For >50 years, it has been recognized that immunity contributes to hypertension. Recent data have defined an important role of T cells and various T cell-derived cytokines in several models of experimental hypertension. These studies have shown that stimuli like angiotensin II, deoxycorticosterone acetate-salt, and excessive catecholamines lead to formation of effector like T cells that infiltrate the kidney and perivascular regions of both large arteries and arterioles. There is also accumulation of monocyte/macrophages in these regions. Cytokines released from these cells, including interleukin-17, interferon-γ, tumor necrosis factorα, and interleukin-6 promote both renal and vascular dysfunction and damage, leading to enhanced sodium retention and increased systemic vascular resistance. The renal effects of these cytokines remain to be fully defined, but include enhanced formation of angiotensinogen, increased sodium reabsorption, and increased renal fibrosis. Recent experiments have defined a link between oxidative stress and immune activation in hypertension. These have shown that hypertension is associated with formation of reactive oxygen species in dendritic cells that lead to formation of gamma ketoaldehydes, or isoketals. These rapidly adduct to protein lysines and are presented by dendritic cells as neoantigens that activate T cells and promote hypertension. Thus, cells of both the innate and adaptive immune system contribute to end-organ damage and dysfunction in hypertension. Therapeutic interventions to reduce activation of these cells may prove beneficial in reducing end-organ damage and preventing consequences of hypertension, including myocardial infarction, heart failure, renal failure, and stroke.

Inflammation, Immunity, and Hypertensive End-Organ Damage

Hypertension is a complex condition and is the most common cardiovascular risk factor, contributing to widespread morbidity and mortality. Approximately 90% of hypertension cases are classified as essential hypertension, where the precise cause is unknown. Hypertension is associated with inflammation; however, whether inflammation is a cause or effect of hypertension is not well understood. The purpose of this review is to describe evidence from human and animal studies that inflammation leads to the development of hypertension, as well as the evidence for involvement of oxidative stress and endothelial dysfunction—both thought to be key steps in the development of hypertension. Other potential proinflammatory conditions that contribute to hypertension—such as activation of the sympathetic nervous system, aging, and elevated aldosterone—are also discussed. Finally, we consider the potential benefit of anti-inflammatory drugs and statins for antihypertensive therapy. The evidence reviewed suggests that inflammation can lead to the development of hypertension and that oxidative stress and endothelial dysfunction are involved in the inflammatory cascade. Aging and aldosterone may also both be involved in inflammation and hypertension. Hence, in the absence of serious side effects, anti-inflammatory drugs could potentially be used to treat hypertension in the future.

https://downloads.hindawi.com/journals/bmri/2014/406960.pdf

Roles of Inflammation, Oxidative Stress, and Vascular Dysfunction in Hypertension

Salt-sensitivity of blood pressure is an abnormal phenotype that confers increased cardiovascular morbidity. We discuss its underlying renal mechanisms, including the role of systems that regulate renal salt handling. We review knockout and congenic strains that have unraveled participation of several genes in rodents inbred to produce pure salt-sensitive and salt-resistant substrains. In humans, salt-sensitivity is a continuous variable, hence, defined with arbitrary cutoffs for blood pressure responses to salt-loading or deprivation. Nonetheless, clustering of phenotypic characteristics in salt-sensitive subjects suggests an inherited component for this trait. This is supported by relationships between salt-sensitivity and gene polymorphisms in renal transporters, vasoactive substances and oxidative systems. Identification of biochemical or genetic markers of salt-sensitivity for use in the clinic would improve risk stratification of hypertensive and prehypertensive subjects. Understanding of its pivotal mechanisms may lead to specific therapies to decrease the cardiovascular risk associated with this trait in humans.

Salt Sensitivity of Blood Pressure

High blood pressure is present in more than one billion adults worldwide and is the most important modifiable risk factor of death resulting from cardiovascular disease While many factors contribute to the pathogenesis of hypertension, a role of the immune system has been firmly established by a large number of investigations from many laboratories around the world Immunosuppressive drugs and inhibition of individual cytokines prevent or ameliorate experimental hypertension, and studies in genetically-modified mouse strains have demonstrated that lymphocytes are necessary participants in the development of hypertension and in hypertensive organ injury Furthermore, immune reactivity may be the driving force of hypertension in autoimmune diseases Infiltration of immune cells, oxidative stress, and stimulation of the intrarenal angiotensin system are induced by activation of the innate and adaptive immunity High blood pressure results from the combined effects of inflammation-induced impairment in the pressure natriuresis relationship, dysfunctional vascular relaxation, and overactivity of the sympathetic nervous system Imbalances between proinflammatory effector responses and anti-inflammatory responses of regulatory T cells to a large extent determine the severity of inflammation Experimental and human studies have uncovered autoantigens (isoketal-modified proteins and heat shock protein 70) of potential clinical relevance Further investigations on the immune reactivity in hypertension may result in the identification of new strategies for the treatment of the disease

Role of the Immune System in Hypertension

Although systemic hypertension affects a large proportion of the population, its etiology remains poorly defined. Emerging evidence supports the concept that immune cells become activated and enter target organs, including the vasculature and the kidney, in this disease. Mediators released by these cells, including reactive oxygen species, metalloproteinases, cytokines, and antibodies promote dysfunction of the target organs and cause damage. In vessels, these factors enhance constriction, remodeling, and rarefaction. In the kidney, these mediators increase expression and activation of sodium transporters, and cause interstitial fibrosis and glomerular injury. Factors common to hypertension, including oxidative stress, increased interstitial sodium, cytokine production, and inflammasome activation promote immune activation in hypertension. Recent data suggest that isolevuglandin-modified self-proteins in antigen-presenting cells are immunogenic, promoting cytokine production by the cells in which they are formed and T cell activation. Efforts to prevent and reverse immune activation may prove beneficial in preventing the long-term sequelae of hypertension and its related cardiovascular diseases.

/pdf/the-immunology-of-hypertension-rf5m0cxqs6.pdf

The immunology of hypertension.

Hypertension and renal damage in Dahl SS rats are associated with increased infiltrating immune cells in the kidney. To examine the role of infiltrating immune cells in this disease process, a zinc...

https://www.physiology.org/doi/pdf/10.1152/ajpregu.00304.2012

Genetic mutation of recombination activating gene 1 in Dahl salt-sensitive rats attenuates hypertension and renal damage

The present studies examined the role and mechanism of action of infiltrating T lymphocytes in the kidney during salt-sensitive hypertension. Infiltrating T lymphocytes in the Dahl salt-sensitive (...

https://www.physiology.org/doi/pdf/10.1152/ajprenal.00454.2010

Infiltrating T lymphocytes in the kidney increase oxidative stress and participate in the development of hypertension and renal disease

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Genetic mutation of recombination activating gene 1 in Dahl salt-sensitive rats attenuates hypertension and renal damage

Infiltrating T lymphocytes in the kidney increase oxidative stress and participate in the development of hypertension and renal disease