molecules and mechanisms involved will provide promising new therapeutic targets that could lower blood pressure and prevent progression from hypertension into renal or cardiac dysfunction.
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