No Brain Renin–Angiotensin System
2017; Lippincott Williams & Wilkins; Volume: 69; Issue: 6 Linguagem: Alemão
10.1161/hypertensionaha.117.09167
ISSN1524-4563
AutoresCurt D. Sigmund, Debra I. Diz, Mark C. Chappell,
Tópico(s)Apelin-related biomedical research
ResumoHomeHypertensionVol. 69, No. 6No Brain Renin–Angiotensin System Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBNo Brain Renin–Angiotensin SystemDéjà vu All Over Again? Curt D. Sigmund, Debra I. Diz and Mark C. Chappell Curt D. SigmundCurt D. Sigmund From the Department of Pharmacology, UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City (C.D.S.); and Department of Surgery, Hypertension and Vascular Research, Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston-Salem, NC (D.I.D., M.C.C.). , Debra I. DizDebra I. Diz From the Department of Pharmacology, UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City (C.D.S.); and Department of Surgery, Hypertension and Vascular Research, Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston-Salem, NC (D.I.D., M.C.C.). and Mark C. ChappellMark C. Chappell From the Department of Pharmacology, UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City (C.D.S.); and Department of Surgery, Hypertension and Vascular Research, Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston-Salem, NC (D.I.D., M.C.C.). Originally published10 Apr 2017https://doi.org/10.1161/HYPERTENSIONAHA.117.09167Hypertension. 2017;69:1007–1010Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2017: Previous Version 1 See related article, pp 1136–1144Few 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?2There 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 of the RAS in the brain. Early studies demonstrated the presence of renin activity, angiotensin-generating activity, and protein or peptide components detected by immunohistochemical approaches.3,4 With the advent of molecular approaches, subsequent studies demonstrated that all RAS genes were expressed in the brain. Moreover, it is clear that the promoter regions of several RAS genes are active in the brain.5 The second major line of evidence supports the physiological functioning of the brain RAS. This includes an extensive and convincing literature that pharmacological blockers administered acutely or chronically into the brain or brain-targeted molecular manipulation of the processing enzymes of the RAS (angiotensin-converting enzyme and angiotensin-converting enzyme 2, in particular) influence cardiovascular and fluid balance regulation. In addition, over the past 20 years, antisense oligonucleotides and other inhibitory RNAs targeting renin or angiotensinogen gene expression (both acute and long term) exhibit potent cardiovascular effects.If one aspect of the brain RAS remains equivocal, it is the precise cellular localization of both renin and angiotensinogen expression. Although numerous studies have reported the presence of renin activity, renin gene expression, and renin promoter activity in the brain, few of us in the field are fully satisfied because the expression of renin is exceptionally low and identification of specific renin-expressing neurons remains elusive. In this regard, numerous hypotheses for the origin of angiotensin peptides in the brain have been evoked. These range from de novo production of renin in the brain, its leakage into cerebrospinal fluid, perhaps through an impaired blood brain barrier in hypertension, to renin-independent mechanisms for the generation of angiotensin peptides from the precursor angiotensinogen. One can find evidence for all of these in the literature. We and others have developed innovative reagents to address this including large transgenes that accurately emulate but amplify the level of renin expression, the use of models where Cre-recombinase has been knocked into the renin locus, and the use of reporter genes to identify cells where the renin promoter is active.5–9 Based on initial studies by 2 different research groups, we also developed the concept that an intracellular form of renin may exist in the brain.6,10,11 This was a compelling hypothesis because it may have explained the long held view that angiotensin acts as a neurotransmitter, at least in the subfornical organ to paraventricular nucleus axis and projections to pontine and medullary cardiovascular centers. We tested this hypothesis directly by generating a novel knockout mouse model where the brain-specific promoter (renin-b) was ablated whereas the classical renin promoter encoding preprorenin (renin-a) was preserved.12 Surprisingly, those mice were hypertensive through a mechanism that was dependent on the activity of renin, angiotensin-converting enzyme, and the angiotensin type 1 receptor in the brain. Thus, these data, which did not involve any exogenous transgenes, strongly support both the de novo synthesis and action of angiotensin in the brain. The data also provided evidence supporting a novel mechanism for the regulation of renin production in the brain.In the current issue of Hypertension, van Thiel et al13 question once more the existence of a local or tissue RAS and conclude that the brain RAS, at least one that actively synthesizes components that generate angiotensin peptides in the brain does not exist. Their methodology was heavily reliant on the assessment of aliskiren-sensitive angiotensin I–generating activity (AGA) in homogenates from different brain regions to demonstrate the presence of both endogenous renin and angiotensinogen. As reviewed previously, there are numerous variables that influence the successful and accurate use of assays designed to detect the RAS.14 In brief, the current findings are as follows: (1) AGA in brain exhibits similar inhibitory kinetics to kidney and plasma by aliskiren inhibition (IC50 of <10 nmol/L), (2) aliskiren-sensitive AGA is detected in several regions of the brain with its highest activity level in the brain stem, (3) deoxycorticosterone acetate-salt did not induce AGA in the brain, (4) the level of AGA correlated with plasma renin, (5) AGA was not detectable in renin-deficient mice, (6) angiotensinogen was absent in brain, and (7) angiotensin II but not angiotensin I was detected in the brains of spontaneously hypertensive rats.The present demonstration of aliskiren-inhibitable renin activity in the brain stem and in several other large regions of the brain actually confirms many previous reports. Indeed, these data suggest that in fact there is renin activity in the brain. Perhaps one of the most controversial tenets of their argument is that the brain renin activity reflect residual blood contamination and not brain synthesis. This is based on their observation that buffer perfusion reduced AGA in all areas of the brain and diminished the percentage of AGA that could be blocked by aliskiren, suggesting the remaining activity is not renin. Indeed, this is where interpretation of the results becomes challenging. First, it is unclear by the language in the article if the decrease in AGA by buffer perfusion is statistically significant in each brain region or is only significant in aggregate, when all the data sets, assayed separately, are combined. In this regard, it is also not clear why there seem to be significant differences between renin and total renin in these brain areas, but that circulating renin and total renin activity are essentially identical. Perhaps more importantly, the loss of AGA in response to buffer perfusion is interpreted by the authors as evidence that brain renin is actually derived from the small amount of blood in brain. That there was a correlation between renin in cortex, midbrain, and brain stem to plasma renin was evoked to support their argument. Unfortunately, this is a false equivalency that could lead anyone to argue that any biological molecule in the body that is also found in blood, and is present in tissue at a concentration less than blood, must be derived from blood. Moreover, the authors predispose that "had local renin synthesis occurred in one or more specific brain regions, the washout percentage should have been much lower in these regions, similar to the fact that in the kidney one cannot wash away stored renin." This is another false equivalency because unlike the kidney, where renin is stored in what can be considered a protected environment of the dense core secretory granules of the juxtaglomerular cells, this unique environment does not exist in extrarenal cells where prorenin is presumed to be secreted through a constitutive pathway (Figure). Given this, one has to predict that buffer perfusion should lead to a decrease in AGA in the brain and in other extrarenal tissues where renin is produced but not stored. Similar arguments were used by these authors to conclude that a local RAS does not exist in other tissues.15,16 An additional point is that the responses to physiological maneuvers designed to alter circulating renin do not necessarily have to be distinct from the renin response in the brain or other tissues, and this may account for their positive correlation curves between brain and plasma renin.Download figureDownload PowerPointFigure. Renin release from renal juxtaglomerular (JG) cells and neurons. Schematic showing one potential mechanism for release of renin and prorenin (PR) from renal JG cells vs neurons and glia. In JG cells, renin (R) is activated from PR and stored in large quantities in dense core secretory vesicles. On a stimulus, the vesicles fuse with the plasma membrane and release active renin into the renal interstitium. Buffer perfusion would presumably wash away interstitial and blood-borne renin. However, renin stored in secretory vesicles would be protected, providing the renin detected by an angiotensin-generating activity (AGA) assay in homogenates of whole kidney. In neurons, PR is not activated to renin and is constitutively secreted into the extracellular space, where on activation, or possible interaction with pro(renin) receptor would convert glial- and neuronal-derived angiotensinogen (AGT) to angiotensin I. Buffer perfusion of the brain would presumably wash away constitutively secreted PR and AGT needed for AGA.Finally, the inability of the authors to detect angiotensinogen protein in the mouse brain is perhaps the most surprising and demands comment. First, angiotensinogen mRNA is abundant in the brain. Second, although the seminal studies by Stornetta et al identified the major site of synthesis as astrocytes, subsequent reports revealed that angiotensinogen is also expressed in certain populations of neurons.17–19 Indeed, angiotensinogen protein can be easily detected by Western blot in astrocytomas.20 Numerous functional studies also clearly support the de novo expression of angiotensinogen in the brain. For example, intracerebroventricular application of renin causes an immediate increase in blood pressure, as well as stimulates thirst and reduces urine output.21,22 Early molecular studies revealed that antisense oligonucleotides targeting angiotensinogen lowered blood pressure and reduced angiotensin levels in the brain stem, the region with the highest AGA activity in the current study.23 Perhaps the strongest supporting data for both the de novo synthesis of angiotensinogen and its function in the brain are a transgenic model expressing an antisense targeting glial angiotensinogen of endogenous origin.21 This model of an altered brain RAS exhibits a marked reduction (≈90%) in angiotensinogen protein expression in various brain regions, but unaltered circulating levels of the precursor protein. Moreover, the thirst response to intracerebroventricular renin infusion was substantially attenuated as compared with control rats.21 These transgenic rats are documented to share many of the functional characteristics of long-term systemic inhibition of the RAS or targeted angiotensinogen knockdown in mice.21,24The inability of the current study to measure endogenous angiotensinogen in the mouse brain or in primary cultures of rat astrocytes may reflect the sensitivity of the angiotensinogen assay (15–50 ng), which was originally developed to detect and measure the protein in plasma that contains microgram quantities of angiotensinogen.14 Indeed, it is not at all surprising that they did not detect secreted angiotensinogen in cells given the assay detection limit, as well as the requirement for intact angiotensinogen as substrate; current ELISAs for angiotensinogen exhibit high sensitivity and selectivity to detect the total protein.14 The issue of detection sensitivity is obviously an important consideration about the final conclusions on the absence or presence of endogenous brain RAS components.In deference to the eminent philosopher Y. Berra that we have been presented with these issues before, one cannot simply conclude that the brain RAS or more specifically, that distinct cardiovascular RAS regions within the brain do not exist. Instead, we should acknowledge the biochemical and functional complexity of the central RAS, as well as that the system may not lend itself to detection methods applicable to the peripheral circulating system in which the protein components are far more abundant. The importance of the brain RAS extends beyond cardiovascular function and clinical trial data indicate that apart from blood pressure–lowering effects, inhibitors of angiotensin-converting enzyme that are lipophilic with a predicted better brain penetration associate with less cognitive decline in the elderly.25 These data can be interpreted as support of local generation of RAS peptides and the detection of key components in brain is not limited to animal studies. Indeed, within the past ≈5 years, evidence for angiotensinogen and prorenin in the cerebrospinal fluid and brain tissue is reported with the potential upregulation in pathological states.26,27 Thus, absent use of newer or improved, more sensitive methods, in particular the application of acute or chronic molecular interventions and more precise cellular and regional localization techniques, the current study does not provide additional insight over the existing literature to disprove the existence of a local functioning brain RAS.AcknowledgmentsWe gratefully acknowledge the generous research support of the Roy J. Carver Trust (University of Iowa), Hypertension & Vascular Research Funds (Wake Forest School of Medicine), and the Farley Hudson Foundation (Wake Forest School of Medicine).Sources of FundingThis study was supported through research grants from the National Institutes of Health HL084207 to C.D. Sigmund, HD047584 to D.I. Diz, and HD08877 to M.C. Chappell.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Curt D. Sigmund, Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 51 Newton Rd, 2-471B-1 Bowen Science Bldg, Iowa City, IA 52242. E-mail [email protected]References1. Paul M, Poyan Mehr A, Kreutz R. Physiology of local renin-angiotensin systems.Physiol Rev. 2006; 86:747–803. doi: 10.1152/physrev.00036.2005.CrossrefMedlineGoogle Scholar2. Diz DI. Approaches to establishing angiotensin II as a neurotransmitter revisited.Hypertension. 2006; 47:334–336. doi: 10.1161/01.HYP.0000203146.72879.c3.LinkGoogle Scholar3. Hermann K, Raizada MK, Sumners C, Phillips MI. Presence of renin in primary neuronal and glial cells from rat brain.Brain Res. 1987; 437:205–213.CrossrefMedlineGoogle Scholar4. Fuxe K, Ganten D, Hökfelt T, Locatelli V, Poulsen K, Stock G, Rix E, Taugner R. 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June 2017Vol 69, Issue 6 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.117.09167PMID: 28396531 Originally publishedApril 10, 2017 PDF download Advertisement SubjectsHypertension
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