Mechanism and Pathophysiology
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  • 1 Department of Physiology and Pharmacology, Liberty University College of Osteopathic Medicine, Lynchburg, Virginia
  • 2 Division of Nephrology, Department of Medicine, University of Rochester School of Medicine, Rochester, New York
  • 3 Department of Physiology and Neuroscience, Keck School of Medicine of USC, Los Angeles, California

Learning Objectives

  1. Define the mechanisms by which extracellular vesicles and myoendothelial projections modulate vascular tone and blood pressure
  2. Describe the mechanisms by which the nervous system is implicated in the pathogenesis of hypertension.
  3. Discuss how the renin-angiotensin-aldosterone and immune systems are implicated in blood pressure regulation and development of hypertension
  4. Compare and contrast the influence of high or low dietary sodium and potassium intakes on natriuresis and blood pressure regulation
  5. Differentiate between the common causes of secondary hypertension and their associated mechanisms

Overview

Essential hypertension is a common disorder affecting nearly 30% of adults in the United States and is a major cardiovascular and kidney disease risk factor. As a complex trait influenced by environmental and genetic factors, identification of its main causes remains challenging. This is illustrated by large-scale genome-wide association studies showing that although there are multiple genetic loci influencing BP, they explain only a very small proportion of the BP trait variability (1). In this review, we will highlight several recent important discoveries of novel factors from key systems that contribute to the dysregulation of BP homeostasis.

Vasculature

The arterial vascular wall consists of three layers—the tunica intima, tunica media, and tunica adventitia—with the endothelial cells of the tunica intima and the smooth muscle of the tunica media being key factors in regulating BP and mediating the development and progression of hypertension. The large smooth muscle content of the resistant vessels contributes to their elastic properties and the ability to drastically change the internal diameter to regulate pressure and flow. The endothelial cells contain little (if any) contractile properties but play a crucial role in maintaining the barrier of the internal lumen as well as regulating the contractile state of the smooth muscle (or vascular tone).

The contraction of smooth muscle is initiated by a calcium-mediated signaling cascade that culminates with the phosphorylation of the regulatory light chain of myosin. This process is regulated by the differential phosphorylation state of myosin mediated by myosin light chain kinase and myosin light chain phosphatase. However, stimulation of vascular smooth muscle from mice with a genetic deficiency of myosin light chain kinase still results in contraction and phosphorylation of regulatory light chain of myosin, suggesting that additional kinases contribute to vasoconstriction. In this regard, Artamonov et al. (2) recently reported that the p90 ribosomal S6 kinase 2 (RSK2) also phosphorylates regulatory light chain of myosin. They showed that resistance arteries from RSK2-deficient mice are dilated and display reduced phosphorylation of the regulatory light chain of myosin, reduced myogenic tone, and lower BP compared with wild-type littermates. As RSK inhibitors are currently being tested in clinical trials for cancer, these findings implicate RSK2 inhibition as a potential therapeutic target for hypertension.

The endothelium regulates smooth muscle contraction through several mechanisms including the production of nitric oxide, prostaglandins, epoxyeicosatrienoic acid, hydrogen peroxide, and the direct transmission of electric signals through gap junctions (3). Nitric oxide, a potent vasodilator, is produced in endothelial cells by endothelial nitric oxide synthase from L-arginine and the cofactor tetrahydrobiopterin. Nitric oxide diffuses from the endothelium into the adjacent smooth muscle cell and induces vasodilation by cyclic guanosine monophosphate–dependent dephosphorylation of the regulatory light chain of myosin.

Extracellular vesicles (EVs) have been a focus of investigation as potential mediators of vascular tone, serving as an interface between the blood and the endothelium. In this regard, Good et al. (4) recently reported that EVs have vasoactive properties that are altered in spontaneously hypertensive rats, an established animal model of essential hypertension. Circulating EVs were isolated from hypertensive and normotensive rats and administered to isolated blood vessels to assess the ability of the EVs to modulate vascular tone. EVs isolated from normotensive rats modulated the degree of vessel relaxation induced by administration of acetylcholine, whereas EVs from spontaneously hypertensive rats had no effect on acetylcholine-induced vasodilation. Furthermore, administration of EV content (by prior destruction of EVs) restored the ability of EVs from spontaneously hypertensive rats to modulate vessel dilation. Similar reductions in vessel dilation were observed in EVs isolated from normotensive humans, but not from humans with hypertension. Taken together, these findings suggest that circulating EVs play a significant role in vascular function and the pathophysiology of human hypertension. Further investigations into their mechanisms of action and how they are altered during hypertension may lead to the development of novel therapies.

Gap junctions and the recently described myoendothelial projections offer additional means by which the endothelial cells modulate smooth muscle contractility and vascular resistance. The myoendothelial projections are protrusions of the endothelium or smooth muscle that infiltrate the internal elastic lamina and interact with smooth muscle or endothelium, respectively (displayed in Figure 11). These protrusions have been characterized as being rich in cellular organelles and machinery needed to produce a variety of signaling molecules (3,5,6). Of note, recent work has shown that α-globin (α-hemoglobin subunit) is concentrated at the myoendothelial projection and modulates the availability of endothelial nitric oxide (7). In a similar manner used to regulate oxygen availability in erythrocytes, the oxidative state of endothelial α-globin influences the availability of nitric oxide to modulate vascular smooth muscle contractile state. Furthermore, it appears that α-globin directly interacts with endothelial nitric oxide synthase to restrict nitric oxide availability. Mice with deficiency of α-globin (Hba1-/-) in parenchyma had lower mean arterial pressure (MAP) (approximately 90 mmHg) as compared to control mice (approximately 110 mmHg), and resistance vessels isolated from Hba1-/- mice displayed significantly reduced phenylephrine-mediated (α1 agonist) vasoconstriction. Taken together, these data highlight an unappreciated role of α-globin in regulating nitric oxide availability and the complex mechanisms by which the endothelium regulates vascular tone and systemic blood pressure. Further studies are needed to understand how myoendothelial projections and the associated molecular machinery are affected with hypertension.

Figure 11.
Figure 11.

(A) Transmission electron and (B) tomography images of myoendothelial projection (or junction) in third-order mesenteric resistance artery from a hamster. EC, endothelial cell; ER, endoplasmic reticulum; IEL, internal elastic lamina; SMC, smooth muscle cell. Reprinted with permission from reference 6 (Maarouf N, Sancho M, Fürstenhaupt T, Tran CH, Welsh DG: Structural analysis of endothelial projections from mesenteric arteries. Microcirculation 24: e12330, 2017).

Citation: Nephrology Self-Assessment Program nephsap 19, 1; 10.1681/nsap.2020.19.1.5

Nervous System

Peripheral and Central

Both the central nervous system (CNS) and the peripheral nervous system are implicated in the regulation of BP and development of hypertension by influencing changes in peripheral vascular resistance and cardiac output. Although the mechanisms by which the nervous system contribute to hypertension are still unclear, overactivation of the sympathetic nervous system is a common finding in patients and animal models of essential hypertension (8).

The CNS is responsible for the integration of a variety of cues and stimuli originating locally within the CNS or in the periphery (911). Peripheral stimuli (such as changes in BP, PCO2, and PO2) activate peripheral receptors that signal back to the CNS by afferent fibers. Afferent signals are received and transmitted through a series of nuclei in the hypothalamus and brainstem that regulate the efferent effector pathways that modulate peripheral vascular resistance and cardiac output. For example, the high-pressure baroreceptors located within the carotid sinus and aortic arch transmit their signals back to the hypothalamus and brainstem through cranial nerves IX and X, respectively. These pressure signals function as a negative feedback mechanism that inhibits the sympathetic outflow from key regions of the brainstem that regulate the function of key organs in BP regulation. Conversely, reduced baroreceptor activation has less inhibitory action on these brainstem regions. The activity of these brainstem areas is also influenced by peripheral low-pressure receptors (cardiopulmonary), peripheral chemoreceptors (PCO2, PO2, cytokines), and muscle activity (stretch receptors and metabolites) (9). Taken together, these signals converge on the lower brain (hypothalamus and brainstem) to buffer BP around a set point. However, it is unclear whether these reflex mechanisms are responsible for the “resetting” of BP in hypertension to a higher value, or if they primarily serve as a buffer to maintain pressures around the new set point (12).

Effect of Psychosocial Events

Hypertension response sensitization refers to a heightened sympathetic outflow that occurs in response to a repeated stimulus (8). This hypertensive “memory” is believed to be beneficial from a historic perspective as a heightened sympathetic nervous system response allows a rapid reaction to threats or other challenges to homeostasis. Challenges can be 1) physiologic in nature such as changes in BP, PO2, PCO2, or glucose, 2) psychosocial including nonconditioned stressors such as sensing danger through sight, sound, and smell, and 3) conditioned stressors where a neutral stimulus is linked to an aversive response. Whereas the physiologic stressors influence BP through the hypothalamus and brainstem pathways directly, psychosocial stressors engage the limbic system and hindbrain to further influence the brainstem and its regulation of sympathetic efferent pathways. Regardless of the stimulus, hypertension response sensitization implies that the neural circuits involved in BP regulation “learn” how to respond to hypertensive stimuli.

To assess the potential mechanisms underlying the development of hypertension response sensitization, rats were exposed to an experimental paradigm involving an exposure to an initial noxious stimulus (Induction phase), followed by a few days of recovery (Delay), and concluded with the administration of another noxious stimulus (Expression phase). Using this model, Xue et al. (13) administered a very low nonhypertensive dose of angiotensin-II (AngII) (10 ng/kg per min) or vehicle into male rats for 1 week during the Induction phase. Following a 1-week delay phase, a higher dose of AngII (120 ng/kg per min) was administered during a 14-day Expression phase. In rats that received saline during the initial Induction period, the second AngII administration caused an expected gradual increase in MAP, reaching approximately 130 mmHg after 14 days. However, rats initially exposed to the low AngII dose during Induction exhibited a higher MAP of approximately 150 mmHg in the same period of time. Molecular analyses of the hypothalamic tissue found upregulation of components of the renin-angiotensin system (RAS) after the Delay period. The results from this initial study suggests that prior exposure to a mild hypertensive stimulus results in changes in RAS signaling in the lower brain that increases the sensitivity to BP.

The authors next assessed this finding in an animal model of posttraumatic stress disorder, which is associated with a higher incidence of cardiovascular disease (CVD) (14). Following the same Induction-Delay-Expression design, the authors modeled posttraumatic stress disorder by placing a smaller male rat into the cage of a larger rat for a period of time over 3 days during the Induction period. After a 1-week Delay, it was found that expression of inflammatory cytokines and components of the RAS system were again markedly upregulated in the hypothalamus of stressed rats but not in control animals. Another group of animals were then exposed to a slow-pressor dose of AngII, and stressed rats had a greater increase in MAP (approximately 160 mmHg) as compared with rats receiving AngII without prior stressful experience (approximately 140 mmHg). The MAP increase in stressed animals was associated with increased expression of angiotensin-converting enzyme and proinflammatory cytokines in the hypothalamus, and these effects (including elevation in BP) were significantly reduced with prior administration of captopril or an inhibitor of tumor necrosis factor-α (pentoxifylline). These findings provide important insights into the development of hypertension. First, these data continue to highlight the development of BP sensitization, or “memory,” where prior exposure to a stimulus may exacerbate the physiologic (cardiovascular) response to a hypertensive stimulus. Second, these data suggest that tissue-specific RAS plays a crucial role in the development of hypertension and may mediate additional benefits of angiotensin receptor blockers and angiotensin-converting enzyme inhibitors. Third, the study highlights the significance of psychologic status and prior experiences in long-term health. Although these mechanisms have not been validated in humans, they do provide important insight into potential mechanisms describing why psychologic stress has such a dramatic impact on cardiovascular health in the human population.

Sleep Apnea

Obstructive sleep apnea (OSA) is associated with cardiovascular consequences, particularly hypertension (15). The autonomic nervous system plays a key role in the fluctuations in heart rate and peripheral vascular resistance that occur over the stages of sleep and likely mediates much of the dysfunction that occurs with OSA. Individuals with OSA have increased muscle sympathetic nerve activity, increased plasma and urine catecholamine concentrations, and increased plasma AngII, decreased plasma renin, and increased urinary aldosterone excretion. These effects appear to be due, at least in part, to intermittent hypoxia as muscle sympathetic nerve activity decreases with the use of continuous positive airway pressure (CPAP) (16,17). Some randomized trials in humans have shown a modest yet significant reduction in 24-hour BP (3–6 mmHg) with CPAP use; however, the magnitude of this effect varies and is dependent upon compliance with CPAP use (17). Animal models of intermittent hypoxia further support the role of oxygen saturation and peripheral chemoreceptors in the development of hypertension. These signals converge in the brainstem and influence sympathetic outflow (18).

Interestingly, recent data suggest that renal denervation has a significant impacts on OSA. In a mouse model of OSA (19), intermittent hypoxia resulted in increased urinary norepinephrine excretion, a approximately 8 mmHg increase in systolic blood pressure, increased production of renal angiotensinogen (AGT), and decreased sodium excretion. All of these parameters were significantly reduced with prior renal denervation, suggesting that the kidneys play a key role in the pathogenesis of OSA-induced hypertension. The value of this study is further supported by a recent proof-of-concept randomized phase II trial assessing the utility of renal denervation in patients with resistant hypertension and OSA. In this study, among 60 patients assigned either to renal denervation or to control, renal denervation reduced systolic (approximately 20 mmHg) and diastolic (approximately 8 mmHg) BP and reduced severity of OSA as indicated by a reduction in the number of apneic or hypopneic events per hour (39.4 events per hour versus 31.2 in control) (20). The mechanism by which renal denervation lessens severity of OSA is not understood but may reflect a decrease in sodium and water retention with diminished edema of the upper airway, or a direct effect of reduced BP (21).

Immune System

Research in the 1960s and 1970s associated the immune system with BP regulation and development of hypertension. Since, several different aspects of the immune system have been implicated in the etiology of hypertension and have been summarized in excellent reviews (2225). Here, we will highlight key findings that illuminate the mechanisms by which the immune system influences the development of hypertension and/or the progression of end-organ damage.

The immune system is divided into two arms: a relatively nonspecific innate immune system and a refined adaptive system. The cellular components of the innate immune system consist of circulating and tissue-specific myeloid cells (conventional monocyte, macrophage, and dendritic cells), granulocytes, natural killer cells, and innate lymphoid cells. The vast majority of the innate immune system is dedicated to pathogen recognition, initiation of phagocytic and lytic processes of invading microorganisms or infected/aberrant cells (cancer), and generating a targeted inflammatory response through activation of the adaptive immune response. Certain cell types of the innate system function as antigen-presenting cells (primarily dendritic cells and some macrophages) that internalize and process extracellular debris or components from phagocytosis and present these antigens on their cell surface with specific receptor classes referred to as histocompatibility complexes. The antigen–histocompatibility complexes on antigen-presenting cells function as a receptor to activate the adaptive immune response (classic T cells and B cells) and facilitates their subsequent maturation through the engagement of additional surface receptors (referred as costimulation) and secretion of cytokines.

Integrating Oxidative Stress to Tissue Inflammation and Hypertension

Several reports over the past 20 years have shown that mice with deficiencies in T cells or B cells have a blunted BP response when challenged with different hypertensive stimuli. A commonly cited study demonstrated blunted AngII-induced hypertension in T cell and B cell deficient RAG1 knockout mice (26). Subsequent studies found that CD8+ T cells were required for the full hypertensive response to AngII (27), highlighting a crucial role of the adaptive immune response in this mouse model of hypertension.

To further delineate the immunologic processes in this model, Kirabo et al. (28) set out to identify the link between oxidative stress, tissue inflammation, and hypertension in AngII-infused mice. The authors first demonstrated an increased production of reactive ox-ygen species (superoxide) by dendritic cells in response to AngII administration, confirming that antigen-presenting cells contribute to the generation of oxidative stress in this model of hypertension. They then performed a series of experiments to determine if this oxidative stress results in the production of inflammatory antigens that are composed of oxidized fatty acids (referred to as isoketals) that crosslink proteins to form protein adducts. In vitro studies demonstrated robust proliferation of CD8+ T cells when cultured with dendritic cells exposed to isoketals or AngII in vivo, providing direct evidence that the dendritic cells and isoketals are able to stimulate CD8+ T cells. Isoketals were present in the tissues of hypertensive, but not normotensive, mice administered AngII or deoxycorticosterone salt. Furthermore, administration of scavengers for isoketals drastically reduced the hypertensive response to AngII (approximately 20 mmHg reduction). The investigators exacerbated hypertension (20–35 mmHg increase) in mice by adoptively transferring dendritic cells isolated from AngII-treated but not control mice, which confirmed the contribution of dendritic cell–derived isoketals to AngII-induced hypertension. To demonstrate the clinical application of their experiments, the investigators reported a correlation between BP and circulating markers of oxidative stress (including isoketal concentration in circulating mononuclear cells) in humans. This study provided direct evidence that oxidative stress plays a key role in hypertension by generating a novel protein antigen that stimulates the immune system.

Dietary Salt and the Immune System

Salt sensitivity is a common feature among individuals with primary hypertension, and salt intake is associated with changes in BP in the general population. Whereas several studies have focused on the contribution of the kidneys, vasculature, and sympathetic nervous system in salt sensitivity, recent work has also shown the immune system to play a key role in animal models of salt-sensitive hypertension (25).

In a recent article, Van Beusecum et al. (29) provide evidence that dendritic cells are activated by increases in extracellular sodium content but not by increases in general osmolarity. The authors found that genetic deletion of serum glucocorticoid kinase 1 (SGK1) in dendritic cells protected mice from salt-sensitive hypertension as compared with control mice. This was associated with preservation of vascular function and reduction in renal inflammation and tissue remodeling. Interestingly, the depletion of SGK1 was associated with a reduction in dendritic cell epithelial sodium channel (ENaC) subunits; normal dendritic cells cultured in high salt exhibited an increase in ENaC expression that was suppressed with an SGK1 inhibitor. Further analysis revealed increased expression of dendritic cells nicotinamide adenine dinucleotide phosphate subunits, isoketal concentration, overall number of activated dendritic cells when exposed to high salt conditions, and all of which were significantly reduced with SGK1 inhibition. The transfer of dendritic cells exposed to high salt in culture into another model (AngII-hypertension) caused a gradual exacerbation of hypertension, further highlighting the significance of dendritic cells in the pathogenesis of hypertension in animal models.

Salt, Dendritic Cells, Gut Health, Microbiota

The gastrointestinal system and its associated microbial content (microbiota) have generated much interest over the past decade as another key player in health and disease pathogenesis. Ferguson et al. (30) characterized the microbiota in individuals with high (>2300 mg) or low (<2300) sodium intake based on short-term and long-term surveys. Individuals with the higher sodium intake had greater systolic BP (117 versus 109 mmHg), body mass index (26 versus 24 kg/m2), and BP was positively associated with the presence of the Prevotella bacterial genus. Analysis of tissues collected from hypertensive individuals revealed increased tissue remodeling and presence of the isoketal neoantigen as compared with tissues from normotensive patients. Similar results were obtained in mice fed a high-salt diet; high-salt diet caused a drastic reduction in lactic acid–producing bacteria and colonization by microbes associated with inflammatory and metabolic diseases. Further analyses revealed increased mesenteric inflammation, increased dendritic cell isoketal content, and an increased susceptibility to hypertension induced by low-dose AngII (approximately 25 mmHg difference in systolic BP). To further highlight the significance of the intestinal microbiota, fecal transplant studies were performed. Germ-free mice were inoculated with feces collected from mice fed normal or high-salt diet and were then administered a low-dose AngII. Germ-free mice receiving fecal material from mice fed a high-salt diet had approximately 20 mmHg increase in systolic BP after exposure to the low-dose AngII as compared with germ-free mice receiving fecal content from mice fed a normal-salt diet and administered low-dose AngII. Taken together, these data support the hypothesis that the intestinal microbiota plays a key role in the pathogenesis of hypertension.

Renal Denervation

Renal sympathetic nerves contribute to both hypertension and renal inflammation in animal models of hypertension (31). To better understand the role of the renal sympathetic nerves, Xiao et al. (32) reported that renal denervation significantly reduced BP (approximately 35 and 20 mmHg reduction in systolic BP and diastolic BP in renal denervation mice, respectively) and renal inflammation in mice with AngII-hypertension. Subsequent studies using unilateral denervation found an intermediate reduction in systolic BP (approximately 15 mmHg) and reduced renal tissue inflammation only in the denervated kidney, suggesting that reduced inflammation was related to denervation per se, not just reduced pressure. The mechanism, however, is unclear. As mentioned above, stimulation of adaptive immunity depends upon antigen-presenting cells, and it is feasible that renal denervation prevented activation of antigen-presenting cells and caused the reduced T cell infiltration observed in this experiment. Indeed, analysis of dendritic cells from mice with renal denervation showed an immature phenotype with low concentration of isoketal neoantigen and decreased secretion of the proinflammatory cytokines IL-1a, IL-1b, and IL-6. To further highlight the contribution of AngII-exposed dendritic cells to the development of hypertension, splenic dendritic cells were isolated from animals exposed to AngII, with and without prior renal denervation, and injected into naïve mice prior to receiving low-dose AngII. Only mice receiving dendritic cells from AngII-treated donors with intact renal nerves had an elevation in systolic BP (approximately 25 mmHg increase), diastolic BP (approximately 20 mmHg), and exacerbated renal inflammation. Renal denervation is used in humans only when hypertension has been established, whereas this model used a prophylactic denervation protocol. Therefore, the authors repeated the denervation experiments after 2 weeks of AngII infusion and found a blunted antihypertensive effect as compared with the prophylactic approach (approximately 20 mmHg reduction).

Preclinical animal studies have routinely reported a BP lowering effect with renal denervation. However, data from human trials have been inconsistent. Early clinical studies using renal nerve ablation to reduce systolic BP in patients with resistant hypertension (SYMPLICITY HTN-1 and 2) reported reductions of 30 to 35 mmHg in systolic BP 30 months after renal denervation. In SYMPLICITY HTN-1, the efficacy of renal denervation appeared to improve with time, inasmuch as approximately 70% of subjects had a >10 mmHg reduction in systolic BP after 1 month and 93% at 36 months (33). Similar findings were reported in SYMPLICITY HTN-2, with >70% of patients receiving renal denervation having >20 mmHg reduction in systolic BP after 30 months, and approximately 85% of patients had >10 mmHg reduction in systolic BP after 36 months (34). However, the remarkable results from SYMPLICITY HTN-1 and 2 (and the field of renal denervation itself) were significantly undermined with the results from the randomized, sham-controlled SYMPLICITY HTN-3 trial, which reported no apparent effect of renal denervation in resistant hypertension as compared with a sham control group (35). However, several pitfalls were identified in these initial studies, and recent studies have shown significant, yet modest (3–9 mmHg) reductions in systolic BP in hypertensive patients within 3 to 6 months (3640). Ongoing clinical trials will provide more insight into the clinical utility of renal denervation in treating hypertension over the next several years.

Splenic Denervation and AngII-Hypertension

A series of studies by Carnevale et al. (41) have highlighted a significant contribution of the spleen and splenic nerve in the development of AngII-hypertension in mice. In a recent report (41), they found increased activity of the splenic nerve in response to two different hypertensive stimuli that was abolished with cervical and coeliac vagotomy and genetic deletion of the α-7 nicotinic acetylcholine receptor subunit (a7nAChR). Furthermore, vagotomy, genetic a7nAChR deficiency, or surgical splenic denervation prevented an elevation in BP and end-organ inflammation induced by administration of AngII. Taken together, these studies highlight the significance of the immune system, lymphoid organs, and peripheral nervous system in the development of hypertension in animal models (Figure 12).

Animal studies highlight the mechanisms linking the nervous system to hypertension. Severe stress influences hypothalamic nuclei that regulate blood pressure, while peripheral denervation (renal or splenic) reduced blood pressure and end-organ damage in hypertensive animals.

Figure 12.
Figure 12.

Overview of physiologic link between the central nervous system, immune system, and BP regulation. Splenectomy or splenic denervation significantly inhibits tissue inflammation (aorta and kidney) and elevation of BP in animal models of hypertension, suggesting that the spleen and splenic nerve play a key role in the etiology of hypertension. Additionally, rats administered angiotensin II display elevated femoral nerve activity and bone marrow–derived leukocytes traffic to the hypothalamus and contribute to the increased BP.

Citation: Nephrology Self-Assessment Program nephsap 19, 1; 10.1681/nsap.2020.19.1.5

Renin-Angiotensin-Aldosterone System

The renin-angiotensin-aldosterone system (RAAS) is a key modulator of BP regulation and is a primary target in the treatment of hypertension. Classic RAAS consists of liver-derived AGT, a 485-amino acid protein that is cleaved by the rate limiting aspartyl protease renin to produce the 10-amino acid angiotensin I. Circulating angiotensin I is rapidly converted to the 8-amino acid effector molecule AngII by angiotensin-converting enzyme (ACE1) in the vasculature (notably pulmonary). AngII raises BP through both vasoconstriction and expansion of the extracellular volume through sodium and water retention mediated by both humoral (AngII, vasopressin, and aldosterone) and neural effector mechanisms (42).

The angiotensin receptors have diverse tissue distribution and tissue-specific effects. The AngII type 1 receptor, AT1, is a 7-transmembrane, G-protein–coupled receptor (GPCR) that activates a series of cellular signaling cascades, including G-protein–dependent activation of phospholipases, G-protein independent pathways (b-arrestin), reactive oxygen species, and nonreceptor-type tyrosine kinase signaling. The AT1 receptor is the predominant angiotensin receptor in heart, vasculature, and kidney that mediates the hypertensive effects of the RAAS (43). AngII type 2 receptor, AT2 (also a GPCR), counterbalances the hypertensive effects of AT1 through complex and less well understood cellular mechanisms. Activation of the AT2 receptor does not result in classic GPCR signaling cascades. Instead, AT2 activation is associated with the inhibition of several intracellular phosphorylation cascades through the stimulation of phosphatases. Additional studies have implicated cross-receptor interactions with AT1, direct interactions with AT2 transcription factors, altered nitric oxide production, and coupling to ion-channel activity, all highlighting the complex intracellular signaling of the AT2 receptor (43). Additional angiotensin peptides have been shown to elicit physiologic responses through additional receptor mechanisms.

Individual tissues express RAAS components or proteins that appear to modify RAAS activity. In fact, many of the tissues directly implicated in the pathophysiology of hypertension are reported to express RAAS components, including the brain (as introduced above), heart, kidneys, vasculature, and adipose tissue (4446). Here we review recent information on the (pro)renin receptor (PRR) (4749) and how its tissue-specific expression influences BP homeostasis (50).

Renin and the (Pro)Renin Receptor

Renin is initially produced as preprorenin in the juxtaglomerular apparatus, with the presequence cleaved during the early stages of intracellular processing through the Golgi apparatus. The cleavage of the prosegment depends upon whether the protein is packaged into dense-core secretory granules or secreted constitutively. Dense-core secretory granules contain a low pH and additional proteases capable of cleaving the prosegment and storing activated renin for regulated release. However, the vast majority (80%–90%) of the total circulating renin in humans is in the inactive prorenin form (51), suggesting that extrarenal sources and constitutively secreted pathways in the kidney predominate.

The (pro)renin receptor (PRR) is highly conserved across species and expressed in kidney, heart, brain, vasculature, and adipose tissue. It is a 350-amino acid peptide with a single transmembrane domain and a short cytoplasmic tail with no known activity. Functioning primarily as a dimer, the PRR binds both prorenin and renin (collectively referred to as (pro)renin). Binding of (pro)renin is associated with activation of intracellular signaling cascades and activation of prorenin through conformational changes of the inhibitory prosegment (52). The extracellular domain of PRR can be cleaved to generate a soluble PRR (sPRR), and both the PRR and sPRR are implicated in several physiologic functions, including regulation of BP (53).

Recent work has highlighted the significance of the PRR in various aspects of renal function, including urinary concentration, acid-base regulation, urinary sodium excretion, and BP regulation. Although several studies have revealed an important function of PRR in the distal nephron, little is known about the influence of the PRR in the juxtaglomerular apparatus (JGA) and secretion of renin. Riquier-Brison et al. (54) performed a series of experiments to determine the presence, signaling, and physiologic significance of PRR in the JGA. Using real-time polymerase chain reaction and tissue staining, they confirmed the presence of PRR around the JGA in tissues from normal (healthy) mice, rats, and humans. Using isolated mouse JGA preparations, the authors reported a marked degranulation of juxtaglomerular cells, consistent with release of renin, with the administration of both renin and prorenin. Taken together, these data suggest that the binding of (pro)renin to PRR in JGA (macula densa) stimulates the release of renin from the kidneys. To further assess the significance of PRR, a mouse model was generated with macula densa depletion of PRR. These mice had a marked reduction in systolic BP (approximately 20 mmHg) and decreased (>75%) plasma renin activity as compared with WT undergoing the same experiments. Taken together, these data suggest that renal PRR (particularly PRR in the JGA) plays a significant role in BP regulation and activation of the RAAS.

Adipose tissue also appears to contribute to activation of the RAAS, with animal and human adipocytes capable of secreting both AngII and aldosterone (55,56). To highlight the functional significance of adipose tissue RAAS, mice were developed with tissue-specific deletion of AGT or the PRR. Initial studies found that adipose-specific deletion of AGT resulted in a modest reduction in systolic BP (approximately 5 mmHg) after 12 months of age. Interestingly, these mice also had approximately 25% reduction in circulating AGT (57). When these mice were fed a high-fat diet, circulating AngII concentrations drastically increased in control animals (approximately 210 pg/mL), whereas AngII levels in adipose AGT–deficient animals were unaltered (approximately 20 pg/mL) (58). To further delineate the significance of adipose RAS, mice with adipose-specific deletion of the PRR were also generated. In contrast to the adipose-AGT knockout mice, adipose-PRR knockout mice exhibit a modest increase in systolic BP associated with an increase in circulating concentrations of the soluble PRR and total plasma renin concentration. The most striking physiologic finding, however, was the phenotype of mice after feeding a high-fat diet: adipose-PRR knockout mice had a fat mass that was approximately 80% lower than wild-type controls after high-fat feeding and approximately 33% lower overall body weight (59). Subsequent studies in female mice displayed similar results and reported a doubling of renal cortical (not circulating) AngII concentrations and three-times-higher urinary excretion of vasopressin. Taken together, these data suggest that the RAAS and adiposity interact to influence BP and overall metabolic status (60) (Figure 13).

Figure 13.
Figure 13.

Overview of the proposed role of adipocytes and the (pro)renin receptor in the renin-angiotensin-aldosterone system (RAAS). Efferent sympathetic signaling can stimulate renin release, and generated subsequent angiotensin II can stimulate efferent sympathetic nerve activity. The (pro)renin receptor plays a crucial role in renin secretion by the kidney, whereas adipocytes produce components of the RAAS (including AGT and aldosterone) as well as adipokines (such as leptin) that can modulate sympathetic nerve activity.

Citation: Nephrology Self-Assessment Program nephsap 19, 1; 10.1681/nsap.2020.19.1.5

Genetic Factors

BP trait is highly heritable across world populations (6164). Genetic factors that contribute to essential hypertension are poorly understood. Genetic models of hypertension that use kidney cross-transplantation in rodents reveal that the genotype of the donor kidney determines hypertension. Consistent with this notion, virtually all genes that have large effects on BP primarily encode sodium transporters or channels in the kidney, or components belonging to the mineralocorticoid pathway, thereby influencing the epithelial sodium transporter or channel activity, ultimately affecting renal salt reabsorption.

However, the mechanisms contributing to BP homeostasis in the general population are complex and are likely modulated by genetic factors and their interactions with environmental and behavioral factors. To date, more than 200 genetic loci have been identified in genome-wide association studies (6572). Yet, these variants explain only approximately 3.5% of interindividual variations in BP (66,67). Furthermore, each locus may contain up to several hundred genes that require functional validation in experimental models. Similarly, in the rat model, over 400 BP quantitative trait loci across the rat genome have been reported (rat genome database: http://rgd.mcw.edu/). Despite integrative approaches using congenic strategies for fine mapping, gene expression arrays, and comparative and functional genomics, identification of causative gene(s) underlying a quantitative trait locus has remained a significant challenge. Factors that contribute to this challenge include small phenotypic effect of a causative gene and epistatic interactions of genes that influence BP but with opposing effects.

Few genes have shown concordance between human and rat genetic studies. Concordant genes include the 11β-hydroxylase gene (Cyp11b1) and the α-adducin (ADD1) gene. In the rat, genetic polymorphisms in the 11b-hydroxylase gene (Cyp11b1) is associated with the adrenal capacity to synthesize 18-hydroxy-11-deoxycorticosterone (18-OH-DOC) and BP (73), but their effects are dependent on genetic background (74), illustrating the importance of gene-gene interactions. Mutations in the CYB11B1 gene have also been identified in rare Mendelian forms of human hypertension such as congenital adrenal hyperplasia (75) and glucocorticoid-remediable hyperaldosteronism (76,77), described below.

Adducin is a membrane skeleton protein composed of the a-, b- and g-subunits that are encoded by genes on separate chromosomes (78). In renal tubular cells in culture, adducin has been shown to associate with cell-to-cell contact sites in a calcium-dependent and phosphorylation-dependent manner (79). Candidate gene analysis revealed that functional polymorphisms in ADD1 are associated with hypertension in Milan rats and salt-sensitive hypertension in humans (80,81). The α-adducin locus also reached the threshold of significance for linkage to BP in quantitative trait locus analysis in the Milan hypertensive and normotensive strains. Functional studies explained that polymorphisms in the α-adducin gene may influence BP by regulating the activity of the Na+-K+-ATPase pump that drives renal tubular sodium reabsorption (82). The concordance of the Cyp11b1 and ADD1 genes in humans and rodents illustrate the evolutionary conservation of renal tubular sodium transport in BP homeostasis (83).

Diet and Sex Influence on Hypertension

Adiposity

Lifestyle and environment are major contributors to the development of hypertension. Improvements in the quality of nutrition and increasing physical activity are considered the primary means to improve overall cardiovascular health. Epidemiologic studies indicate that approximately 70% of essential hypertension is due to adiposity (44,84,85), and several clinical studies show a significant reduction in BP with weight loss (86). However, the precise mechanisms linking poor nutrition, low physical activity, and subsequent adiposity are unclear.

As recently reviewed by Hall et al. (85), research in humans and animals implicate several different mechanisms by which an increase in adipose tissue mass influences BP regulation. Several reports have suggested that the adipokines adiponectin and leptin contribute to hypertension. For example, mice with a genetic deficiency of adiponectin have normal BP at baseline but develop salt sensitivity as evidenced by a approximately 20 mmHg increase in systolic BP with a high-salt diet as compared with a lack of difference in the control mice (87). In regard to leptin, Mark et al. (88) found an incremental increase in renal sympathetic nerve activity with increasing concentrations of leptin injected into the brainstem that resulted in a approximately 15 mmHg increase in MAP without a noticeable change in heart rate. Taken together, these data highlight the role of adipokines in altering BP. This concept has been supported by a recent study in overweight youth and adolescents, which showed that circulating adipokine levels are associated with systolic BP (89).

Dietary Sodium and Potassium

There is general consensus that lowering dietary sodium intake lowers BP (and that increasing dietary sodium raises BP) (9093), and that increasing dietary potassium and alkali load (e.g., with fruits and vegetables) may lower BP and reduce progression of renal diseases (9498). Adults in industrialized societies consume an average of 3.5 to 6 grams of sodium per day, which is far more than the 2.3 g/day recommended by the American Heart Association (AHA) (92,99). In 2019, the National Academies of Sciences, Engineering and Medicine (NASEM) published updated dietary reference intakes (DRIs) for sodium and potassium (100) based on a systematic review by the Agency for Healthcare Research and Quality (AHRQ) (101). This meta-analysis concluded that dietary sodium reduction can lower systolic and diastolic BP (3.2 mmHg and 2.3 mmHg, respectively) depending on the dietary sodium reduction and baseline BP. Thus, the 2019 NASEM provides a chronic disease risk reduction (the intake level above which reducing intake is expected to reduce the risk of chronic disease) for sodium of 2.3 g/day (consistent with AHA guidelines) (100).

A 2014 highly publicized study of pooled populations from 40 countries (n approximately 100,000) examined the association of urinary sodium excretion (a surrogate marker for sodium intake) with cardiovascular events (92,99). Interestingly, high sodium excretion (6–12 g/day) was associated with increased risk of cardiovascular events and death only in the hypertensive population (no association within the normotensive population with sodium excretion between 4 and 12 g/day) (99). This led authors to advise specifically targeting hypertensive individuals for reducing dietary sodium. Unexpectedly, in this and a similar meta-analysis, the consuming of 2.3 g/day (102) was associated with elevated risk of cardiovascular events (99,103). This finding stimulated valid criticisms of the study design: only 4% of the population showed sodium excretion of <2.4 g/day, the results were based on a single morning urine, this low-sodium population may have been fasting or ill, and there was no consideration of potassium excretion (104). The 2019 NASEM concluded that these studies had a high risk of bias and maintained the recommended adequate intake for sodium at the previous DRI value of 1.5 g/day (100).

Even with AHA and NASEM recommendations to consume sodium at no more than 2.3 g/day, it is difficult to lower dietary sodium in 2020 unless one avoids both packaged food and “eating out” (105). In healthy individuals, plasma sodium and potassium are tightly regulated, inasmuch as they are critical for maintaining cell volume and membrane potential, respectively (106). Whereas dietary sodium predicts BP across populations, hypertension correlates far better with dietary Na+/K+ ratio (107109). Prospective studies suggest that higher potassium intake correlates with lower incidence of hypertension and slower progression of chronic kidney disease (110,111). An interventional study (Dietary Approaches to Stop Hypertension, DASH) showed that participants with hypertension who consumed a low-sodium DASH diet (rich in fruits, vegetables, and low-fat dairy products and naturally high in potassium and alkali) lowered systolic BP more than sodium reduction alone, especially in the highest BP group (112).

Mechanistic insight into the BP-lowering potential of raising dietary potassium is provided by recent studies in rodents that show that raising dietary potassium provokes natriuresis (96). Interestingly, potassium excretion is a function of sodium delivery and volume flow to the cortical collecting duct, where potassium channels are poised to secrete potassium into tubular fluid in response to the electrochemical driving force created by sodium reabsorption through ENaC. Rodents provided with potassium-enriched diets exhibit lower proximal tubular fluid reabsorption associated with decreased expression and activity of the proximal tubule Na+/H+ exchanger isoform 3, the thick ascending limb Na-K-2Cl co transporter (the loop diuretic target) and the distal convoluted tubule Na-Cl-cotransporter (NCC, the thiazide diuretic receptor). This culminates into increased Na+ delivery and volume flow downstream to the collecting duct ENaCs, which reabsorb more sodium, resulting in a negative luminal potential that drives more potassium secretion (113,114). These mechanisms complete the homeostatic response initiated by the increased potassium intake and minimize changes in plasma potassium. Important for BP, the depression in upstream sodium reabsorption causes delivery of far more sodium to ENaCs than can be reabsorbed, resulting in a significant potassium-rich diet—induced natriuresis. Thus, raising dietary potassium provokes a significant natriuretic response analogous to taking a loop or thiazide diuretic without the accompanying risk of hypokalemia (115). A diet rich in fruits and vegetables and other plants also contains alkali, which brings the benefits of buffering dietary acid and of increasing “poorly reabsorbed anions” such as bicarbonate in the tubular fluid that drive diuresis. Conversely, and very important for recommendations to hypertensive patients, low dietary potassium and alkali intake activate sodium transporters along the nephron to minimize sodium delivery and volume flow to collecting duct ENaC regardless of sodium intake. That is, the impact of lowering dietary sodium intake on BP is made ineffective by a potassium-poor diet as a result of transporter activation to conserve potassium (114), and the impact of a low-sodium diet is facilitated by a potassium- and alkali-rich diet (114,116). An important takeaway message is that handling of sodium and potassium are intrinsically linked and that potassium homeostasis has precedence over sodium homeostasis. This message suggests that independent DRIs for sodium and potassium may be insufficient and that reference intakes for a sodium/potassium ratio may be warranted.

As described above, mechanistic studies in experimental animals and the association studies in humans indicate that increasing dietary potassium and reducing acid load increases sodium excretion, lowers BP, and reduces progression of renal diseases (9498,117). However, the NASEM did not provide chronic disease risk reduction intake values for potassium in the 2019 DSI, citing “heterogeneity of studies, lack of evidence for intake-response relationship for potassium, and lack of supporting evidence for benefit of potassium on CVD (100).” Because of the issues raised in the AHRQ report, the 2019 DSI lowered the potassium adequate intake recommendation from the 2005 value of 4.7 g/day for all adults (118) to 3.4 and 2.6 g/day for men and women, respectively (based on median intakes from surveys in the United States and Canada). Nonetheless, the NASEM committee noted moderate strength of evidence suggesting that raising potassium intake may reduce BP. The DSI highlighted the need for randomized controlled trials investigating the relationship between dietary potassium intake and hypertension along with other chronic disease endpoints (100). Such studies controlling and evaluating potassium intake over significant time periods are difficult and costly and do not promise profit from a new marketable antihypertensive drug. Yet, two relevant studies are under way that may provide the sought-after data: the Salt Substitute and Stroke Study is a 5-year trial investigating the impact of potassium-enriched salt substitute on stroke in >20,000 people in rural China (119). A 2-year randomized placebo-controlled clinical trial in the Netherlands (n = 400) is addressing renoprotective effects of potassium, including BP as an endpoint (107). If the results indicate a significant benefit of raising potassium intake, there will be an impetus for societies to recommend potassium-enriched table salt and to facilitate consumption of potassium and alkali-rich fruits and vegetables that are more costly and less readily available so as to reduce the prevalence of hypertension and associated medical costs (120,121). In the meantime, populations should aim to lower the overall Na+/K+ dietary intake ratio to <1 based on current DSI guidelines (2.3 g sodium to 3.4 g potassium per day). Newly mandated inclusion of potassium along with sodium on nutrition labels will aid consumers in calculating this ratio for food items.

Proper nutrition and weight management significantly influence blood pressure. Adiposity influences blood pressure through several proposed mechanisms, whereas dietary potassium may significantly mitigate the detrimental effects of high dietary sodium intake.

Sex Differences in Hypertension

Hypertension prevalence varies substantially with both age and sex. Premenopausal women have lower BP and lower risk of CVD compared with age-matched men (122). This “female advantage” is also implicated in the milder phenotypes observed in chronic kidney disease and diabetic kidney disease in women versus men (123). Conversely, hypertension is more common in elderly women than men (124), and <50% of elderly male or female patients achieve BP control (124). Evidence for sex-related disparities in the progression of CVD disease is accumulating (125). These findings indicate that age and sex are essential determinants of the mechanisms that underlie hypertension. In recognition, the National Institutes of Health released a mandate on consideration of sex as a biological variable (SABV) in 2015 that sex as a biological variable must be addressed in all research studies. A recent review of the SABV mandate summarizes the following important messages: 1) <20% of published studies include female individuals; 2) between 1997 and 2000, four of ten drugs were withdrawn from market by the US Food and Drug Administration because of severe adverse side effects in women; 3) whereas women have the variable of estrous cycle, men have fluctuating testosterone and higher overall data variability; and 4) when investigated, significant sexual dimorphisms emerge (126). For example, a 2017 preclinical study of sex-specific patterns of renal transporters and electrolyte homeostasis and the modeling studies that emanated from it (127130) established that the interrelations between different nephron segments were distinctly different in males versus females. Specifically, sex-specific differences in 11 of 23 transporters were evident, and females (versus males) exhibited faster natriuresis and diuresis in response to a saline challenge, and lower proximal tubule (PT) HCO3- reabsorption, along with higher volume flow from the proximal tubule (127). Another group reported higher sodium-dependent glucose transporter-2 (SGLT2) in females versus males that compensates for the shorter proximal tubules in the females (129,131). The higher volume flow to the distal nephron was associated with more abundant and activated distal convoluted tubule Na-Cl-cotransporter, and the female rats exhibited lower fasting plasma potassium, which correlated with the higher NCC activation (127). A follow-up study was recently conducted in the AngII infusion model of hypertension in rats and mice (132). Despite baseline sexual dimorphisms, AngII infusion in female and male rodents provoked similar increases in BP, aldosterone, NKCC2, NCC, and ENaC activation, and provoked similar potassium loss and suppression of proximal and loop sodium transporters, as well as similar natriuresis, and diuresis. However, female rodents did exhibit less proteinuria during AngII. The takeaway message is that the nephrons in female rodents are organized in a manner that facilitates sodium and volume excretion, which may contribute to the “female advantage” regarding BP. A study of approximately 1900 Chinese men and women in the Genetic Epidemiology Network of Salt Sensitivity study supports an important role of gender in renal sodium handling (133). As compared with age-matched men, women appeared to have greater BP responses to changes in dietary sodium. Women had a greater reduction in BP following a week-long low-salt diet (3 g/day), greater hypertensive response to a weeklong high-salt diet (18 g/day), and greater 24-hour sodium excretion as compared with men in each of the dietary groups. It should be noted that there were differences in body composition between men and women in this study that may have influenced sodium distribution and metabolism. Furthermore, it is difficult to interpret and apply the data from this study, given the relatively high sodium intake in the low-sodium group (3 g/day, whereas recommended is 2.3 g/day), and the extremely high values in the high-salt diet group (approximately threefold higher than the 95th percentile of sodium intake in America) (134). Despite these limitations, these data support the hypothesis that there are significant physiologic differences in men and women in regard to renal handling of sodium and subsequent changes in volume and BP.

Secondary Hypertension

Primary Aldosteronism

Primary aldosteronism is a common cause of secondary hypertension. Primary aldosteronism, defined as aldosterone secretion independent of renin, AngII, or sodium status, is expressed over a wide range from mild to severe and correlates with cardiovascular risk. A recent review by Vaidya et al. (135) cautions that the prevalence of primary aldosteronism is much greater than previously recognized and that the milder less obvious forms still increase cardiovascular and kidney disease risk; additionally, that normalizing BP may not reduce the risk for cardiovascular and kidney disease. They conclude that “Public health efforts to prevent aldosterone-mediated end-organ disease will require improved capabilities to diagnose all forms of primary aldosteronism (135).” The evaluation of secondary hypertension is discussed elsewhere in this nephSAP issue.

Renovascular Disease

Renovascular disease (RVD) refers to a series of conditions that result in reduced blood flow to the kidney in a manner that triggers activation of the RAAS and alters the ability of the kidney to appropriately handle sodium and water balance. RVD is most commonly associated with atherosclerosis, with recent population-based studies showing that approximately 7% of individuals over the age of 65 have a >60% occlusion of the renal artery, and approximately 25% in those over 70 (136,137). Interestingly, unless other insults exist, this degree of vessel narrowing may not be sufficient to induce overt renin secretion because of the abundant perfusion of the kidneys (138). Therefore, RVD remains undetected in many individuals, and BP is appropriately managed with antihypertensive therapy if no overt kidney disease exists.

Tissue ischemia is thought to play a major role in the pathogenesis of RVD, and irreversible inflammatory damage to renal parenchyma poses a significant physiologic consequence of this disease and the development of hypertension (139,140). In this regard, animal models of renal ischemia have routinely shown the immune system to play a significant role in tissue injury, with depletion of major components of the innate immune system significantly preserving kidney structure and function following ischemia-reperfusion injury (141,142). Recent work has also implicated a neuroimmune mechanism that significantly reduces ischemic kidney injury in animal models and involves similar brainstem regions associated with BP control (143,144). Whereas a majority of these studies have used vagal nerve stimulation to initiate this pathway, earlier studies reported that a noninvasive, pulsed ultrasound regimen initiated this protective pathway and resulted in significant reduction in acute kidney injury and subsequent fibrosis (145,146). Although BP was not considered in these studies, these findings are relevant considering the potential involvement of ischemic renal damage in advanced RVD.

Pheochromocytoma

Pheochromocytomas are catecholamine-secreting tumors arising from the adrenal medulla, whereas paragangliomas are chromaffin cell tumors found in extra-adrenal tissues. Paragangliomas account for <20% of all chromaffin cell tumors. Whereas the normal adrenal gland produces and secretes primarily epinephrine, norepinephrine secretion predominates in >80% of all chromaffin tumors. As such, classic symptoms of pheochromocytomas and paragangliomas include sweating, headaches, and palpitations. Hypertension is another common finding due to the activation of adrenergic receptors (α1 and α2) in vasculature causing vasoconstriction, increased cardiac output (β1), and additional effects on the kidney, including increased renin secretion from the JGA (β) and retention of sodium and water (α) (147,148).

Summary

Hypertension has a complex physiologic basis that includes several organ systems. Circulating EVs and myoendothelial junctions offer exciting new insight into the means by which peripheral vascular resistance is regulated and altered in the context of hypertension. The CNS appears to play a tremendous role in the etiology of hypertension in animal models, and the concept of hypertensive response syndrome suggests that the lower brain becomes sensitized to hypertensive stimuli with prior exposure to stressful or noxious stimuli. Furthermore, preclinical animal studies suggest that denervation of the spleen and kidneys has a significant impact on the development of hypertension and that efferent sympathetic signaling is a key factor in disease etiology. The recent identification of proinflammatory neoantigen generation with oxidative stress explains how oxidative stress triggers an inflammatory response and sustains hypertension and end-organ damage. The RAAS has expanded beyond its classic physiology to include tissue-specific expression that significantly influences local and systemic homeostasis, including BP regulation. Environmental factors such as lifestyle (diet and exercise) remain key culprits in the development of hypertension, with dietary sodium and potassium directing the regulation of extracellular volume and thus BP. Biological sex dictates these responses to a degree. Although many of these findings remain to be validated in humans, the data presented offer exciting insights into new potential therapeutic targets for the millions affected by hypertension.

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    (A) Transmission electron and (B) tomography images of myoendothelial projection (or junction) in third-order mesenteric resistance artery from a hamster. EC, endothelial cell; ER, endoplasmic reticulum; IEL, internal elastic lamina; SMC, smooth muscle cell. Reprinted with permission from reference 6 (Maarouf N, Sancho M, Fürstenhaupt T, Tran CH, Welsh DG: Structural analysis of endothelial projections from mesenteric arteries. Microcirculation 24: e12330, 2017).

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    Overview of physiologic link between the central nervous system, immune system, and BP regulation. Splenectomy or splenic denervation significantly inhibits tissue inflammation (aorta and kidney) and elevation of BP in animal models of hypertension, suggesting that the spleen and splenic nerve play a key role in the etiology of hypertension. Additionally, rats administered angiotensin II display elevated femoral nerve activity and bone marrow–derived leukocytes traffic to the hypothalamus and contribute to the increased BP.

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    Overview of the proposed role of adipocytes and the (pro)renin receptor in the renin-angiotensin-aldosterone system (RAAS). Efferent sympathetic signaling can stimulate renin release, and generated subsequent angiotensin II can stimulate efferent sympathetic nerve activity. The (pro)renin receptor plays a crucial role in renin secretion by the kidney, whereas adipocytes produce components of the RAAS (including AGT and aldosterone) as well as adipokines (such as leptin) that can modulate sympathetic nerve activity.

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