Invited reviewAngiotensin-(1–7): an update☆
Introduction
Classically, the renin–angiotensin system (RAS) has been viewed solely as a hormonal circulating system involved in the regulation of blood pressure and salt and fluid homeostasis [1], [2], [3], [4]. According to this view, liver-derived circulating angiotensinogen (Aogen) is acting by renin released from the kidney forming the decapeptide angiotensin (Ang) I. Finally, angiotensin converting enzyme (ACE) present on the luminal surface of vascular endothelium converts Ang I to the biologically active end product Ang II by cleavage of the Phe8–His9-bond [3]. This traditional concept has undergone several and important changes in recent years. Components of RAS have been identified by molecular biology and biochemical techniques in many tissues leading to the concept of tissue RAS or more properly local Ang-forming systems [5], [6], [7], [8]. The concept of a single Ang II receptor has also changed with the cloning and pharmacological characterization of AT1 (AT1a and AT1b in rodents) and AT2 receptors [9], [10], [11], [12], [13], [14]. Thus, the RAS is viewed now not only as an endocrine system but also as an autocrine/paracrine modulator of tissue functions (heart, blood vessels, kidney, brain and endocrine glands) [6], [8], [15], [16], [17], [18], [19], [20].
In the last decade several studies also contributed to change the classical view of the RAS as a single biologically active end-product system to the more flexible concept of a multiple mediators system (see [15], [19], [21]). According to this, once formed Ang I can be processed generating several biologically active products. This new concept of the RAS, still not universally accepted [16], [20], is much more in keeping with the general feature of several peptidergic systems including tachykinins [22], [23], kinins [24], [25], vasopressin (AVP) [26], natriuretic peptides [27], [28], enkephalins [22] and endothelins [29], and allows a more comprehensive approach to the multiple functions of the RAS [8], [30], [31]. In this review we will focus on some biochemical and physio-pharmacological aspects of Ang-(1–7), now considered a biologically active member of the Ang peptides family [14], [15], [19], [21], [30], [31], [32], [33], [34] which up to now include in addition to it, Ang II, Ang-(2–8) (Ang III) [3], [15], Ang-(3–8) (Ang IV) [15], [32], [33] and Ang-(3–7) [35], [36], [37], [38]. The possibility of being formed directly from Ang I by an enzymatic pathway not involving ACE and its high selectivity confers to Ang-(1–7) a central role in counteracting several actions of Ang II including its vasoconstrictive and proliferative effects.
Section snippets
Ang-(1–7): synthesis and catabolism
Metabolic studies using iodinated angiotensins and direct measurements of endogenous peptides using HPLC coupled to specific radioimmunoassays [15], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53] have contributed to establish the major enzymatic pathways for the synthesis and catabolism of biologically active Ang peptides. As shown in Fig. 1, once formed Ang I can be processed by several proteases originating in addition to Ang II several biologically
Biological actions
The first demonstration of a biological action for Ang-(1–7) was made by Schiavone et al. [67] showing an AVP-secretagogue action in neurohypophyseal-hypothalamic explants. Since then, several studies have contributed to demonstrate that Ang-(1–7) is a biologically active member of the RAS [19], [21], [30], [31], [32], [33], [34], [35], [62], [68], [69], [70], [71], [72], [73], [74]. This angiotensin is the most pleiotropic of the Ang II derivatives producing effects that are similar [75], [76]
Mediation of Ang-(1–7) actions: receptors and signal transduction
As recently reviewed by Feener and King [210] in several systems ligands may bind to multiple receptor isoforms to produce their effects. This appears to be also true for the RAS. Ang II binds to the AT1 and AT2 subtypes, which display different actions, and in some cases, cellular expression [13], [14]. In addition, the extracellular processing of Ang I or Ang II re-direct the ligation to other binding sites (Ang-(1–7) and Ang IV, at least), producing additional effects. This additional level
Interaction Ang-(1–7)–BK
In 1995, Paula et al. [168] described that in bolus intravenous or intra-arterial administration of Ang-(1–7) potentiates the hypotensive effect of BK. A similar result was obtained with short-term intravenous infusion of the peptide. The BK-potentiating activity of Ang-(1–7), which can explain early observations with other angiotensin congeners [225], [226], has been confirmed in several studies using in vivo [106], [169], [171], [177], [178] or in vitro [37], [56], [61], [86], [94], [170],
Summary
Our present knowledge about the heptapeptide Ang-(1–7) reveals its high biological activity selectivity. In most situations, Ang II and Ang-(1–7) have opposing actions suggesting a primary role for Ang-(1–7) as a counter-regulatory angiotensin for the vascular and proliferative actions of Ang II. In this regard, the important interaction of Ang-(1–7) with the kallikrein–kinin system appears to play a key role. It is also particularly relevant to note that Ang-(1–7) may be part of the endogenous
References (230)
- et al.
Molecular cloning and sequencing of the gene encoding human angiotensin II type 1 receptor
Biochem Biophys Res Commun
(1992) - et al.
Expression cloning of type 2 angiotensin II receptor reveals a unique class of seven-transmembrane receptors
J Biol Chem
(1993) - et al.
Regulatory role of brain angiotensins in the control of physiological and behavioral responses
Brain Res Rev
(1992) - et al.
Angiotensin II in central nervous system physiology
Regul Pept
(1998) Role of atrial natriuretic factor in volume control
Kidney Int
(1996)- et al.
The 3–7 fragment of angiotensin II is probably responsible for its psychoactive properties
Brain Res
(1991) - et al.
Potentiation of the hypotensive effect of bradykinin by angiotensin-(1–7)-related peptides
Peptides
(1999) - et al.
Identification of angiotensin-(1–7) in rat brain. Evidence for differential processing of angiotensin peptides
J Biol Chem
(1989) - et al.
Processing of angiotensin peptides by NG108-15 neuroblastoma×glioma hybrid cell line
Peptides
(1990) - et al.
Angiotensin-(1–7) in the spontaneously hypertensive rat
Peptides
(1993)
Metabolism of angiotensin I in isolated rat hearts. Effect of angiotensin converting enzyme inhibitors
Biochem Pharmacol
A human platelet angiotensin I-processing system: identification of components and inhibition of angiotensin-converting enzyme by product
J Biol Chem
Sequencing and cloning of human prolylcarboxypeptidase (angiotensinase C): similarity to both serine carboxypeptidase and prolylendopeptidase families
J Biol Chem
Differential response of angiotensin peptides in the urine of hypertensive animals
Regul Pept
Angiotensin-(1–7): a bioactive fragment of the renin–angiotensin system
Regul Pept
Differential actions of angiotensin-(1–7) in the kidney
Kidney Int
Cardiovascular effects produced by microinjection of angiotensin-(1–7) on vasopressor and vasodepressor sites of the ventrolateral medulla
Brain Res
Effects of angiotensin analogues and angiotensin receptor antagonists on paraventricular neurones
Regul Pept
Cardiovascular actions of angiotensin-(1–7)
Peptides
Opposing actions of angiotensins on angiogenesis
Life Sci
Biological activities of angiotensin II-(1–6) hexapeptide and angiotensin II-(1–7) heptapeptide in man
Life Sci
Prostaglandin production in response to angiotensin-(1–7) in rabbit isolated vasa deferentia
Prostaglandins
The association of thirst, sodium appetite and vasopressin release with c-fos expression in the forebrain of the rat after intracerebroventricular injection of angiotensin II, angiotensin-(1–7) or carbachol
Neuroscience
Actions of angiotensin peptides on the rabbit pulmonary artery
Life Sci
Essential hypertension: renin and aldosterone, heart attack and stroke
N Engl J Med
Angiotensins
Renin–angiotensin system: biochemistry and mechanism of action
Physiol Rev
The biochemistry of the renin–angiotensin system
Evidence for an endogenous brain renin–angiotensin system
Fed Proc
Molecular and physiological aspects of tissue renin–angiotensin system: emphasis on cardiovascular control
J Hypertens
Levels of angiotensin and molecular biology of the tissue renin–angiotensin systems
Regul Pept
The renin–angiotensin system and experimental heart failure
Cardiovasc Res
Isolation of a c-DNA encoding the vascular type-1 angiotensin II receptor
Nature
Molecular cloning of a novel angiotensin II isoform involved in phosphotyrosine phosphatase inhibition
J Biol Chem
Molecular biology and signaling of angiotensin receptors: an overview
J Am Soc Nephrol
Angiotensin II receptors
J Am Soc Nephrol
Angiotensin receptors and their therapeutic implications
Annu Rev Pharmacol Toxicol
Functional testing of components of the brain renin–angiotensin system in transgenic animals
Novel angiotensin peptides regulate blood pressure, endothelial function, and natriuresis
J Am Soc Nephrol
Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases
Pharmacol Rev
Central and peripheral actions of angiotensin-(1–7)
Braz J Med Biol Res
Neuropeptides: multiple molecular forms, metabolic pathways, and receptors
Annu Rev Biochem
Tachykinins
Annu Rev Neurosci
Kallikreins and kinins — some unanswered questions about system characteristics and roles in human disease
Hypertension
Bioregulation of kinins: kallikreins, kininogens, and kininases
Pharmacol Rev
Vasopressin metabolites: a link between vasopressin and memory?
Prog Brain Res
Atrial natriuretic peptide in brain and pituitary gland
Physiol Rev
Endothelins — vasoactive peptides and growth factors
Cell Tissue Res
Counterregulatory actions of angiotensin-(1–7)
Hypertension
Interactions among ACE, kinins and NO
Cardiovasc Res
Cited by (359)
Renin-Angiotensin-Aldosterone System
2022, Comprehensive PharmacologyRenin angiotensin aldosterone system in pulmonary fibrosis: Pathogenesis to therapeutic possibilities
2021, Pharmacological ResearchAdvancement in Beneficial Effects of AVE 0991: A Brief Review
2024, Mini-Reviews in Medicinal ChemistryThe Angiotensin AT<inf>2</inf> Receptor: Froma Binding Site to a Novel Therapeutic Target
2022, Pharmacological Reviews
- ☆
Brief review: “100 Years of Renin” series and 20th Anniversary Special Issue.