Renin-angiotensin system: a novel target for brain health.

Since the first description of renin, angiotensinogen and angiotensin as well as converting enzyme and angiotensin receptors in the brain exactly 30 years ago,1–5⇓⇓⇓⇓ there was a heated debate, whether an endogenous intrinsic brain renin- angiotensin system (RAS) exists or not.6,7⇓ For a long time, the “believers” of local angiotensin II generation by the brain RAS were in a minority. Even at a symposium 1981, celebrating the 10-year anniversary of the discovery of the brain RAS, there was skepticism and the question whether the “renin-like” enzyme in brain was identical with cathepsins, tonin, or other proteases was a matter of debate. Historically, it is interesting that the presence in the brain of other classically peripheral peptides such as insulin, glucagon, and substance P was accepted without identification of the local synthetic pathway and less controversial than angiotensin as neuropeptide. Open letters, public debates, and personal accusations nourished sometimes emotional controversy whether angiotensin could be generated locally in tissue. The brain was a model for angiotensin generating pathways in other extrarenal tissues because the blood-brain barrier, which is impermeable for proteins and peptides, made it more unlikely that the RAS components measured in the brain were contaminations from the plasma. Angiotensin has extremely powerful effects on the brain that synergistically increase blood volume and blood pressure, eg, by stimulation of water intake and salt appetite, release of various pituitary hormones, increase of sympathetic tone, and decrease of baroreceptor reflex.7 The local generation of angiotensin II in the brain by an endogenous intrinsic RAS could therefore be extremely important for cardiovascular control and beyond. With the advent of transgenic technology, novel approaches to study the mechanistic and functional aspects of the brain RAS became available. Renin and angiotensinogen could be overexpressed or ablated …

The Brain Renin-Angiotensin System Controls Divergent Efferent Mechanisms to Regulate Fluid and Energy Balance

During the past 3 to 4 decades, there has been debate on the presence as well as the role of local tissue renin–angiotensin systems (RAS) in cardiovascular physiology and pathophysiology. Although it is now accepted that all components of the RAS are present in a variety of extrarenal tissues and their regulation may be independent of the circulating hormonal system, the factors contributing to this regulation are still not well understood. Also apparent is that our understanding of the relationships among various cell types expressing individual RAS components and production of specific angiotensin peptides in each tissue is still lacking. This is particularly true of the brain RAS, where even after 20years the question of whether there are angiotensinergic versus reninergic neurons or a complete functioning RAS in cerebrospinal fluid (CSF) or extracellular fluid or glia remains in question.1 Ever since early reports provided biochemical evidence of RAS components in brain, controversy regarding their cellular localization, independence from the circulating system, and authenticity of the proteins and peptides persists. It is well accepted that angiotensinogen is present in CSF/interstitial fluid and localization via immunocytochemistry and in situ hybridization histochemistry reveals that production of the precursor protein is primarily in glia, but also in neurons, within key cardiovascular nuclei. Lingering questions remain concerning local expression of authentic renin in tissues, especially given that prorenin or active renin can be sequestered from the circulation2 and other enzymes can exhibit similar proteolytic profiles under certain conditions. However, there is unequivocal evidence of discrete cells within the pituitary, choroid plexus, medulla oblongata, and hypothalamus that are positive for renin immunoreactivity colocalizing mainly with neurons, but in the medulla oblongata and subfornical organ, in glial elements as well. Evidence of renin mRNA in brain tissue provides a mechanism for local synthesis of the …

The central renin angiotensin system (RAS) is one of the most widely investigated cardiovascular systems in the brain. It is implicated in a myriad of cardiovascular diseases. However, studies from the last decade have identified its involvement in several neurologic abnormalities. Understanding the molecular functionality of the various RAS components can thus provide considerable insight into the phenotypic differences and mechanistic drivers of not just cardiovascular but also neurologic disorders. Since activation of one of its primary receptors, the angiotensin type 1 receptor (AT1R), results in an augmentation of oxidative stress and inflammatory cytokines, it becomes essential to investigate not just neuronal RAS but glial RAS as well. Glial cells are key homeostatic regulators in the brain and are critical players in the resolution of overt oxidative stress and neuroinflammation. Designing better and effective therapeutic strategies that target the brain RAS could well hinge on understanding the molecular basis of both neuronal and glial RAS. This review provides a comprehensive overview of the major studies that have investigated the mechanisms and regulation of the brain RAS, and it also provides insight into the potential role of glial AT1Rs in the pathophysiology of cardiovascular and neurologic disorders.

The concept of a “local” renin angiotensin system (RAS) can mean different things to different people. Its main purpose is to differentiate the “local” RAS operating in tissues from the classical “circulating” RAS, but it is difficult to differentiate between the two systems because of their extensive overlap. The circulating RAS comprises kidney-derived renin acting on liver-derived angiotensinogen to generate angiotensin (Ang) I that is converted to Ang II by angiotensin converting enzyme (ACE). However, tissues are the main site of production of angiotensin peptides by the circulating RAS, whereby plasma-derived renin acts on plasma-derived angiotensinogen to generate Ang I, which is converted to Ang II by endothelial ACE (1–4). Local RAS refers to tissue-based mechanisms of Ang peptide formation that operate separately from the circulating RAS. Although many different concepts of local RAS have been described, a key feature is the local synthesis of RAS components including angiotensinogen and enzymes such as renin that cleave angiotensinogen to produce Ang peptides independently of the circulating RAS. ACE and Ang II type 1 (AT1) and type 2 (AT2) receptors are invariably locally synthesized, but these are also components of the circulating RAS. Many other potential components of local RAS have been described that may contribute to tissue-specific mechanisms of Ang peptide formation, and that may either participate in disease processes or contribute to mechanisms that protect from tissue injury. These include the (pro)renin receptor (5), renin-independent mechanisms of Ang peptide generation from Ang- (1-12) (6), intracellular (or intracrine) RAS that may contribute to cardiovascular disease (7, 8), and AT2 receptors (7) and the ACE2/Ang-(1-7)/Mas receptor pathway (6–8) that may mediate therapeutic benefit in cardiovascular disease. In addition, novel Ang peptides with novel pharmacology, including Ang IV, Ang A, alamandine, and angioprotectin (6, 8), have the potential to contribute to disease or to protective mechanisms. Moreover, the brain RAS, including the ACE2/Ang-(1-7)/Mas receptor and the Ang IV/insulin regulated aminopeptidase pathways may play a role in Alzheimer’s and Parkinson’s diseases (9). Local production of aldosterone may have a pathogenic role (7, 10), ACE, AT2 receptors, Ang-(1-7) and acetyl-Ser-Asp-Lys-Pro may have a role in hematopoiesis (11), and the ACE2/Ang-(1-7)/Mas receptor pathway may contribute to fetal programing, reproduction, and cancer (6, 12). This short opinion piece discusses the potential clinical relevance of local RAS. The challenge in demonstrating the independence of local from circulating RAS, and the potential interaction of ACE inhibitor and AT1 receptor blocker (ARB) therapies with local RAS are discussed. Attempts to define local RAS that are independent of the circulating RAS have been primarily based on animal models and the clinical relevance of local RAS is uncertain. However, this area of research continues to evolve, and today’s opinions may change as we gain better understanding of how these novel components and mechanisms impact on clinical medicine.

Stimulation of ADH release by the renin-angiotensin system.

Abstracts

The kallikrein-kinin system (KKS) is an intricate endogenous pathway involved in several physiological and pathological cascades in the brain. Due to the pathological effects of kinins in blood vessels and tissues, their formation and degradation are tightly controlled. Their components have been related to several central nervous system diseases such as stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy and others. Bradykinin and its receptors (B1R and B2R) may have a role in the pathophysiology of certain central nervous system diseases. It has been suggested that kinin B1R is up-regulated in pathological conditions and has a neurodegenerative pattern, while kinin B2R is constitutive and can act as a neuroprotective factor in many neurological conditions. The renin angiotensin system (RAS) is an important blood pressure regulator and controls both sodium and water intake. AngII is a potent vasoconstrictor molecule and angiotensin converting enzyme is the major enzyme responsible for its release. AngII acts mainly on the AT1 receptor, with involvement in several systemic and neurological disorders. Brain RAS has been associated with physiological pathways, but is also associated with brain disorders. This review describes topics relating to the involvement of both systems in several forms of brain dysfunction and indicates components of the KKS and RAS that have been used as targets in several pharmacological approaches.

P198 Introduction: The systemic renin angiotensin system (RAS) plays an important role in blood pressure (BP) regulation during the development of two-kidney, one clip hypertension (2K1C). Its contributions decrease with time after constriction of the renal artery. During the chronic phase, the peripheral RAS returns to normal, nevertheless for months the hypertension is sustained. We hypothesized that during this phase of 2K1C hypertension, the brain RAS contributes to the maintenance of high BP. Methods: Therefore, we studied in the role of brain RAS by decreasing the synthesis of angiotensinogen (AGT) and angiotensin type 1a receptors (AT1R) with intracerebroventricular (ICV) injection of antisense oligonucleotides (AS-ODN). The response of systolic BP (SBP) to AS-ODN to AGT was studied at 6 mo(Group 1) and the response to AS-ODN to AT1R at 10 mo post clipping (Group 2). Each group was divided into AS-ODN, sense or inverted ODN, and saline subgroups. All groups were implanted with ICV cannulae one week before treatment. SBP was monitored by tail cuff method. Plasma and brain angiotensin II (AngII) content was measured by radioimmunoassay in all treated 2K1C groups and in nonclipped rats. Results: The results show that in Group 1, at 6 mo post clipping, the ICV AS-ODN to AGT (200 μg/kg, n=5) significantly decreased SBP(≈−22±6 mmHg, P<0.05)compared to sense ODN and saline group (n=5). The hypothalamic AngII content in sense ODN and saline groups was significantly (P<0.05) higher than in nonclipped rats. AS-ODN to AGT reduced the elevated hypothalamic AngII level. Plasma AngII was significantly decreased in the clipped group (40±12 pg/ml) compared with nonclipped group (75±8 pg/ml). In Group 2, 10 mo post clipping, the ICV injection of AS-ODN to AT1R (250 μg/kg, n=6) significantly decreased SBP(≈−26±8 mmHg, P<0.05) for 3 days post injection, compared to inverted ODN. In contrast, intravenous AS-ODN to AT1R in dose of 250-500 μg/kg did not affect SBP. Conclusion: These results suggest that the brain RAS plays an important role in maintaining the elevated SBP in chronic hypertension phase.

A brain renin angiotensin system (RAS) and its role in cardiovascular control and fluid homeostasis was at first controversial. This was because a circulating kidney-derived renin angiotensin system was so similar and well established. But, the pursuit of brain RAS has proven to be correct. In the course of accepting brain RAS, high standards of proof attracted state of the art techniques in all the new developments of biolo1gy. Consequently, brain RAS is a robust concept that has enlightened neuroscience as well as cardiovascular physiology and is a model neuropeptide system. Molecular biology confirmed the components of brain RAS and their location in the brain. Transgenic mice and rats bearing renin and extra copies of angiotensinogen genes revealed the importance of brain RAS. Cre-lox delivery in vectors has enabled pinpoint gene deletion of brain RAS in discrete brain nuclei. The new concept of brain RAS includes ACE-2, Ang1–7, and prorenin and Mas receptors. Angiotensin II (ANG II) generated in the brain by brain renin has many neural effects. It activates behavioral effects by selective activation of ANG II receptor subtypes in different locations. It regulates sympathetic activity and baroreflexes and contributes to neurogenic hypertension. New findings implicate brain RAS in a much wider range of neural effects. We review brain RAS involvement in Alzheimer’s disease, stroke memory, and learning alcoholism stress depression. There is growing evidence to consider developing treatment strategies for a variety of neurological disease states based on brain RAS.

See related article, pp 1136–1144 Few would argue that the renin–angiotensin system (RAS) is the most extensively studied regulatory pathway controlling arterial blood pressure. That its inhibition remains a key target of the current antihypertensive therapy strongly evidences the sustained clinical importance of the system. Since its initial discovery nearly 120 years ago, new components and mechanisms of the RAS are discovered with uncommon regularity. Thus, the RAS, once thought elegant in its simplicity, is now considered one of the most complex regulators of blood pressure and electrolyte homeostasis. Adding to this inherent complexity is the simultaneous action of the endocrine and tissue RAS, functional interaction among the various tissue RAS, and the activity of counter-regulatory peptides and receptors within this system.1 In particular, the RAS in the brain is further complicated by the intricate neural circuitry between cardiovascular, fluid homeostasis, and metabolic control regions where a large number of studies support not only the actions of angiotensin peptides but also the capacity for their local generation. As addressed in a previous 2006 Editorial Commentary in Hypertension , molecular techniques are required for manipulation of specific cell types in brain expressing RAS components to address what was controversial then and remains controversial now, specifically, how are the components configured to exert its well-known functional effects?2 There is extensive evidence for the existence and function of all components of the RAS in brain that goes back several decades and reflects studies in almost every species including humans, dogs, sheep, rats, and mice.1 Although impossible to accurately cite the thousands of articles on this topic in the context of this short editorial, evidence supporting a central local brain RAS can be broadly divided into 2 types. First, there is compelling evidence for the de novo production of all components …

The renin-angiotensin system (RAS) strongly modulates not only cardiovascular homeostasis but also other non-cardiovascular physiological processes like erythropoiesis. The production of the peptide hormone angiotensin II (Ang II) in the circulatory system constitutes the main source of the RAS activity. However, Ang II has also been recognized to be generated locally by various tissues, because RAS components are either locally expressed and/or imported from the circulation. Contrary to peripheral organs, the blood-brain-barrier limits the traffic of all circulating RAS proteins into the brain, thus, brain Ang II formation relies exclusively on locally expressed RAS precursor and enzymes. Several brain cardiovascular centers contain neuronal populations responsive to Ang II that take part in sympathetic nerve outflow, vasopressin secretion, thirst and salt appetite. Angiotensinogen (Agt), the RAS precursor, is mostly produced by astrocytes in the brain. To investigate the role of the brain RAS in cardiovascular control and erythropoiesis, two transgenic rodent models with astrocyte-specific Agt gain- and loss-of-function were phenotyped. In both models, astrocyte-specific transgene expression was delivered using the human GFAP promoter. The gain-of-function model is a transgenic mouse overexpressing rat Agt, and the loss-of-function model is a rat expressing an antisense RNA against the endogenous Agt mRNA. The transgenic mouse line overexpresses the rat Agt mRNA distributed across the brain, including areas containing cardiovascular centers. Overexpression of Agt increased brain Ang II formation but reduced the peripheral Ang II levels. Rats expressing the antisense RNA exhibited a brain-specific decrease of Agt protein by ∼90%. The cardiovascular phenotyping of the two lines demonstrated opposing effects for the brain RAS. Increased brain RAS reactivity was associated with high BP, vascular sympathetic tone and vasopressin secretion, and downregulation of the brain RAS reduced BP and vasopressin secretion. Similarly, the brain RAS modulated erythropoiesis in contrary directions because capillary hematocrit experiments revealed that overproduction of Ang II in the brain correlates with increased erythropoiesis while reduced Ang II production with moderated erythropoiesis. These findings were further validated using detailed blood cell counting with an automated hematology analyzer. Submitting the transgenic mice with increased brain Ang II and respective controls to peripheral sympathectomy with 6-hydroxydopamine revealed that brain Ang II via sympathetic nerve activity increases erythropoiesis in transgenic mice. Altogether, these models confirmed the functionality of the brain RAS, and that baseline BP and erythropoiesis depends on its integrity and reactivity.

Brain renin–angiotensin system (RAS) is significantly involved in the roles of the endocrine RAS in cardiovascular regulation. Our studies indicate that the brain RAS participates in the development of cardiac hypertrophy and fibrosis through sympathetic activation. Inhibition of sympathetic hyperactivity after myocardial infarction through suppression of the brain RAS appears beneficial. Furthermore, the brain RAS modulates the cardiovascular and fluid–electrolyte homeostasis not only by interacting with the autonomic nervous system but also by modulating hypothalamic–pituitary axis and vasopressin release. The brain RAS is also involved in the modulation of circadian rhythms of arterial pressure, contributing to non-dipping hypertension. We conclude that the brain RAS in pathophysiological states interacts synergistically with the chronically overactive RAS through a positive biofeedback in order to maintain a state of alert in diseased conditions, such as cardiac hypertrophy and failure. Therefore, targeting brain RAS with drugs such as renin or angiotensin converting enzyme inhibitors or receptor blockers having increased brain penetrability could be of advantage.

Intrauterine programming of hypertension is associated with evidence of increased renin-angiotensin system (RAS) activity. The current study was undertaken to investigate whether arterial baroreflex and blood pressure variability are altered in a model of in utero programming of hypertension secondary to isocaloric protein deprivation and whether activation of the RAS plays a role in this alteration. Pregnant Wistar rats were fed a normal-protein (18%) or low-protein (9%) diet during gestation, which had no effect on litter size, birth weight, or pup survival. Mean arterial blood pressure (MABP; 126 +/- 3 mm Hg 9% versus 108 +/- 4 mm Hg 18%; p < 0.05) and blood pressure variability were significantly greater in the adult offspring of the 9% protein-fed mothers. Arterial baroreflex control of heart rate, generated by graded i.v. infusion of phenylephrine and nitroprusside, was significantly shifted toward higher pressure; i.v. angiotensin-converting enzyme inhibitor normalized MABP and shifted the arterial baroreflex curve of the 9% offspring toward lower pressure without affecting the 18% offspring. For examining whether brain RAS is also involved in programming of hypertension, angiotensin-converting enzyme inhibitor and losartan (specific AT(1) receptor antagonist) were administered intracerebroventricularly; both significantly reduced MABP of the 9% but not the 18% offspring. Autoradiographic receptor binding studies demonstrated an increase in brain AT(1) expression in the subfornical organ and the vascular organ of the lamina terminalis in the 9% offspring. These data demonstrate a major tonic role of brain and peripheral RAS on hypertension associated with antenatal nutrient deprivation.

the renin-angiotensin system (RAS) is a coordinated hormonal cascade playing a major role in cardiovascular, renal, and adrenal homeostasis ([4][1]). Derangements in the RAS have been implicated in the pathogenesis of many disease states, including hypertension and of target organ damage related to