Hypertension is a major health problem with great consequences for public health. Despite its role as the primary cause of significant morbidity and mortality associated with cardiovascular disease, the pathogenesis of essential hypertension remains largely unknown. The central nervous system (CNS) in general, and the hypothalamus in particular, are intricately involved in the development and maintenance of hypertension. Over the last several decades, the understanding of the brain's role in the development of hypertension has dramatically increased. This brief review is to summarize the neural mechanisms of hypertension with a focus on neuroendocrine and neurotransmitter involvement, highlighting recent findings that suggest that hypothalamic inflammation disrupts key signalling pathways to affect the central control of blood pressure, and therefore suggesting future development of interventional strategies that exploit recent findings pertaining to the hypothalamic control of blood pressure as well as the inflammatory–sympathetic mechanisms involved in hypertension.

INTRODUCTION

Hypertension is characterized by a chronic elevation in arterial pressure and is a major risk factor for many common causes of morbidity and mortality including stroke, myocardial infarction, congestive heart failure and end-stage renal disease in many segments of the population [1]. In the United States alone, high blood pressure affects an estimated 65 million individuals [2,3] and contributes to the deaths of as many as 360000 Americans every year. Globally, hypertension is the biggest contributor to disease burden and mortality in the world, accounting for 9.4 million deaths each year [4]. Over the next decade, the global prevalence of hypertension is predicted to increase by 60% [5], despite advancements in awareness, anti-hypertensive therapy and control of high blood pressure [6]. For this reason, preventive strategies for those at risk and methods to both identify the undiagnosed and manage uncontrolled hypertension are urgently needed. Resolving these issues requires a deeper understanding of the physiology of blood pressure regulation, the genetic traits that contribute to hypertensive phenotypes and the identity of environmental factors that confer risk in susceptible individuals. Pertinently, attempts to study the pathogenic mechanisms of hypertension increasingly point to alterations in central nervous system (CNS) regulation of arterial pressure as a critical modulating factor [7]. Many of these functional changes are concentrated in the hypothalamus [8], an area of the brain consisting of several nuclei that acts as the interface between the nervous and endocrine systems. The hypothalamus plays a crucial role in co-ordinating and integrating the activity of neural networks that control central blood pressure [9,10]. The intent of this brief review is to highlight recent findings that implicate the nervous system and the hypothalamus in particular in the pathogenesis and maintenance of hypertension. Particular emphasis is placed on recent findings that point to hypothalamic inflammation as a potential driver of pathogenic hypertension and therefore likely to inform new translational advances in the field.

BRIEF OVERVIEW ON PATHOPHYSIOLOGY OF BLOOD PRESSURE REGULATION

Hypertension is broadly categorized as primary or secondary depending on the underlying pathogenic mechanism [11]. Primary or essential hypertension represents the majority of cases, typically arising in middle or old age as a result of the interaction between non-specific genetic and environmental factors. A genetic link is supported by high heritability of blood pressures, elevated sibling recurrence–risk ratio and higher concordance of blood pressures among monozygotic twins in comparison with dizygotic twins [12]. Although rare Mendelian hypertensive phenotypes are associated with mutations in a single gene [1317], the genetic risk seems to be more commonly derived from variations in at least 65 distinct loci affecting blood pressure, each of modest effect size [1822]. Progression from a normotensive to hypertensive phenotype among genetically predisposed individuals is likely to be influenced by a combination of environmental, behavioural and dietary factors. Common determinants of primary hypertension include aging, obesity, insulin resistance and excessive intake of salt, calories and alcohol [11]. Other potential risk factors that have garnered attention in recent years include sedentary lifestyle, stress, depression, low potassium intake, low calcium intake, intrauterine programming and early life events. In contrast with essential hypertension, secondary hypertension affects far fewer patients, develops at an earlier age and is linked to an identifiable cause such as renal or endocrine disorder and oral contraceptive use. Notwithstanding the insights into the multi-factorial nature of hypertension, the precise cellular and molecular mechanisms that influence physiology to raise blood pressure remain poorly understood.

Unravelling the aetiology of hypertension requires consideration of different systems that contribute to short-term blood pressure control. These include the well-characterized interactions between the vasculature, the kidney and the CNS and sympathetic nervous system (SNS), mediated by various, often shared, receptors and ligands. Mechanisms that maintain normotensive arterial pressure include baroreceptors that sense acute changes in blood vessel pressure and decrease or increase SNS activity; activation of the renin–angiotensin system (RAS) due to a fall in renal perfusion pressure; adrenergic receptors (or adrenoceptors) that bind catecholamines and increase heart rate; factors produced by endothelial cells that cause vasodilation (e.g. nitric oxide) or vasoconstriction (e.g. endothelin); secretion of natriuretic peptides in response to increased pressure and the kinin–kallikrein system, which influences vascular tone and renal salt handling (Figure 1). Many of these systems function autonomously to locally regulate blood flow (via alterations in cardiac output and blood volume), resistance (via arterial contraction and relaxation) and ultimately blood pressure.

Systemic responses to blood pressure change

Figure 1
Systemic responses to blood pressure change

The body responds to changes in blood pressure by activating multiple homeostatic mechanisms. In response to decreased blood pressure, baroreceptors immediately sense decreased tension and signal for increased SNS outflow and decreased PNS outflow, effectively increasing heart rate. Concurrently, endothelial cells secrete endothelin, which constricts blood vessels. Renin released from juxtaglomerular cells of the kidney activates the RAS. In response to increased blood pressure, baroreceptors detect stretching and signal increased PNS outflow and decreased SNS outflow, effectively decreasing heart rate. Endothelial cells secrete nitric oxide, which dilates blood vessels. Cardiac muscle secretes natriuretic peptides in conjunction with activation of the kinin–kallikrein system to promote natriuresis and vasodilatory effects.

Figure 1
Systemic responses to blood pressure change

The body responds to changes in blood pressure by activating multiple homeostatic mechanisms. In response to decreased blood pressure, baroreceptors immediately sense decreased tension and signal for increased SNS outflow and decreased PNS outflow, effectively increasing heart rate. Concurrently, endothelial cells secrete endothelin, which constricts blood vessels. Renin released from juxtaglomerular cells of the kidney activates the RAS. In response to increased blood pressure, baroreceptors detect stretching and signal increased PNS outflow and decreased SNS outflow, effectively decreasing heart rate. Endothelial cells secrete nitric oxide, which dilates blood vessels. Cardiac muscle secretes natriuretic peptides in conjunction with activation of the kinin–kallikrein system to promote natriuresis and vasodilatory effects.

At the same time, the nervous system integrates signals from peripheral organs and helps to co-ordinate homoeostatic responses [23,24]. The contributions of central pathways are perhaps best exemplified in the pathophysiological hallmarks of “neurogenic” essential hypertension. This form of hypertension is due to autonomic nervous system abnormalities originating in the afferent arm (e.g. baroreceptors, chemoreceptors and renal afferents) or in the central circuitry without a primary vascular or renal defect [10]. Studies in animals–in which the contribution of causal factors and pathways underlying hypertension can be studied in a more systematic manner–reveal that circumventricular organs (CVOs), the hypothalamus and the brain stem are critical regulatory regions. Some of the earliest studies in experimental models found that damage to the brain stem or the afferent components of the baroreceptor reflex pathway that terminate within the nucleus tractus solitarius (NTS) produces short-term [25] and long-term elevations in arterial pressure [2628]. Mechanistically, the increased arterial pressure is caused by increased regional vascular resistance [29] as a result of enhanced sympathetic tone [30] that is normally suppressed by inhibitory baroreceptor input. Thus, activation of carotid baroreceptors [31] or chemical stimulation of the NTS with adrenaline, noradrenaline and dopamine [32] decreases arterial pressure and heart rate. These early studies were instrumental in documenting neural mechanisms that could lead to enhanced central sympathetic outflow in hypertension.

Central modulation of blood pressure also involves the RAS. As mentioned above, it is well studied that peripheral RAS activation controls fluid and electrolyte balance when renal blood flow is reduced. However, components of the RAS [i.e. renin, angiotensinogen, angiotensin, angiotensin-converting enzyme (ACE), angiotensin II (Ang II) and Ang II receptor subtypes] are also found in the brain [33] and compelling evidence suggests the RAS can contribute to hypertension by modulating cardiovascular effects through the CNS [34,35]. In particular, Ang II stimulates the organum vasculosum and the subfornical organ, CVOs surrounding the anterior part of the third ventricle [36]. Both sites are highly vascularized and lack a blood–brain barrier (BBB) making them responsive to both locally produced [37] and circulating Ang II [38]. Indeed, high levels of circulating Ang II induce the development of hypertension, which is mediated by increased production of reactive oxygen species (ROS) in the subfornical organ [39,40]. Most of the known actions of Ang II are mediated by angiotensin II type 1 (AT1) receptors. Their activation in hypertension is likely to have an effect on multiple brain structures in the network that controls SNS outflow including the paraventricular nucleus (PVN) in the hypothalamus, the median preoptic nucleus and the rostral ventrolateral medulla in the brain stem [24,4143]. Consistent with this point, several studies suggest that oxidative stress in the rostral ventrolateral medulla is a potent factor in the dysregulation of sympathetic outflow that accompanies the spontaneous development of hypertension [4446]. Ang II derived from the brain's RAS (as opposed to circulating Ang II) is likely to play similar roles in the development of hypertension [47], but the factors that regulate this pathway's activity remain unknown.

Salt sensitivity is one such factor that is likely to affect this pathway. High salt intake acutely reduces circulating renin–angiotensin activity and aldosterone concentration [48,49]. A third of essential hypertension patients with high-sodium consumption have lower plasma renin activity [50,51], but are responsive to RAS inhibitors [52]. One hypothesis to reconcile this apparent discrepancy is that the brain's RAS response to salt intake may differ from the body's RAS response [50,53]. High sodium intake in rats leads to a sustained increase in renin gene expression in the hypothalamus, despite reduced renal renin expression [54]. In line with this evidence, ACE and AT1 expression in the hypothalamus and brain stem are elevated in salt-sensitive hypertension, particularly following activation of sodium channels in the brain [55]. Blocking these sodium channels reduces blood pressure and SNS hyperactivity induced by hypertonic saline loading in the brain [56,57]. These results suggest high sodium loading increases brain RAS activity locally, which in turn increases sympathetic outflow to promote hypertension.

Central hypertensive regulation is also tightly co-ordinated by mineralocorticoid receptor (MR) expression and ligand responsiveness. Upon ligand binding, neuronal MRs enter the nucleus, forming dimers that complex with transcription factors to activate or repress target gene expression that culminates in increased SNS activity [5860]. Importantly, they have similar affinity to physiologic mineralocorticoids (aldosterone) and glucocorticoids (cortisol and corticosterone). However, aldosterone-targeted cells express both the MR and localized 11β-hydroxysteroid dehydrogenase 2 (11βHSD2), an enzyme that converts cortisol and corticosterone into inactive metabolites; this increases relative aldosterone concentrations in close proximity to MRs [61]. 11βHSD2 utilizes NAD+ as a cofactor, producing NADH and depleting MR-proximal concentrations of NAD+ [62]. In the brain, 11βHSD2 is expressed at low levels apart from aldosterone-target neurons in the BBB-deficient zone of the NTS that influences sodium appetite [6264]. With sodium intake, these neurons quiesce resulting in decreased sodium appetite [64]. However, NADH generated from 11βHSD2 activity limits the transcriptional activity of glucocorticoid-bound MRs. In the absence of 11βHSD2, increased NAD+ is thought to change the conformation of glucocorticoid-bound MR allowing it to have similar transcriptional activity to aldosterone-bound MR [62]. Oxidative stress mimics this NADH-depleted state by redox imbalance, impairing normal MR function and activating glucocorticoid-bound MRs [65]. Additionally, plasma levels of glucocorticoids are 1000-fold (total) or 100-fold (free) higher than that of aldosterone, and brain levels of these hormones have been shown to be similar [61,62]. Thus, neuronal MRs are bound and activated by basal glucocorticoids in normal physiological conditions.

MRs also work in congruence with AT1 receptors in the brain to drive SNS activity and subsequent hypertensive drive in the presence of excess mineralocorticoid [66]. Both MR and the AT1 receptors in the subfornical organ increase Ang II-induced ROS production in the PVN and rostral ventrolateral medulla [67]. Ang II activates NADPH oxidase to drive ROS production [68,69], potentiating SNS hyperactivity [70]. ACE mRNA and AT1 receptor mRNA are up-regulated by aldosterone in hypothalamic tissue, further increasing Ang II production and subsequent ROS formation to drive hypertension [71].

Interestingly, the glucocorticoid receptor (GR) has only 1/10th the affinity for glucocorticoids that the MR does. Despite their widespread expression in the brain, GRs are thought to only be occupied with ligand during stress or the zenith of the circadian cycle for this reason [62,72]. The highest concentration of MRs is localized to the hippocampus, and activated GRs help to regulate the MR-mediated non-genomic stress response [73,74] as well as hippocampal explicit memory formation [75]. Imbalance between MR and GR function and expression contributes simultaneously to psychopathological disorders such as anxiety and PTSD and loss of cognitive function by dysregulating the hypothalamic–pituitary–adrenal (HPA) axis [75,76]. Increased GR increases HPA axis activity, whereas decreased GR decreases HPA axis activity. Due to the diurnal levels of glucocorticoids, the MR regulates HPA axis activity basally, and the GR during stressed conditions [77]. In the hippocampus, MR and GR signal to inhibit or stimulate respectively secretion of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) from the PVN of the hypothalamus [78]. Taken together, these studies demonstrate the complexity of action and signalling of glucocorticoids, mineralocorticoids and their respective receptors in the nervous system.

HYPOTHALAMIC MECHANISMS OF HYPERTENSION

Regulation of vasopressin secretion in hypertension

Accumulating evidence implicates increased AVP signalling in the pathogenesis of hypertension. AVP is produced by magnocellular neurons in the PVN and supraoptic nucleus (SON) of the hypothalamus, and stimulates water reabsorption in the kidney to help maintain blood pressure. The concentration of circulating AVP is normally too low to have a measureable effect on blood pressure, but the AVP neuronal activity is dysregulated [79] fairly early in the development of hypertension [80]. This effect on AVP neurons may be attributable, at least in part, to reduced inhibitory GABAergic input from baroreceptors in response to high salt intake [81]. More recent findings suggest that such impairments in inhibitory signalling are mediated by brain-derived neurotrophic factor leading to increased excitability of hypothalamic AVP-secreting neurons. This in turn drives excess AVP release, which elevates arterial pressure [82,83]. Indeed, increased AVP expression is critical in the maintenance of hypertension in several experimental models involving RAS hyperactivity [79,8486]. Although the precise mechanisms by which excess AVP secretion drives high blood pressure remain an ongoing topic of discussion, several pathways may be implicated including sympathoexcitation via V1a receptors in the PVN [87], brain RAS hyperactivity via V2 receptors [88] and peripheral vasoconstriction via V1 receptors (Figure 2) [82].

Hypothalamic mechanisms of hypertension

Figure 2
Hypothalamic mechanisms of hypertension

The hypothalamus activates the SNS and other pathways contributing to the pathogenesis of hypertension. Dysregulated AVP neurons in the SON and PVN produce excess AVP, which activates hypothalamic V1a, brain V2 and peripheral V1a receptors, thus activating the SNS, RAS or endothelial cells respectively. Circulating cortisol activates MRs in the hypothalamus to simultaneously stimulate the SNS and RAS. Leptin binds to the LepR to activate AMPK and the SNS. The ARC produces α-MSH, which binds to the MC4 in the hypothalamus to increase SNS outflow. Dysregulated clock gene expression promotes aldosterone production leading to salt-sensitive hypertension.

Figure 2
Hypothalamic mechanisms of hypertension

The hypothalamus activates the SNS and other pathways contributing to the pathogenesis of hypertension. Dysregulated AVP neurons in the SON and PVN produce excess AVP, which activates hypothalamic V1a, brain V2 and peripheral V1a receptors, thus activating the SNS, RAS or endothelial cells respectively. Circulating cortisol activates MRs in the hypothalamus to simultaneously stimulate the SNS and RAS. Leptin binds to the LepR to activate AMPK and the SNS. The ARC produces α-MSH, which binds to the MC4 in the hypothalamus to increase SNS outflow. Dysregulated clock gene expression promotes aldosterone production leading to salt-sensitive hypertension.

Hypertensive effect of steroid hormones in hypothalamus

Although the mechanisms underlying the centrally mediated hypertensive responses to aldosterone have been well studied [89], the central effects of glucocorticoids are less understood. For example, intracerebroventricular injection of hydrocortisol increases SNS activity and induces hypertensive responses that are reversible with pre-treatment using an Ang II antagonist or ACE inhibitor [90]. As discussed previously, under normal conditions, cortisol can be converted into inactive metabolites by 11βHSD2 before acting on MRs [50,91]. Although MRs are expressed in the hypothalamus, 11βHSD2 is barely detectable [92,93], suggesting that circulating cortisol can act on the hypothalamus directly through the third ventricle, to increase sympathetic activity and blood pressure. Recent findings suggest that MR stimulation by cortisol may also modulate RAS activity downstream [91,94]. Thus, hypothalamic MRs sit at a delicate interface between glucocorticoid and mineralocorticoid stimulation.

Leptin-induced SNS activity in hypertension

Leptin is a hormone produced by adipose cells that helps to regulate energy balance by inhibiting hunger. Leptin levels are increased in obese humans [95] and have been shown to drive hypertension in rats [96]. In addition, peripheral administration of an anti-leptin antibody decreases blood pressure and SNS activity in obese mice fed with a high-fat diet [97]. Although the leptin receptor (LepR) is expressed in multiple sites in the brain, leptin's effects on SNS activity prominently involve the ventromedial hypothalamus, arcuate nucleus (ARC) and dorsomedial areas in the hypothalamus [97,98]. LepR deletion in the ARC attenuates leptin-induced increase in renal sympathetic discharge and resolves increased arterial pressure in diet-induced obese mice [99]. In fact, ablation of LepR specifically in proopiomelanocortin (POMC) neurons, a major type of neuron in the ARC, can effectively reduce blood pressure [100]. Recent evidence suggests that leptin-evoked increase in SNS activity is mediated by intracellular AMP-activated protein kinase [101] and mammalian target of rapamycin (mTORC1) signalling pathways [102], thus offering potential therapeutic targets to treat obesity-associated hypertension in the future.

Melanocortin receptor 4 signalling in hypertension

Melanocortin receptor 4 (MC4) is a member of the G-protein coupled receptor family and is activated by α-melanocyte-stimulating hormone (α-MSH). POMC neurons in the ARC send projections to the PVN and lateral hypothalamus where they release α-MSH. Thus, MC4 expression in POMC neurons is a critical component in the melanocortin system's actions on feeding behaviour, regulation of metabolism, SNS activation and blood pressure homoeostasis [103]. Microinjection of an MC4 agonist into the PVN increases renal SNS activity and blood pressure in rats [104], whereas pharmacological blockade of MC4 in the PVN attenuates lumbar sympathetic nerve activity due to hyperinsulinaemia [105]. Intracerebroventricular injection of an MC4 antagonist markedly reduces blood pressure in spontaneously hypertensive rats in an SNS-dependent manner, irrespective of body weight fluctuations [106]. Renal SNS activity due to central leptin and insulin administration can be attenuated and abolished in heterozygous and homozygous MC4 knockout mice respectively [107]. Taken together, MC4 in POMC neurons plays a key role in several forms of hypertension.

Hypertension caused by circadian rhythm in the hypothalamus

It is well known that cardiovascular functions, including blood pressure, show diurnal oscillation. Incidences of life-threatening cardiovascular events, such as stroke and acute myocardial infraction, also display a diurnal pattern, with increased incidence during the morning [108]. The suprachiasmatic nucleus of the hypothalamus is the “central clock” that regulates physiological functions through the autonomic nervous system and humoral mediators. Clock genes are expressed in a circadian manner in the SCN; circadian variations associated with blood pressure are related to modifications in clock gene-regulated endogenous sleep–wake rhythms [109]. Indeed, acute changes in blood pressure brought on by morning or sleep surge can modify cardiovascular risk [110]. The underlying mechanism is hypothesized to involve multiple components including increased circulating blood volume due to salt sensitivity, excessive salt intake, autonomic nervous dysfunction, abnormal clock genes and/or altered secretion of melatonin [109]. The generation and maintenance of circadian rhythms involve two flavoproteins: cryptochrome (Cry)-1 (Cry1) and Cry2 [111]. Cry1- and Cry2-deficient mice are prone to salt sensitive hypertension due to increased activity of the adrenocortical aldosterone-producing enzyme, 3β-hydroxysteroid dehydrogenase [111]. Recent studies also suggest that melatonin has multiple beneficial effects on the cardiovascular system; melatonin administration at bedtime reduces blood pressure in hypertensive patients [112]. Thus, it is possible that alterations in circadian rhythm may affect melatonin levels resulting in autonomic nervous dysfunction, increased aldosterone and subsequent hypertension.

HYPOTHALAMIC INFLAMMATORY MECHANISMS OF HYPERTENSION

As detailed above, the hypothalamus acts as the central regulator of energy homoeostasis–it senses metabolic cues and in turn modulates neurohormonal and neurotransmitter systems via endocrine signalling, inflammatory signalling and neuronal plasticity [113115]. POMC and neuropeptide Y/agouti-related peptide (AGRP) neurons are the two major cell types in the mediobasal hypothalamus that play a vital role in energy balance. They reciprocally regulate energy homoeostasis via anorexigenic and orexigenic effects respectively. In addition, both POMC and AGRP neurons are regulated by leptin in opposite manners to affect energy homoeostasis via negative and positive energy balance [116119]. Mounting evidence from experimental and clinical studies unequivocally has shown overnutrition is an important environmental factor capable of promoting neuroinflammation [120,121]. Obesity-associated hypertension is associated with the activation of pro-inflammatory signalling pathways [122] that promote the development of metabolic syndromes in several tissues [123127]. Metabolic inflammation chronically and negatively affects neuronal regulatory functions including leptin and insulin signalling. This results in altered regulations, including central leptin and insulin resistance, that can drive increased blood pressure and energy imbalance [97,128]. Overactivity of the hypothalamic inhibitor of nuclear factor-κB kinase subunit β (IKKβ)/nuclear factor-κB (NF-κB) pathway has been recently shown to be a critical modulator of hypothalamic inflammation (Figure 3). In particular, IKKβ/NF-κB driven hypothalamic inflammation induces blood pressure imbalance and insulin resistance in an obesity-independent manner [129133]. This inflammation seems to originate from the network of neurons, astrocytes and microglia, representing a new perspective on central inflammatory metabolic disorders [134,135]. The following describes the hypothalamic mechanisms of hypertension from a few bases that have been consistently connected with hypothalamic inflammation.

Pro-inflammatory hypertensive signalling in the hypothalamus

Figure 3
Pro-inflammatory hypertensive signalling in the hypothalamus

In response to overnutrition states, pro-inflammatory signalling including IKKβ/NF-κB is activated in certain hypothalamic neurons such as POMC neurons in the ARC. NF-κB activation triggers a variety of molecular reactions, such as increased levels of SOCS3 and of PTP1B, contributing to SNS activation and subsequent increased blood pressure. In addition, POMC neurons bind TNF-α, which further stimulates SNS activation. Also, TNF-α and IL-1β activate perivascular macrophages that produce prostaglandin E2 (PGE2), which signals through the PVN to activate the SNS and subsequent hypertension. Central RAS activation and Ang II production stimulate IKKβ/NF-κB activation and ROS production in PVN neurons. Subsequent release of pro-inflammatory cytokines further contributes to ROS production, mitochondrial dysfunction, neuroinflammation and sustained increase in blood pressure leading to pathological hypertension.

Figure 3
Pro-inflammatory hypertensive signalling in the hypothalamus

In response to overnutrition states, pro-inflammatory signalling including IKKβ/NF-κB is activated in certain hypothalamic neurons such as POMC neurons in the ARC. NF-κB activation triggers a variety of molecular reactions, such as increased levels of SOCS3 and of PTP1B, contributing to SNS activation and subsequent increased blood pressure. In addition, POMC neurons bind TNF-α, which further stimulates SNS activation. Also, TNF-α and IL-1β activate perivascular macrophages that produce prostaglandin E2 (PGE2), which signals through the PVN to activate the SNS and subsequent hypertension. Central RAS activation and Ang II production stimulate IKKβ/NF-κB activation and ROS production in PVN neurons. Subsequent release of pro-inflammatory cytokines further contributes to ROS production, mitochondrial dysfunction, neuroinflammation and sustained increase in blood pressure leading to pathological hypertension.

Hypothalamic cytokines in hypertension

Cytokines orchestrate all phases of the immune response and function in highly complex networks to maintain homoeostasis. A dynamic balance between pro- and anti-inflammatory cytokines is required, and this contributes to changes in CNS physiology that promote hypertension. Circulating pro-inflammatory cytokines can pass through leaky blood vessels in CVOs or in areas where the BBB is disrupted. Alternatively, neuroactive cytokines including tumour necrosis factor-α (TNF-α) and interleukin (IL)-1β can increase the activity of cyclooxygenase-2 in perivascular macrophages to generate prostaglandin E2. This chain of events results in increased discharge from PVN neurons, which regulate adrenocorticotropic hormone release, sympathetic outflow and ultimately blood pressure elevation [136138]. Increased expression of pro-inflammatory cytokines in the hypothalamus is also associated with hypertension, including RAS-mediated blood pressure increases in rats [139]. Bilateral NF-κB inhibition within the PVN attenuates Ang II-induced hypertensive response by reducing pro-inflammatory cytokines and ROS [140]. Central administration of the ROS scavenger tempol attenuates Ang II-induced hypertension by decreasing the expression of pro-inflammatory cytokines in PVN [141]. These findings highlight how pro-inflammatory signal transduction involving ROS drives central RAS-mediated hypertension.

Several pathways have been implicated in this response. Inhibiting the p44/42 mitogen-activated protein kinase (MAPK) signalling pathway in the PVN lessens Ang II-induced hypertension by reducing SNS activity [142]. However, the expression of pro-inflammatory cytokines in this study failed to decrease after disruption of PVN p44/42 MAPK signalling, suggesting an alternative source for these cytokines. Possible cytokine-secreting cell types that contribute to the development of hypertension include glia and neurons [143145]. Supporting this, overexpression of anti-inflammatory IL-10 reduces both activated microglia and blood pressure in rats [146]. Interestingly, Ang II can directly pass through the BBB to affect neuronal circuits [147,148], or alternatively, increase BBB permeability, further contributing to baroreceptor reflex dysfunction and hypertension [149]. IL-1β and TNF-α can also increase BBB permeability via disruption of tight junctions [150,151]. This finding is particularly intriguing considering that prorenin can increase the expression of TNF-α and IL-1β in the NTS via the NF-κB complex [152]. TNF-α stimulation of the NF-κB pathway in POMC neurons leads to increased in blood pressure by increasing SNS outflow [131,132]. Taken together, Ang II and prorenin increase the expression of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and decrease the expression of anti-inflammatory cytokines in the hypothalamus. Subsequent activation of NF-κB signalling augments the pro-inflammatory response and increases permeability of BBB in the Ang II-induced hypertension. This results in further inflammation and SNS activity further increasing blood pressure.

Hypothalamic endoplasmic reticulum stress in hypertension

The endoplasmic reticulum (ER) is a cellular organelle that regulates protein synthesis and secretion. The unfolded protein response (UPR) is an intracellular stress response to a build-up of newly synthesized, unfolded proteins in the ER. Several inflammatory signalling systems, including JAK-AP1 and NF-κB pathways, interact with the three prototypical branches of the UPR that regulate metabolism and SNS activity [153158]. Overnutrition-related ER stress in the hypothalamus activates NF-κB and is sufficient to cause insulin and leptin resistance, which increases SNS outflow and hypertension [131,132]. Similarly, reduced ER capacity in the hypothalamus of mice on a high-fat diet results in severe leptin resistance and leads to increased obesity [159]. Intracerebroventricular injection of the ER stress inducer thapsigargin induces systemic insulin resistance and hypertension [132], whereas blocking ER stress induces leptin sensitization [159] and reduces obesity-related hypertension [132]. In line with these findings, acute induction of hypertension by hypothalamus ER stress can also be abrogated by NF-κB inhibition [132]. In summary, brain ER stress is likely involved in some form of hypothalamic inflammation and certain aspects of neurogenic hypertension involving increased SNS activity.

Hypothalamic oxidative stress in hypertension

As mentioned above, ROS help to drive hypertension both locally and systemically. Mitochondrial oxidative stress is frequent in overnutrition conditions and high levels of ROS in the PVN can modulate SNS activity as well as hypertension [160]. Chronic Ang II infusion into the PVN leads to membrane mobilization of p47phox, a cytoplasmic NADPH oxidase subunit required to initiate ROS production [161]. ROS reduce nitric oxide signal transduction in the PVN and increase glutamatergic signalling, which can contribute to neural dysfunction. However, enhanced nitric oxide signalling reduces blood pressure, decreases SNS activity and shows anti-hypertensive effect via adrenomedullin receptors [162]. Antioxidative treatments, such as overexpression of superoxide dismutase 1 (SOD1), or bilateral infusion of the radical scavenger tempol into the PVN inhibit ROS-driven SNS activation and hypertension [163]. Regarding the mechanisms involved, inflammation is likely involved in the mitochondrial dysfunction [164]. Mitochondrial dysfunction itself can also directly lead to the overexpression of pro-inflammatory cytokines, resulting in a feedforward loop characterized by increasing neuronal dysfunction. Notably, NF-κB inhibition in the PVN also abrogates the ROS production, which reduces inflammation in the hypothalamus and attenuates Ang II-dependent hypertension [140].

Hypothalamic pro-inflammatory IKKβ/NF-κB signalling in hypertension

Hypothalamic inflammation is frequently observed in overnutrition or obesity and is associated with IKKβ/NF-κB signalling pathway activation in the brain [131]. Besides various cytokines and various intracellular stress responses that lead to activation of hypothalamic NF-κB, it can also be activated by excess leptin [165]. Thus, although leptin's anorexic effects are blunted in obese mice [166], the resultant chronic elevation of leptin levels may contribute to activating the NF-κB pathway in the hypothalamus. Activation of the NF-κB complex is a critical modulator for the expression of the suppressor of cytokine signalling 3 (SOCS3), which plays an important role in the development of leptin and insulin resistance in feeding dysregulation [167], as indeed SOCS3 deficiency in the hypothalamus causes elevated leptin sensitivity and resistance to diet-induced obesity [168170]. Activation of IKKβ/NF-κB pathway is also responsible for the up-regulation of protein tyrosine phosphatase 1B (PTP1B), which further inhibits leptin and insulin signalling in a manner similar to SOCS3 [170]. Therefore, there appears to be a vicious cycle consisting of inflammation, leptin resistance and pathological increase in leptin release. Of interest, although leptin resistance caused by hypothalamic IKKβ/NF-κB activation leads to impaired function in controlling appetite, the action of leptin in elevating blood pressure is abnormally augmented under this inflammatory condition of obesity. The underling divergence remains puzzling, but possibly involves different downstream molecular events and neural circuitries in the hypothalamus and brain.

CONTROL OF HYPERTENSION VIA TARGETING INFLAMMATORY–SYMPATHETIC MECHANISM

As hypothalamic and neuroinflammation-related hypertension continues to attract more attention by researchers, treatments targeting central mechanisms of hypertension may be promising in the near future. The animal studies discussed above support the potential for novel pharmacological therapies and lifestyle modifications. Given that high sodium-mediated activation of RAS leads to expression of pro-inflammatory cytokines [55,56], one promising option includes local inhibition of epithelial sodium channels in the CNS to prevent hypertension [171]. Inhibition of RAS by renin inhibitors, ACEIs, angiotensin receptor blockers or MR blockers already shows benefit in clinical practice, and treatment with such drugs can prevent future cardiovascular complications [171]. Animal studies indicate that systematic administration of an angiotensin receptor blocker has anti-hypertensive effects that also prevent the SNS hyperactivity [172]. Additionally, a leptin antagonist was recently shown to reduce blood pressure independent of body weight changes [97]. ROS scavengers and immunosuppressive agents can also reduce blood pressure and have shown promise in both experimental models and humans [173,174]. Finally, epigallocatechin-3-O-gallate is a polyphenol present in green tea that is currently being tested for its antioxidant and anti-inflammatory properties. It has been shown to prevent hypertension and sympathetic outflow [175].

CONCLUSION

Over the last several decades, the understanding of the brain's role in the development of hypertension has dramatically increased. Current understanding postulates that neurogenic hypertension involves dysregulation of different neural cell types and signalling pathways. As outlined in this review, hypothalamic inflammation is one such signalling pathway that can result in cellular dysfunction that is detrimental to blood pressure homoeostasis. Future studies should be aimed at delineating hypothalamic inflammatory pathways and their cross-talk as it pertains to neurogenic hypertension. Further recognition of the underlying mechanisms of hypertension will help generate more therapeutic targets for further treatment of human hypertension.

We thank the members of the Cai Laboratory for their contributions to projects that were related to this review.

FUNDING

This work was supported by the National Institutes of Health (NIH) [grant numbers R01 DK078750, R01 AG031774, R01 HL113180 and R01 DK099136 (to D.C.)].

Abbreviations

     
  • ACE

    angiotensin-converting enzyme

  •  
  • ACEI

    angiotensin-converting enzyme inhibitor

  •  
  • AGRP

    agouti-related peptide

  •  
  • Ang II

    angiotensin II

  •  
  • AP-1

    activator protein-1

  •  
  • ARC

    arcuate nucleus

  •  
  • AT1

    angiotensin II type 1

  •  
  • AVP

    arginine vasopressin

  •  
  • BBB

    blood–brain barrier

  •  
  • CNS

    central nervous system

  •  
  • Cry

    cryptochrome

  •  
  • CVO

    circumventricular organ

  •  
  • ER

    endoplasmic reticulum

  •  
  • GABA

    gamma-aminobutyric acid

  •  
  • GR

    glucocorticoid receptor

  •  
  • HPA

    hypothalamic–pituitary–adrenal

  •  
  • 11βHSD2

    11β-hydroxysteroid dehydrogenase 2

  •  
  • IKKβ

    inhibitor of nuclear factor-κB kinase subunit β

  •  
  • IL

    interleukin

  •  
  • JAK

    Janus kinase

  •  
  • LepR

    leptin receptor

  •  
  • MC4

    melanocortin receptor 4

  •  
  • MR

    mineralocorticoid receptor

  •  
  • α-MSH

    α-melanocyte-stimulating hormone

  •  
  • NF-κB

    nuclear factor-kappa B

  •  
  • NTS

    nucleus tractus solitarius (solitary nucleus)

  •  
  • POMC

    proopiomelanocortin

  •  
  • PTP1B

    protein tyrosine phosphatase 1B

  •  
  • PTSD

    posttraumatic stress disorder

  •  
  • PVN

    paraventricular nucleus

  •  
  • RAS

    renin–angiotensin system

  •  
  • ROS

    reactive oxygen species

  •  
  • SCN

    suprachiasmatic nucleus

  •  
  • SNS

    sympathetic nervous system

  •  
  • SOCS3

    suppressor of cytokine signalling 3

  •  
  • SON

    supraoptic nucleus

  •  
  • TNF-α

    tumour necrosis factor-α

  •  
  • UPR

    unfolded protein response

References

References
1
Lackland
D.T.
Weber
M.A.
Global burden of cardiovascular disease and stroke: hypertension at the core
Can. J. Cardiol.
2015
, vol. 
31
 (pg. 
569
-
571
)
2
Yoon
S.S.
Gu
Q.
Nwankwo
T.
Wright
J.D.
Hong
Y.
Burt
V.
Trends in blood pressure among adults with hypertension: United States, 2003 to 2012
Hypertension
2015
, vol. 
65
 (pg. 
54
-
61
)
3
Egan
B.M.
Zhao
Y.
Axon
R.N.
US trends in prevalence, awareness, treatment, and control of hypertension, 1988–2008
J. Am. Med. Assoc.
2010
, vol. 
303
 (pg. 
2043
-
2050
)
4
Lim
S.S.
Vos
T.
Flaxman
A.D.
Danaei
G.
Shibuya
K.
Adair-Rohani
H.
Amann
M.
Anderson
H.R.
Andrews
K.G.
Aryee
M.
, et al. 
A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010
Lancet
2013
, vol. 
380
 (pg. 
2224
-
2260
)
5
Kearney
P.M.
Whelton
M.
Reynolds
K.
Muntner
P.
Whelton
P.K.
He
J.
Global burden of hypertension: analysis of worldwide data
Lancet (London, England)
2005
, vol. 
365
 (pg. 
217
-
223
)
6
Chobanian
A.V.
Shattuck lecture. The hypertension paradox–more uncontrolled disease despite improved therapy
N. Engl. J. Med.
2009
, vol. 
361
 (pg. 
878
-
887
)
7
DiBona
G.F.
Sympathetic nervous system and hypertension
Hypertension
2013
, vol. 
61
 (pg. 
556
-
560
)
8
de Wardener
H.E.
The hypothalamus and hypertension
Physiol. Rev.
2001
, vol. 
81
 (pg. 
1599
-
1658
)
9
Hirooka
Y.
Kishi
T.
Ito
K.
Sunagawa
K.
Potential clinical application of recently discovered brain mechanisms involved in hypertension
Hypertension
2013
, vol. 
62
 (pg. 
995
-
1002
)
10
Parati
G.
Esler
M.
The human sympathetic nervous system: its relevance in hypertension and heart failure
Eur. Heart J.
2012
, vol. 
33
 (pg. 
1058
-
1066
)
11
Poulter
N.R.
Prabhakaran
D.
Caulfield
M.
Hypertension
Lancet (London, England)
2015
, vol. 
386
 (pg. 
801
-
812
)
12
Lifton
R.P.
Gharavi
A.G.
Geller
D.S.
Molecular mechanisms of human hypertension
Cell
2001
, vol. 
104
 (pg. 
545
-
556
)
13
Lifton
R.P.
Molecular genetics of human blood pressure variation
Science
1996
, vol. 
272
 (pg. 
676
-
680
)
14
Boyden
L.M.
Choi
M.
Choate
K.A.
Nelson-Williams
C.J.
Farhi
A.
Toka
H.R.
Tikhonova
I.R.
Bjornson
R.
Mane
S.M.
Colussi
G.
, et al. 
Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities
Nature
2012
, vol. 
482
 (pg. 
98
-
102
)
15
Louis-Dit-Picard
H.
Barc
J.
Trujillano
D.
Miserey-Lenkei
S.
Bouatia-Naji
N.
Pylypenko
O.
Beaurain
G.
Bonnefond
A.
Sand
O.
Simian
C.
, et al. 
KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron
Nat. Genet.
2012
, vol. 
44
 (pg. 
456
-
460
s1–s3
16
Choi
M.
Scholl
U.I.
Yue
P.
Bjorklund
P.
Zhao
B.
Nelson-Williams
C.
Ji
W.
Cho
Y.
Patel
A.
Men
C.J.
, et al. 
K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension
Science
2011
, vol. 
331
 (pg. 
768
-
772
)
17
Beuschlein
F.
Boulkroun
S.
Osswald
A.
Wieland
T.
Nielsen
H.N.
Lichtenauer
U.D.
Penton
D.
Schack
V.R.
Amar
L.
Fischer
E.
, et al. 
Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension
Nat. Genet.
2013
, vol. 
45
 (pg. 
440
-
444
444e1–444e2
18
International Consortium for Blood Pressure Genome-Wide Association Studies Ehret
G.B.
Munroe
P.B.
Rice
K.M.
Bochud
M.
Johnson
A.D.
Chasman
D.I.
Smith
A.V.
Tobin
M.D.
Verwoert
G.C.
, et al. 
International Consortium for Blood Pressure Genome-Wide Association Studies
Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk
Nature
2011
, vol. 
478
 (pg. 
103
-
109
)
19
Wain
L.V.
Verwoert
G.C.
O'Reilly
P.F.
Shi
G.
Johnson
T.
Johnson
A.D.
Bochud
M.
Rice
K.M.
Henneman
P.
Smith
A.V.
, et al. 
Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure
Nat. Genet.
2011
, vol. 
43
 (pg. 
1005
-
1011
)
20
Munroe
P.B.
Barnes
M.R.
Caulfield
M.J.
Advances in blood pressure genomics
Circ. Res.
2013
, vol. 
112
 (pg. 
1365
-
1379
)
21
Tragante
V.
Barnes
M.R.
Ganesh
S.K.
Lanktree
M.B.
Guo
W.
Franceschini
N.
Smith
E.N.
Johnson
T.
Holmes
M.V.
Padmanabhan
S.
, et al. 
Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci
Am. J. Hum. Genet.
2014
, vol. 
94
 (pg. 
349
-
360
)
22
Kato
N.
Loh
M.
Takeuchi
F.
Verweij
N.
Wang
X.
Zhang
W.
Kelly
T.N.
Saleheen
D.
Lehne
B.
Mateo Leach
I.
, et al. 
Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation
Nat. Genet.
2015
, vol. 
47
 (pg. 
1282
-
1293
)
23
Malpas
S.C.
Sympathetic nervous system overactivity and its role in the development of cardiovascular disease
Physiol. Rev.
2010
, vol. 
90
 (pg. 
513
-
557
)
24
Guyenet
P.G.
The sympathetic control of blood pressure
Nat. Rev. Neurosci.
2006
, vol. 
7
 (pg. 
335
-
346
)
25
Doba
N.
Reis
D.J.
Acute fulminating neurogenic hypertension produced by brainstem lesions in the rat
Circ. Res.
1973
, vol. 
32
 (pg. 
584
-
593
)
26
Thrasher
T.N.
Effects of chronic baroreceptor unloading on blood pressure in the dog
Am. J. Physiol. Regul. Integr. Comp. Physiol.
2005
, vol. 
288
 (pg. 
R863
-
R871
)
27
Ferrario
C.M.
McCubbin
J.W.
Page
I.H.
Hemodynamic characteristics of chronic experimental neurogenic hypertension in unanesthetized dogs
Circ. Res.
1969
, vol. 
24
 (pg. 
911
-
922
)
28
Nathan
M.A.
Reis
D.J.
Chronic labile hypertension produced by lesions of the nucleus tractus solitarii in the cat
Circ. Res.
1977
, vol. 
40
 (pg. 
72
-
81
)
29
Snyder
D.W.
Doba
N.
Reis
D.J.
Regional distribution of blood flow during arterial hypertension produced by lesions of the nucleus tractus solitarii in rats
Circ. Res.
1978
, vol. 
42
 (pg. 
87
-
91
)
30
Doba
N.
Reis
D.J.
Role of central and peripheral adrenergic mechanisms in neurogenic hypertension produced by brainstem lesions in rat
Circ. Res.
1974
, vol. 
34
 (pg. 
293
-
301
)
31
Lohmeier
T.E.
Iliescu
R.
Chronic lowering of blood pressure by carotid baroreflex activation: mechanisms and potential for hypertension therapy
Hypertension
2011
, vol. 
57
 (pg. 
880
-
886
)
32
Zandberg
P.
De Jong
W.
De Wied
D.
Effect of catecholamine-receptor stimulating agents on blood pressure after local application in the nucleus tractus solitarii of the medulla oblongata
Eur. J. Pharmacol.
1979
, vol. 
55
 (pg. 
43
-
56
)
33
Lippoldt
A.
Paul
M.
Fuxe
K.
Ganten
D.
The brain renin-angiotensin system: molecular mechanisms of cell to cell interactions
Clin. Exp. Hypertens.
1995
, vol. 
17
 (pg. 
251
-
266
)
34
Phillips
M.
Angiotensin in the brain
Neuroendocrinology
1978
, vol. 
25
 (pg. 
354
-
377
)
35
Andersson
B.
Eridsson
S.
Rundgren
M.
Angiotensin and the brain
Acta Physiol. Scand.
1995
, vol. 
155
 (pg. 
117
-
125
)
36
McKinley
M.J.
Albiston
A.L.
Allen
A.M.
Mathai
M.L.
May
C.N.
McAllen
R.M.
Oldfield
B.J.
Mendelsohn
F.A.
Chai
S.Y.
The brain renin-angiotensin system: location and physiological roles
Int. J. Biochem. Cell Biol.
2003
, vol. 
35
 (pg. 
901
-
918
)
37
Ganten
D.
Fuxe
K.
Phillips
M.I.
Mann
J.F.
Ganten
U.
The brain isorenin-angiotensin system: biochemistry, localization, and possible role in drinking and blood pressure regulation
Front. Neuroendocrinol.
1978
, vol. 
5
 (pg. 
61
-
99
)
38
Fink
G.D.
Haywood
J.R.
Bryan
W.J.
Packwood
W.
Brody
M.J.
Central site for pressor action of blood-borne angiotensin in rat
Am. J. Physiol. Regul. Integr. Comp. Physiol.
1980
, vol. 
239
 (pg. 
R358
-
R361
)
39
Montezano
A.C.
Touyz
R.M.
Molecular mechanisms of hypertension–reactive oxygen species and antioxidants: a basic science update for the clinician
Can. J. Cardiol.
2012
, vol. 
28
 (pg. 
288
-
295
)
40
Zimmerman
M.C.
Lazartigues
E.
Sharma
R.V.
Davisson
R.L.
Hypertension caused by angiotensin II infusion involves increased superoxide production in the central nervous system
Circ. Res.
2004
, vol. 
95
 (pg. 
210
-
216
)
41
Peterson
J.R.
Sharma
R.V.
Davisson
R.L.
Reactive oxygen species in the neuropathogenesis of hypertension
Curr. Hypertens. Rep.
2006
, vol. 
8
 (pg. 
232
-
241
)
42
Ito
S.
Komatsu
K.
Tsukamoto
K.
Kanmatsuse
K.
Sved
A.F.
Ventrolateral medulla AT1 receptors support blood pressure in hypertensive rats
Hypertension
2002
, vol. 
40
 (pg. 
552
-
559
)
43
Osborn
J.W.
Hendel
M.D.
Collister
J.P.
Ariza-Guzman
P.A.
Fink
G.D.
The role of the subfornical organ in angiotensin II-salt hypertension in the rat
Exp. Physiol.
2012
, vol. 
97
 (pg. 
80
-
88
)
44
Nishihara
M.
Hirooka
Y.
Matsukawa
R.
Kishi
T.
Sunagawa
K.
Oxidative stress in the rostral ventrolateral medulla modulates excitatory and inhibitory inputs in spontaneously hypertensive rats
J. Hypertens.
2012
, vol. 
30
 (pg. 
97
-
106
)
45
Kishi
T.
Hirooka
Y.
Kimura
Y.
Ito
K.
Shimokawa
H.
Takeshita
A.
Increased reactive oxygen species in rostral ventrolateral medulla contribute to neural mechanisms of hypertension in stroke-prone spontaneously hypertensive rats
Circulation
2004
, vol. 
109
 (pg. 
2357
-
2362
)
46
Nishihara
M.
Hirooka
Y.
Kishi
T.
Sunagawa
K.
Different role of oxidative stress in paraventricular nucleus and rostral ventrolateral medulla in cardiovascular regulation in awake spontaneously hypertensive rats
J. Hypertens.
2012
, vol. 
30
 (pg. 
1758
-
1765
)
47
Morimoto
S.
Cassell
M.D.
Beltz
T.G.
Johnson
A.K.
Davisson
R.L.
Sigmund
C.D.
Elevated blood pressure in transgenic mice with brain-specific expression of human angiotensinogen driven by the glial fibrillary acidic protein promoter
Circ. Res.
2001
, vol. 
89
 (pg. 
365
-
372
)
48
Adrogue
H.J.
Madias
N.E.
Sodium and potassium in the pathogenesis of hypertension
N. Engl. J. Med.
2007
, vol. 
356
 (pg. 
1966
-
1978
)
49
Blaustein
M.P.
Leenen
F.H.
Chen
L.
Golovina
V.A.
Hamlyn
J.M.
Pallone
T.L.
Van Huysse
J.W.
Zhang
J.
Wier
W.G.
How NaCl raises blood pressure: a new paradigm for the pathogenesis of salt-dependent hypertension
Am. J. Physiol. Heart Circ. Physiol.
2012
, vol. 
302
 (pg. 
H1031
-
H1049
)
50
Takahashi
H.
Yoshika
M.
Komiyama
Y.
Nishimura
M.
The central mechanism underlying hypertension: a review of the roles of sodium ions, epithelial sodium channels, the renin-angiotensin-aldosterone system, oxidative stress and endogenous digitalis in the brain
Hypertens. Res.
2011
, vol. 
34
 (pg. 
1147
-
1160
)
51
Woods
J.W.
Pittman
A.W.
Pulliam
C.C.
Werk
E.E.
Jr
Waider
W.
Allen
C.A.
Renin profiling in hypertension and its use in treatment with propranolol and chlorthalidone
N. Engl. J. Med.
1976
, vol. 
294
 (pg. 
1137
-
1143
)
52
Minami
J.
Ishimitsu
T.
Matsuoka
H.
Is there overlap in blood-pressure response to the blockers of the renin-angiotensin system between lower and higher renin subjects?
Am. J. Hypertens.
2008
, vol. 
21
 (pg. 
130
-
131
)
53
Sumners
C.
Phillips
M.I.
Central injection of angiotensin II alters catecholamine activity in rat brain
Am. J. Physiol.
1983
, vol. 
244
 (pg. 
R257
-
R263
)
54
Nishimura
M.
Nanbu
A.
Ohtsuka
K.
Takahashi
H.
Iwai
N.
Kinoshita
M.
Yoshimura
M.
Sodium intake regulates renin gene expression differently in the hypothalamus and kidney of rats
J. Hypertens.
1997
, vol. 
15
 (pg. 
509
-
516
)
55
Nishimura
M.
Ohtsuka
K.
Takahashi
H.
Yoshimura
M.
Role of FMRFamide-activated brain sodium channel in salt-sensitive hypertension
Hypertension
2000
, vol. 
35
 
(Pt 2)
(pg. 
443
-
450
)
56
Nishimura
M.
Ohtsuka
K.
Nanbu
A.
Takahashi
H.
Yoshimura
M.
Benzamil blockade of brain Na+ channels averts Na(+)-induced hypertension in rats
Am. J. Physiol.
1998
, vol. 
274
 
(Pt 2)
(pg. 
R635
-
R644
)
57
Wang
H.
Huang
B.S.
Leenen
F.H.
Brain sodium channels and ouabain-like compounds mediate central aldosterone-induced hypertension
Am. J. Physiol. Heart Circ. Physiol.
2003
, vol. 
285
 (pg. 
H2516
-
H2523
)
58
Pascual-Le Tallec
L.
Lombes
M.
The mineralocorticoid receptor: a journey exploring its diversity and specificity of action
Mol. Endocrinol.
2005
, vol. 
19
 (pg. 
2211
-
2221
)
59
Grossmann
C.
Ruhs
S.
Langenbruch
L.
Mildenberger
S.
Stratz
N.
Schumann
K.
Gekle
M.
Nuclear shuttling precedes dimerization in mineralocorticoid receptor signaling
Chem. Biol.
2012
, vol. 
19
 (pg. 
742
-
751
)
60
Huang
B.S.
Wang
H.
Leenen
F.H.
Enhanced sympathoexcitatory and pressor responses to central Na+ in Dahl salt-sensitive vs. -resistant rats
Am. J. Physiol. Heart Circ. Physiol.
2001
, vol. 
281
 (pg. 
H1881
-
H1889
)
61
Chen
J.
Gomez-Sanchez
C.E.
Penman
A.
May
P.J.
Gomez-Sanchez
E.
Expression of mineralocorticoid and glucocorticoid receptors in preautonomic neurons of the rat paraventricular nucleus
Am. J. Physiol. Regul. Integr. Comp. Physiol.
2014
, vol. 
306
 (pg. 
R328
-
R340
)
62
Gomez-Sanchez
E.P.
Gomez-Sanchez
C.E.
Central regulation of blood pressure by the mineralocorticoid receptor
Mol. Cell. Endocrinol.
2012
, vol. 
350
 (pg. 
289
-
298
)
63
Shekhtman
E.
Geerling
J.C.
Loewy
A.D.
Aldosterone-sensitive neurons of the nucleus of the solitary tract: multisynaptic pathway to the nucleus accumbens
J. Comp. Neurol.
2007
, vol. 
501
 (pg. 
274
-
289
)
64
Geerling
J.C.
Engeland
W.C.
Kawata
M.
Loewy
A.D.
Aldosterone target neurons in the nucleus tractus solitarius drive sodium appetite
J. Neurosci.
2006
, vol. 
26
 (pg. 
411
-
417
)
65
Funder
J.W.
Mineralocorticoid receptor activation and oxidative stress
Hypertension
2007
, vol. 
50
 (pg. 
840
-
841
)
66
Xue
B.
Beltz
T.G.
Yu
Y.
Guo
F.
Gomez-Sanchez
C.E.
Hay
M.
Johnson
A.K.
Central interactions of aldosterone and angiotensin II in aldosterone- and angiotensin II-induced hypertension
Am. J. Physiol. Heart Circ. Physiol.
2011
, vol. 
300
 (pg. 
H555
-
H564
)
67
Wang
H.W.
Huang
B.S.
White
R.A.
Chen
A.
Ahmad
M.
Leenen
F.H.
Mineralocorticoid and angiotensin II type 1 receptors in the subfornical organ mediate angiotensin II-induced hypothalamic reactive oxygen species and hypertension
Neuroscience
2016
, vol. 
329
 (pg. 
112
-
121
)
68
Gao
L.
Wang
W.
Li
Y.L.
Schultz
H.D.
Liu
D.
Cornish
K.G.
Zucker
I.H.
Superoxide mediates sympathoexcitation in heart failure: roles of angiotensin II and NAD(P)H oxidase
Circ. Res.
2004
, vol. 
95
 (pg. 
937
-
944
)
69
Zimmerman
M.C.
Lazartigues
E.
Lang
J.A.
Sinnayah
P.
Ahmad
I.M.
Spitz
D.R.
Davisson
R.L.
Superoxide mediates the actions of angiotensin II in the central nervous system
Circ. Res.
2002
, vol. 
91
 (pg. 
1038
-
1045
)
70
Campese
V.M.
Shaohua
Y.
Huiquin
Z.
Oxidative stress mediates angiotensin II-dependent stimulation of sympathetic nerve activity
Hypertension
2005
, vol. 
46
 (pg. 
533
-
539
)
71
Zhang
Z.H.
Yu
Y.
Kang
Y.M.
Wei
S.G.
Felder
R.B.
Aldosterone acts centrally to increase brain renin-angiotensin system activity and oxidative stress in normal rats
Am. J. Physiol. Heart Circ. Physiol.
2008
, vol. 
294
 (pg. 
H1067
-
H1074
)
72
De Kloet
E.R.
Hormones and the stressed brain
Ann. N.Y. Acad. Sci.
2004
, vol. 
1018
 (pg. 
1
-
15
)
73
Joels
M.
Sarabdjitsingh
R.A.
Karst
H.
Unraveling the time domains of corticosteroid hormone influences on brain activity: rapid, slow, and chronic modes
Pharmacol. Rev.
2012
, vol. 
64
 (pg. 
901
-
938
)
74
Gomez-Sanchez
E.P.
Brain mineralocorticoid receptors in cognition and cardiovascular homeostasis
Steroids
2014
, vol. 
91
 (pg. 
20
-
31
)
75
Kellendonk
C.
Gass
P.
Kretz
O.
Schutz
G.
Tronche
F.
Corticosteroid receptors in the brain: gene targeting studies
Brain Res. Bull.
2002
, vol. 
57
 (pg. 
73
-
83
)
76
Harris
A.P.
Holmes
M.C.
de Kloet
E.R.
Chapman
K.E.
Seckl
J.R.
Mineralocorticoid and glucocorticoid receptor balance in control of HPA axis and behaviour
Psychoneuroendocrinology
2013
, vol. 
38
 (pg. 
648
-
658
)
77
Holsboer
F.
The corticosteroid receptor hypothesis of depression
Neuropsychopharmacology
2000
, vol. 
23
 (pg. 
477
-
501
)
78
De Kloet
E.R.
Vreugdenhil
E.
Oitzl
M.S.
Joels
M.
Brain corticosteroid receptor balance in health and disease
Endocr. Rev.
1998
, vol. 
19
 (pg. 
269
-
301
)
79
Yi
S.S.
Kim
H.J.
Do
S.G.
Lee
Y.B.
Ahn
H.J.
Hwang
I.K.
Yoon
Y.S.
Arginine vasopressin (AVP) expressional changes in the hypothalamic paraventricular and supraoptic nuclei of stroke-prone spontaneously hypertensive rats
Anat. Cell Biol.
2012
, vol. 
45
 (pg. 
114
-
120
)
80
Han
S.Y.
Bouwer
G.T.
Seymour
A.J.
Korpal
A.K.
Schwenke
D.O.
Brown
C.H.
Induction of hypertension blunts baroreflex inhibition of vasopressin neurons in the rat
Eur. J. Neurosci.
2015
, vol. 
42
 (pg. 
2690
-
2698
)
81
Kim
Y.B.
Kim
Y.S.
Kim
W.B.
Shen
F.Y.
Lee
S.W.
Chung
H.J.
Kim
J.S.
Han
H.C.
Colwell
C.S.
Kim
Y.I.
GABAergic excitation of vasopressin neurons: possible mechanism underlying sodium-dependent hypertension
Circ. Res.
2013
, vol. 
113
 (pg. 
1296
-
1307
)
82
Choe
K.Y.
Han
S.Y.
Gaub
P.
Shell
B.
Voisin
D.L.
Knapp
B.A.
Barker
P.A.
Brown
C.H.
Cunningham
J.T.
Bourque
C.W.
High salt intake increases blood pressure via BDNF-mediated downregulation of KCC2 and impaired baroreflex inhibition of vasopressin neurons
Neuron
2015
, vol. 
85
 (pg. 
549
-
560
)
83
Marosi
K.
Mattson
M.P.
Hold the salt: vasopressor role for BDNF
Cell Metab
2015
, vol. 
21
 (pg. 
509
-
510
)
84
Davisson
R.L.
Yang
G.
Beltz
T.G.
Cassell
M.D.
Johnson
A.K.
Sigmund
C.D.
The brain renin-angiotensin system contributes to the hypertension in mice containing both the human renin and human angiotensinogen transgenes
Circ. Res.
1998
, vol. 
83
 (pg. 
1047
-
1058
)
85
Morimoto
S.
Cassell
M.D.
Sigmund
C.D.
The brain renin-angiotensin system in transgenic mice carrying a highly regulated human renin transgene
Circ. Res.
2002
, vol. 
90
 (pg. 
80
-
86
)
86
Crofton
J.T.
Share
L.
Shade
R.E.
Lee-Kwon
W.
Manning
M.
Sawyer
W.H.
The importance of vasopressin in the development and maintenance of DOC-salt hypertension in the rat
Hypertension
1979
, vol. 
1
 (pg. 
31
-
38
)
87
Ribeiro
N.
do Nascimento Panizza
H.
dos Santos
K.M.
Ferreira-Neto
H.C.
Antunes
V.R.
Salt-induced sympathoexcitation involves vasopressin V1a receptor activation in the paraventricular nucleus of the hypothalamus
Am. J. Physiol. Regul. Integr. Comp. Physiol.
2015
, vol. 
309
 (pg. 
R1369
-
R1379
)
88
Littlejohn
N.K.
Siel
R.B.
Ketsawatsomkron
P.
Pelham
C.J.
Pearson
N.A.
Hilzendeger
A.M.
Buehrer
B.A.
Weidemann
B.J.
Li
H.
Davis
D.R.
, et al. 
Hypertension in mice with transgenic activation of the brain renin-angiotensin system is vasopressin dependent
Am. J. Physiol. Regul. Integr. Comp. Physiol.
2013
, vol. 
304
 (pg. 
R818
-
R828
)
89
Gomez-Sanchez
E.P.
Gomez-Sanchez
C.M.
Plonczynski
M.
Gomez-Sanchez
C.E.
Aldosterone synthesis in the brain contributes to Dahl salt-sensitive rat hypertension
Exp. Physiol.
2010
, vol. 
95
 (pg. 
120
-
130
)
90
Takahashi
H.
Takeda
K.
Ashizawa
H.
Inoue
A.
Yoneda
S.
Yoshimura
M.
Ijichi
H.
Centrally induced cardiovascular and sympathetic responses to hydrocortisone in rats
Am. J. Physiol.
1983
, vol. 
245
 (pg. 
H1013
-
H1018
)
91
Geerling
J.C.
Loewy
A.D.
11beta-hydroxysteroid dehydrogenase 2 vs. transgene: discrepant loci of expression in the adult brain
Am. J. Physiol. Renal Physiol.
2007
, vol. 
293
 (pg. 
F440
-
F441
)
92
Geerling
J.C.
Kawata
M.
Loewy
A.D.
Aldosterone-sensitive neurons in the rat central nervous system
J. Comp. Neurol.
2006
, vol. 
494
 (pg. 
515
-
527
)
93
Robson
A.C.
Leckie
C.M.
Seckl
J.R.
Holmes
M.C.
11 Beta-hydroxysteroid dehydrogenase type 2 in the postnatal and adult rat brain
Brain Res. Mol. Brain Res.
1998
, vol. 
61
 (pg. 
1
-
10
)
94
Leenen
F.H.
Actions of circulating angiotensin II and aldosterone in the brain contributing to hypertension
Am. J. Hypertens.
2014
, vol. 
27
 (pg. 
1024
-
1032
)
95
Maffei
M.
Halaas
J.
Ravussin
E.
Pratley
R.E.
Lee
G.H.
Zhang
Y.
Fei
H.
Kim
S.
Lallone
R.
Ranganathan
S.
, et al. 
Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects
Nat. Med.
1995
, vol. 
1
 (pg. 
1155
-
1161
)
96
Shek
E.W.
Brands
M.W.
Hall
J.E.
Chronic leptin infusion increases arterial pressure
Hypertension
1998
, vol. 
31
 
(Pt 2)
(pg. 
409
-
414
)
97
Simonds
S.E.
Pryor
J.T.
Ravussin
E.
Greenway
F.L.
Dileone
R.
Allen
A.M.
Bassi
J.
Elmquist
J.K.
Keogh
J.M.
Henning
E.
, et al. 
Leptin mediates the increase in blood pressure associated with obesity
Cell
2014
, vol. 
159
 (pg. 
1404
-
1416
)
98
Mark
A.L.
Selective leptin resistance revisited
Am. J. Physiol. Regul. Integr. Comp. Physiol.
2013
, vol. 
305
 (pg. 
R566
-
R581
)
99
Harlan
S.M.
Morgan
D.A.
Agassandian
K.
Guo
D.F.
Cassell
M.D.
Sigmund
C.D.
Mark
A.L.
Rahmouni
K.
Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin-induced sympathetic activation
Circ. Res.
2011
, vol. 
108
 (pg. 
808
-
812
)
100
do Carmo
J.M.
da Silva
A.A.
Cai
Z.
Lin
S.
Dubinion
J.H.
Hall
J.E.
Control of blood pressure, appetite, and glucose by leptin in mice lacking leptin receptors in proopiomelanocortin neurons
Hypertension
2011
, vol. 
57
 (pg. 
918
-
926
)
101
Tanida
M.
Yamamoto
N.
Shibamoto
T.
Rahmouni
K.
Involvement of hypothalamic AMP-activated protein kinase in leptin-induced sympathetic nerve activation
PloS One
2013
, vol. 
8
 pg. 
e56660
 
102
Harlan
S.M.
Guo
D.-F.
Morgan
D.A.
Fernandes-Santos
C.
Rahmouni
K.
Hypothalamic mTORC1 signaling controls sympathetic nerve activity and arterial pressure and mediates leptin effects
Cell Metab.
2013
, vol. 
17
 (pg. 
599
-
606
)
103
Tao
Y.X.
The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology
Endocr. Rev.
2010
, vol. 
31
 (pg. 
506
-
543
)
104
Li
P.
Cui
B.P.
Zhang
L.L.
Sun
H.J.
Liu
T.Y.
Zhu
G.Q.
Melanocortin 3/4 receptors in paraventricular nucleus modulate sympathetic outflow and blood pressure
Exp. Physiol.
2013
, vol. 
98
 (pg. 
435
-
443
)
105
Ward
K.R.
Bardgett
J.F.
Wolfgang
L.
Stocker
S.D.
Sympathetic response to insulin is mediated by melanocortin 3/4 receptors in the hypothalamic paraventricular nucleus
Hypertension
2011
, vol. 
57
 (pg. 
435
-
441
)
106
da Silva
A.A.
do Carmo
J.M.
Kanyicska
B.
Dubinion
J.
Brandon
E.
Hall
J.E.
Endogenous melanocortin system activity contributes to the elevated arterial pressure in spontaneously hypertensive rats
Hypertension
2008
, vol. 
51
 (pg. 
884
-
890
)
107
Rahmouni
K.
Haynes
W.G.
Morgan
D.A.
Mark
A.L.
Role of melanocortin-4 receptors in mediating renal sympathoactivation to leptin and insulin
J. Neurosci.
2003
, vol. 
23
 (pg. 
5998
-
6004
)
108
Muller
J.E.
Tofler
G.H.
Stone
P.H.
Circadian variation and triggers of onset of acute cardiovascular disease
Circulation
1989
, vol. 
79
 (pg. 
733
-
743
)
109
Takeda
N.
Maemura
K.
Circadian clock and vascular disease
Hypertens. Res.
2010
, vol. 
33
 (pg. 
645
-
651
)
110
Sheppard
J.P.
Hodgkinson
J.
Riley
R.
Martin
U.
Bayliss
S.
McManus
R.J.
Prognostic significance of the morning blood pressure surge in clinical practice: a systematic review
Am. J. Hypertens.
2015
, vol. 
28
 (pg. 
30
-
41
)
111
Doi
M.
Takahashi
Y.
Komatsu
R.
Yamazaki
F.
Yamada
H.
Haraguchi
S.
Emoto
N.
Okuno
Y.
Tsujimoto
G.
Kanematsu
A.
, et al. 
Salt-sensitive hypertension in circadian clock-deficient cry-null mice involves dysregulated adrenal Hsd3b6
Nat. Med.
2010
, vol. 
16
 (pg. 
67
-
74
)
112
Gubin
D.G.
Gubin
G.D.
Gapon
L.I.
Weinert
D.
Daily melatonin administration attenuates age-dependent disturbances of cardiovascular rhythms
Curr. Aging Sci.
2016
, vol. 
9
 (pg. 
5
-
13
)
113
Schwartz
M.W.
Woods
S.C.
Porte
D.
Jr
Seeley
R.J.
Baskin
D.G.
Central nervous system control of food intake
Nature
2000
, vol. 
404
 (pg. 
661
-
671
)
114
Blouet
C.
Schwartz
G.J.
Hypothalamic nutrient sensing in the control of energy homeostasis
Behav. Brain Res.
2010
, vol. 
209
 (pg. 
1
-
12
)
115
Zelzer
E.
Levy
Y.
Kahana
C.
Shilo
B.Z.
Rubinstein
M.
Cohen
B.
Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ARNT
EMBO J.
1998
, vol. 
17
 (pg. 
5085
-
5094
)
116
Barsh
G.S.
Schwartz
M.W.
Genetic approaches to studying energy balance: perception and integration
Nat. Rev. Genet.
2002
, vol. 
3
 (pg. 
589
-
600
)
117
Saper
C.B.
Chou
T.C.
Elmquist
J.K.
The need to feed: homeostatic and hedonic control of eating
Neuron
2002
, vol. 
36
 (pg. 
199
-
211
)
118
Schwartz
M.W.
Woods
S.C.
Seeley
R.J.
Barsh
G.S.
Baskin
D.G.
Leibel
R.L.
Is the energy homeostasis system inherently biased toward weight gain?
Diabetes
2003
, vol. 
52
 (pg. 
232
-
238
)
119
Zigman
J.M.
Elmquist
J.K.
Minireview: from anorexia to obesity–the yin and yang of body weight control
Endocrinology
2003
, vol. 
144
 (pg. 
3749
-
3756
)
120
Tang
Y.
Purkayastha
S.
Cai
D.
Hypothalamic microinflammation: a common basis of metabolic syndrome and aging
Trends Neurosci.
2015
, vol. 
38
 (pg. 
36
-
44
)
121
Purkayastha
S.
Cai
D.
Neuroinflammatory basis of metabolic syndrome
Mol. Metab.
2013
, vol. 
2
 (pg. 
356
-
363
)
122
Mathieu
P.
Poirier
P.
Pibarot
P.
Lemieux
I.
Després
J.-P.
Visceral obesity the link among inflammation, hypertension, and cardiovascular disease
Hypertension
2009
, vol. 
53
 (pg. 
577
-
584
)
123
Cai
D.
NFkappaB-mediated metabolic inflammation in peripheral tissues versus central nervous system
Cell Cycle
2009
, vol. 
8
 (pg. 
2542
-
2548
)
124
Gregor
M.F.
Hotamisligil
G.S.
Inflammatory mechanisms in obesity
Annu. Rev. Immunol.
2011
, vol. 
29
 (pg. 
415
-
445
)
125
Lumeng
C.N.
Saltiel
A.R.
Inflammatory links between obesity and metabolic disease
J. Clin. Invest.
2011
, vol. 
121
 (pg. 
2111
-
2117
)
126
Schenk
S.
Saberi
M.
Olefsky
J.M.
Insulin sensitivity: modulation by nutrients and inflammation
J. Clin. Invest.
2008
, vol. 
118
 (pg. 
2992
-
3002
)
127
Shoelson
S.E.
Goldfine
A.B.
Getting away from glucose: fanning the flames of obesity-induced inflammation
Nat. Med.
2009
, vol. 
15
 (pg. 
373
-
374
)
128
Zhang
X.
Zhang
G.
Zhang
H.
Karin
M.
Bai
H.
Cai
D.
Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity
Cell
2008
, vol. 
135
 (pg. 
61
-
73
)
129
Meng
Q.
Cai
D.
Defective hypothalamic autophagy directs the central pathogenesis of obesity via the IkappaB kinase beta (IKKbeta)/NF-kappaB pathway
J. Biol. Chem.
2011
, vol. 
286
 (pg. 
32324
-
32332
)
130
Posey
K.A.
Clegg
D.J.
Printz
R.L.
Byun
J.
Morton
G.J.
Vivekanandan-Giri
A.
Pennathur
S.
Baskin
D.G.
Heinecke
J.W.
Woods
S.C.
, et al. 
Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet
Am. J. Physiol. Endocrinol. Metab.
2009
, vol. 
296
 (pg. 
E1003
-
E1012
)
131
Purkayastha
S.
Zhang
G.
Cai
D.
Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-beta and NF-kappaB
Nat. Med.
2011
, vol. 
17
 (pg. 
883
-
887
)
132
Purkayastha
S.
Zhang
H.
Zhang
G.
Ahmed
Z.
Wang
Y.
Cai
D.
Neural dysregulation of peripheral insulin action and blood pressure by brain endoplasmic reticulum stress
Proc. Natl. Acad. Sci. U.S.A.
2011
, vol. 
108
 (pg. 
2939
-
2944
)
133
Arruda
A.P.
Milanski
M.
Coope
A.
Torsoni
A.S.
Ropelle
E.
Carvalho
D.P.
Carvalheira
J.B.
Velloso
L.A.
Low-grade hypothalamic inflammation leads to defective thermogenesis, insulin resistance, and impaired insulin secretion
Endocrinology
2011
, vol. 
152
 (pg. 
1314
-
1326
)
134
Horvath
T.L.
Sarman
B.
Garcia-Caceres
C.
Enriori
P.J.
Sotonyi
P.
Shanabrough
M.
Borok
E.
Argente
J.
Chowen
J.A.
Perez-Tilve
D.
, et al. 
Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity
Proc. Natl. Acad. Sci. U.S.A.
2010
, vol. 
107
 (pg. 
14875
-
14880
)
135
Thaler
J.P.
Yi
C.X.
Schur
E.A.
Guyenet
S.J.
Hwang
B.H.
Dietrich
M.O.
Zhao
X.
Sarruf
D.A.
Izgur
V.
Maravilla
K.R.
, et al. 
Obesity is associated with hypothalamic injury in rodents and humans
J. Clin. Invest.
2012
, vol. 
122
 (pg. 
153
-
162
)
136
Felder
R.B.
Mineralocorticoid receptors, inflammation and sympathetic drive in a rat model of systolic heart failure
Exp. Physiol.
2010
, vol. 
95
 (pg. 
19
-
25
)
137
Felder
R.B.
Yu
Y.
Zhang
Z.H.
Wei
S.G.
Pharmacological treatment for heart failure: a view from the brain
Clin. Pharmacol. Ther.
2009
, vol. 
86
 (pg. 
216
-
220
)
138
Schiltz
J.C.
Sawchenko
P.E.
Signaling the brain in systemic inflammation: the role of perivascular cells
Front. Biosci.
2003
, vol. 
8
 (pg. 
s1321
-
s1329
)
139
Qi
J.
Zhang
D.M.
Suo
Y.P.
Song
X.A.
Yu
X.J.
Elks
C.
Lin
Y.X.
Xu
Y.Y.
Zang
W.J.
Zhu
Z.
, et al. 
Renin-angiotensin system modulates neurotransmitters in the paraventricular nucleus and contributes to angiotensin II-induced hypertensive response
Cardiovasc. Toxicol.
2013
, vol. 
13
 (pg. 
48
-
54
)
140
Cardinale
J.P.
Sriramula
S.
Mariappan
N.
Agarwal
D.
Francis
J.
Angiotensin II-induced hypertension is modulated by nuclear factor-kappaBin the paraventricular nucleus
Hypertension
2012
, vol. 
59
 (pg. 
113
-
121
)
141
Su
Q.
Qin
D.N.
Wang
F.X.
Ren
J.
Li
H.B.
Zhang
M.
Yang
Q.
Miao
Y.W.
Yu
X.J.
Qi
J.
, et al. 
Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin-angiotensin system and proinflammatory cytokines in hypertension
Toxicol. Appl. Pharmacol.
2014
, vol. 
276
 (pg. 
115
-
120
)
142
Yu
Y.
Xue
B.J.
Zhang
Z.H.
Wei
S.G.
Beltz
T.G.
Guo
F.
Johnson
A.K.
Felder
R.B.
Early interference with p44/42 mitogen-activated protein kinase signaling in hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension
Hypertension
2013
, vol. 
61
 (pg. 
842
-
849
)
143
Saavedra
J.M.
Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders
Clin. Sci. (Lond.)
2012
, vol. 
123
 (pg. 
567
-
590
)
144
Wu
K.L.
Chan
S.H.
Chan
J.Y.
Neuroinflammation and oxidative stress in rostral ventrolateral medulla contribute to neurogenic hypertension induced by systemic inflammation
J. Neuroinflammation
2012
, vol. 
9
 pg. 
212
 
145
de Kloet
A.D.
Krause
E.G.
Shi
P.D.
Zubcevic
J.
Raizada
M.K.
Sumners
C.
Neuroimmune communication in hypertension and obesity: a new therapeutic angle?
Pharmacol. Ther
2013
, vol. 
138
 (pg. 
428
-
440
)
146
Shi
P.
Diez-Freire
C.
Jun
J.Y.
Qi
Y.
Katovich
M.J.
Li
Q.
Sriramula
S.
Francis
J.
Sumners
C.
Raizada
M.K.
Brain microglial cytokines in neurogenic hypertension
Hypertension
2010
, vol. 
56
 (pg. 
297
-
303
)
147
Zhang
M.
Mao
Y.
Ramirez
S.H.
Tuma
R.F.
Chabrashvili
T.
Angiotensin II induced cerebral microvascular inflammation and increased blood-brain barrier permeability via oxidative stress
Neuroscience
2010
, vol. 
171
 (pg. 
852
-
858
)
148
Paton
J.F.
Wang
S.
Polson
J.W.
Kasparov
S.
Signalling across the blood brain barrier by angiotensin II: novel implications for neurogenic hypertension
J. Mol. Med. (Berl.)
2008
, vol. 
86
 (pg. 
705
-
710
)
149
Biancardi
V.C.
Son
S.J.
Ahmadi
S.
Filosa
J.A.
Stern
J.E.
Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood-brain barrier
Hypertension
2014
, vol. 
63
 (pg. 
572
-
579
)
150
Labus
J.
Hackel
S.
Lucka
L.
Danker
K.
Interleukin-1beta induces an inflammatory response and the breakdown of the endothelial cell layer in an improved human THBMEC-based in vitro blood-brain barrier model
J. Neurosci. Methods
2014
, vol. 
228
 (pg. 
35
-
45
)
151
Rochfort
K.D.
Collins
L.E.
Murphy
R.P.
Cummins
P.M.
Downregulation of blood-brain barrier phenotype by proinflammatory cytokines involves NADPH oxidase-dependent ROS generation: consequences for interendothelial adherens and tight junctions
PLoS One
2014
, vol. 
9
 pg. 
e101815
 
152
Zubcevic
J.
Jun
J.Y.
Lamont
G.
Murca
T.M.
Shi
P.
Yuan
W.
Lin
F.
Carvajal
J.M.
Li
Q.
Sumners
C.
, et al. 
Nucleus of the solitary tract (pro)renin receptor-mediated antihypertensive effect involves nuclear factor-kappaB-cytokine signaling in the spontaneously hypertensive rat
Hypertension
2013
, vol. 
61
 (pg. 
622
-
627
)
153
Kleinridders
A.
Schenten
D.
Konner
A.C.
Belgardt
B.F.
Mauer
J.
Okamura
T.
Wunderlich
F.T.
Medzhitov
R.
Brüning
J.C.
MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity
Cell Metab.
2009
, vol. 
10
 (pg. 
249
-
259
)
154
Sabio
G.
Cavanagh-Kyros
J.
Barrett
T.
Jung
D.Y.
Ko
H.J.
Ong
H.
Morel
C.
Mora
A.
Reilly
J.
Kim
J.K.
Davis
R.J.
Role of the hypothalamic-pituitary-thyroid axis in metabolic regulation by JNK1
Genes Dev.
2010
, vol. 
24
 (pg. 
256
-
264
)
155
Hirosumi
J.
Tuncman
G.
Chang
L.
Gorgun
C.Z.
Uysal
K.T.
Maeda
K.
Karin
M.
Hotamisligil
G.S.
A central role for JNK in obesity and insulin resistance
Nature
2002
, vol. 
420
 (pg. 
333
-
336
)
156
Sabio
G.
Das
M.
Mora
A.
Zhang
Z.
Jun
J.Y.
Ko
H.J.
Barrett
T.
Kim
J.K.
Davis
R.J.
A stress signaling pathway in adipose tissue regulates hepatic insulin resistance
Science
2008
, vol. 
322
 (pg. 
1539
-
1543
)
157
Sabio
G.
Cavanagh-Kyros
J.
Ko
H.J.
Jung
D.Y.
Gray
S.
Jun
J.Y.
Barrett
T.
Mora
A.
Kim
J.K.
Davis
R.J.
Prevention of steatosis by hepatic JNK1
Cell Metab.
2009
, vol. 
10
 (pg. 
491
-
498
)
158
Solinas
G.
Vilcu
C.
Neels
J.G.
Bandyopadhyay
G.K.
Luo
J.L.
Naugler
W.
Grivennikov
S.
Wynshaw-Boris
A.
Scadeng
M.
Olefsky
J.M.
Karin
M.
JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity
Cell Metab.
2007
, vol. 
6
 (pg. 
386
-
397
)
159
Ozcan
L.
Ergin
A.S.
Lu
A.
Chung
J.
Sarkar
S.
Nie
D.
Myers
M.G.
Jr
Ozcan
U.
Endoplasmic reticulum stress plays a central role in development of leptin resistance
Cell Metab.
2009
, vol. 
9
 (pg. 
35
-
51
)
160
Carmichael
C.Y.
Wainford
R.D.
Hypothalamic signaling mechanisms in hypertension
Curr. Hypertens Rep.
2015
, vol. 
17
 pg. 
39
 
161
Coleman
C.G.
Wang
G.
Faraco
G.
Marques Lopes
J.
Waters
E.M.
Milner
T.A.
Iadecola
C.
Pickel
V.M.
Membrane trafficking of NADPH oxidase p47(phox) in paraventricular hypothalamic neurons parallels local free radical production in angiotensin II slow-pressor hypertension
J. Neurosci.
2013
, vol. 
33
 (pg. 
4308
-
4316
)
162
Zhou
Y.B.
Sun
H.J.
Chen
D.
Liu
T.Y.
Han
Y.
Wang
J.J.
Tang
C.S.
Kang
Y.M.
Zhu
G.Q.
Intermedin in paraventricular nucleus attenuates sympathetic activity and blood pressure via nitric oxide in hypertensive rats
Hypertension
2014
, vol. 
63
 (pg. 
330
-
337
)
163
Yuan
N.
Zhang
F.
Zhang
L.L.
Gao
J.
Zhou
Y.B.
Han
Y.
Zhu
G.Q.
SOD1 gene transfer into paraventricular nucleus attenuates hypertension and sympathetic activity in spontaneously hypertensive rats
Pflugers Arch.
2013
, vol. 
465
 (pg. 
261
-
270
)
164
Vitale
G.
Salvioli
S.
Franceschi
C.
Oxidative stress and the ageing endocrine system
Nat. Rev. Endocrinol.
2013
, vol. 
9
 (pg. 
228
-
240
)
165
Jang
P.G.
Namkoong
C.
Kang
G.M.
Hur
M.W.
Kim
S.W.
Kim
G.H.
Kang
Y.
Jeon
M.J.
Kim
E.H.
Lee
M.S.
, et al. 
NF-kappaB activation in hypothalamic pro-opiomelanocortin neurons is essential in illness- and leptin-induced anorexia
J. Biol. Chem.
2010
, vol. 
285
 (pg. 
9706
-
9715
)
166
Morgan
D.A.
Thedens
D.R.
Weiss
R.
Rahmouni
K.
Mechanisms mediating renal sympathetic activation to leptin in obesity
Am. J. Physiol. Regul. Integr. Comp. Physiol.
2008
, vol. 
295
 (pg. 
R1730
-
R1736
)
167
Howard
J.K.
Flier
J.S.
Attenuation of leptin and insulin signaling by SOCS proteins
Trends Endocrinol. Metab.
2006
, vol. 
17
 (pg. 
365
-
371
)
168
Reed
A.S.
Unger
E.K.
Olofsson
L.E.
Piper
M.L.
Myers
M.G.
Jr
Xu
A.W.
Functional role of suppressor of cytokine signaling 3 upregulation in hypothalamic leptin resistance and long-term energy homeostasis
Diabetes
2010
, vol. 
59
 (pg. 
894
-
906
)
169
Kievit
P.
Howard
J.K.
Badman
M.K.
Balthasar
N.
Coppari
R.
Mori
H.
Lee
C.E.
Elmquist
J.K.
Yoshimura
A.
Flier
J.S.
Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells
Cell Metab.
2006
, vol. 
4
 (pg. 
123
-
132
)
170
Mori
H.
Hanada
R.
Hanada
T.
Aki
D.
Mashima
R.
Nishinakamura
H.
Torisu
T.
Chien
K.R.
Yasukawa
H.
Yoshimura
A.
Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity
Nat. Med.
2004
, vol. 
10
 (pg. 
739
-
743
)
171
Romero
C.A.
Orias
M.
Weir
M.R.
Novel RAAS agonists and antagonists: clinical applications and controversies
Nat. Rev. Endocrinol.
2015
, vol. 
11
 (pg. 
242
-
252
)
172
Horiuchi
M.
Mogi
M.
Iwai
M.
Signaling crosstalk angiotensin II receptor subtypes and insulin
Endocr. J.
2006
, vol. 
53
 (pg. 
1
-
5
)
173
Bencini
A.
Failli
P.
Valtancoli
B.
Bani
D.
Low molecular weight compounds with transition metals as free radical scavengers and novel therapeutic agents
Cardiovasc. Hematol. Agents Med. Chem.
2010
, vol. 
8
 (pg. 
128
-
146
)
174
Berzigotti
A.
Bosch
J.
Pharmacologic management of portal hypertension
Clin. Liver Dis.
2014
, vol. 
18
 (pg. 
303
-
317
)
175
Yi
Q.Y.
Qi
J.
Yu
X.J.
Li
H.B.
Zhang
Y.
Su
Q.
Zhang
D.M.
Guo
J.
Feng
Z.P.
Wang
M.L.
, et al. 
Paraventricular nucleus infusion of epigallocatechin-3-O-gallate improves renovascular hypertension
Cardiovasc. Toxicol.
2015
, vol. 
16
 (pg. 
276
-
285
)