Review Article
Update on the Renin-Angiotensin System
Robert C. Speth* and Michael J. Giese
Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328

The physiological and pathophysiological actions of the renin-angiotensin system (RAS) extend far beyond its role as a regulator of cardiovascular homeostasis. The “classical” RAS has evolved into a complex system with multiple pathways and counterbalancing axes which are pivotal to the function of most organ systems in the body. The discovery of “local” RAS's which began with the characterization of a brain RAS now includes a diverse array of tissues: liver, kidney, heart, lungs, reproductive organs, adipose tissue, pancreas, spleen, adrenal and the eye. This review describes the classical RAS as a framework upon which the newest discoveries in the RAS are described. These include the discovery of new enzymatic pathways by which novel angiotensinergic signaling molecules are formed, the expanding number of angiotensin receptor subtypes and molecules that transduce their increasing array of cellular responses. This new understanding is leading to the development of new drugs that can mimic or promote the axes of the RAS that counteract the classical axis that causes its pathophysiological actions.
Renin-angiotensin systeml; Angiotensin peptides; Angiotensin receptors; (pro) Renin receptor; Peptidases

AP: Aminopeptidase; Ang: Angiotensin; Ang I: Angiotensin I; Ang II: Angiotensin II; Ang III: Angiotensin III; Ang IV: Angiotensin IV; Ang (1-7): Angiotensin (1-7); ACE: Angiotensin Converting Enzyme; ARB: Angiotensin Receptor Blocker; AGT: Angiotensinogen; AT1R: Angiotensin type 1 receptor; AT2R: Angiotensin type 2 receptor ; AT4R: Angiotensin type 4 receptor; BK: Bradykinin; GPCR: G Protein Coupled Receptor; HRP: Handle Region Peptide; KO: Knockout; PKC: Protein Kinase C; (P)RR: (Pro) Renin Receptor; ROS: Reactive Oxygen Species; RAS: Renin-Angiotensin System
The renin-angiotensin system (RAS) is a potent short term regulator of systemic blood pressure, as well as fluid and electrolyte homeostasis. The classic RAS is a cascade comprised of several different components (Figure 1). The key components are: 1) the systemically circulating enzyme renin and its precursor, prorenin, derived from the juxtaglomerular cells of the renal afferent arterioles; 2) angiotensinogen (AGT), a high molecular weight protein, released from the liver, which is the only substrate of renin and is the precursor for the decapeptide angiotensin (Ang) I; 3) angiotensin-converting enzyme (ACE), a dipeptidyl carboxypeptidase, which converts Ang I into the active hormone of the system, Ang II; and 4) the Ang II receptor located in arterioles, the adrenal gland and circumventricular regions of the brain. In this classical system these Ang II receptors caused vascular smooth muscle cells in resistance vessels to contract, thereby reducing the arteriolar lumen and increasing resistance to blood flow thereby increasing blood pressure. The receptor behavior was that of a G protein coupled receptor (GPCR) using Gq protein to activate phospholipase C, which ultimately increased cytoplasmic calcium which then promoted shortening of myofilaments. In the adrenal glomerulosa, this cytoplasmic calcium mobilization promoted secretion of aldosterone. And, in the circumventricular organs of the brain, Ang II receptor stimulation activated the sympathetic nervous system and stimulated vasopressin/antidiuretic hormone release from the posterior pituitary.
Figure 1 Flow diagram of the classic renin-angiotensin system cascade.

Figure 1 Flow diagram of the classic renin-angiotensin system cascade.

It is generally accepted that the stimuli for renin release into the bloodstream are low blood pressure in the renal artery, hyponatremia, and sympathetic nervous system activation of β1 adrenergic receptors. Angiotensinogen, constitutively released into the blood stream by the liver, is a circulating α-2 macroglobulin, a member of the serpin family of proteins. However, AGT does not appear to have significant serine protease inhibitory capacity. While the stimulated release of renin from the kidney into the bloodstream is the major influence for the production of Ang II, circulating levels of AGT, which approximate or slightly exceed the Km of renin, have long been thought to also regulate production of Ang II. Recently, it was shown that the Km of AGT for renin varies with redox state. In conditions of oxidative stress, a disulfide bond forms between cys18 and cys138 in AGT which makes it more readily converted to Ang I by renin [1].
This change in affinity of AGT for renin may explain the difficulty in determining the significance of plasma AGT levels on Ang I formation. The hepatic synthesis of AGT is increased by hormones that activate nuclear receptors for glucocorticoids, estrogen, thyroxine, as well as plasma membrane receptors for Ang II. Numerous pathological conditions such as inflammation alter the synthesis of AGT [2].
In the classical RAS cascade, prorenin (which is also constitutively expressed) is converted to renin via proteolytic and nonproteolytic activation [3].
Renin then converts the circulating plasma protein AGT, into Ang I and other weakly active peptides. Previously, prorenin has been thought to be inactive but increased levels in the plasma and vitreous of diabetic patients with retinopathy have suggested otherwise [4-8].
Angiotensin I generally is not considered to be biologically active. Once Ang I is formed in the bloodstream it is quickly converted into the octapeptide Ang II by the abundance of ACE on the luminal side of the vascular endothelium [9] as well as circulating ACE that has been shed into the bloodstream [10]. Angiotensin converting enzyme is also known as kininase II because of its ability to metabolize bradykinin (BK) [11,12]. to inactive peptides. In the classic RAS there is a single Ang II receptor, which for the most part mediates the same effects as the angiotensin type-1 (AT1R) Ang II receptor subtype. These effects include elevation of blood pressure, stimulation of aldosterone synthesis and release, and induction of thirst and salt appetite. The primary signaling system for the effects of Ang II employed Gq to activate phospholipase C, which generated inositol trisphosphate which then caused the release of calcium (Ca++) into the cytoplasm from the endoplasmic reticulum, promoting the contraction of myofilaments of vascular smooth muscle cells. The mobilization of Ca++ to the cytoplasm in zona glomerulosa cells of the adrenal cortex stimulated exocytosis of aldosterone into the bloodstream. As the stimulation of aldosterone synthesis and release is such an integral component of the RAS, occasionally this system is referred to as the renin-angiotensin aldosterone system.
In recent years there has been a substantial expansion of our knowledge of the RAS with the discovery of new components and peptides (Figure 2) whose function complements, antagonizes or differs from the classic effects of the RAS. These include the recognition that the des-Asp1 fragment of Ang II, known as Ang III, acts in a manner similar to Ang II [13].
Figure 2 Flow diagram of the current renin-angiotensin system cascade. Ang, Angiotensin; ACE, Angiotensin converting enzyme; APA, Aminopeptidase A; APN, Aminopeptidase N; APB, Aminopeptidase B; Asp AP, Aspartyl aminopeptidase; IRAP, Insulin-regulated aminopeptidase; AT1R, Angiotensin type 1 receptor; AT2R, Angiotensin type 2 receptor. Black text and lines delineate the classical RAS cascade. Green text and lines delineate newer pathways of the RAS. Blue text and lines delineate hypothetical components and pathways of the RAS.

Figure 2 Flow diagram of the current renin-angiotensin system cascade. Ang, Angiotensin; ACE, Angiotensin converting enzyme; APA, Aminopeptidase A; APN, Aminopeptidase N; APB, Aminopeptidase B; Asp AP, Aspartyl aminopeptidase; IRAP, Insulin-regulated aminopeptidase; AT1R , Angiotensin type 1 receptor; AT2R, Angiotensin type 2 receptor. Black text and lines delineate the classical RAS cascade. Green text and lines delineate newer pathways of the RAS. Blue text and lines delineate hypothetical components and pathways of the RAS.

The identification of two Ang II receptor subtypes; AT1R and AT2R, [14], whose functions for the most part appear to be antagonistic [15-17], akin to the opposing effects of epinephrine on α1 and β2 adrenergic receptors in vascular smooth muscle. The discovery of an AT4R for the des-Asp1, des-Arg2 Ang II (Ang IV) [18], now known to be the enzyme insulin regulated aminopeptidase (IRAP) [19]. The discovery of a homolog of ACE, ACE-2 a monocarboxypeptidase that acts primarily to metabolize Ang II to Ang (1-7) [20-22], but also forms Ang (1-9) from Ang I [20]. Ang (1-9) can then be converted to Ang (1-7) by ACE.
The identification of the Mas protein as the receptor for Ang (1-7) and characterization of its functional antagonism of the AT1R Ang II receptor subtype [23].
Discovery of additional alternative enzymatic pathways of formation of angiotensin peptides such as chymase conversion of Ang I to Ang II [24], neutral endopeptidase (neprilysin), thimet oligopeptidase, prolyl endopeptidase, and neurolysin mediated conversion of Ang I to Ang (1-7) see review [25], aspartyl aminopeptidase conversion of Ang I to Ang (2-10) [26].
Discovery of a receptor for renin and prorenin that increases the catalytic activity of renin and unmasks the catalytic activity of prorenin on AGT [27].
Angiotensin II receptor subtypes
Discovery of the two major subtypes: In the 1980's several drug companies were developing antagonists to Ang II receptors in order to reduce the pressor actions of Ang II in people with hypertension (HTN). There had been hints that different subtypes of Ang II receptors existed. These hints were based on different relative potencies of Ang II and Ang III to elevate blood pressure and to stimulate aldosterone secretion [13].
The second was documentation of the differential effects of the sulfhydryl reducing agent, dithiothreitol (DTT), on the inhibition of angiotensin receptor binding in the vasculature versus enhancing angiotensin receptor binding in the adrenal gland and brain. Until 1989, it was generally thought that the classic RAS exerted its physiological effects via a single angiotensin receptor. In 1989 two distinct subtypes of Ang II receptors were identified [28,29].
The Ang II receptor antagonist losartan was shown to bind preferentially to a receptor subtype of Ang II that caused constriction of vascular smooth muscle while showing little affinity for Ang II receptors in adrenal medullary area [28]. Other Ang II receptor antagonists, CGP-42112A (Ciba Geigy) and PD 123319 (Parke Davis), showed high affinity for adrenal and uterine Ang II receptor binding sites, but little ability to inhibit the vasoconstrictor actions of Ang II or to bind to liver Ang II receptor binding sites [28-30]. Of note, CGP-42112A is now known to be an AT2R agonist [31]. These two Ang II receptor subtypes were subsequently identified as G protein-coupled receptors and were named AT1R and AT2R [32].
  • AT1 receptor subtype: As noted above, the AT1R subtype mediates the classic, acute Ang II responses of vasoconstriction, aldosterone synthesis and release, as well as dipsogenesis and salt appetite. Angiotensin II elevates blood pressure by causing the release of vasopressin from the posterior pituitary, noradrenaline and adrenaline via sympathetic nervous system activation, and endothelin-1 [33]. Chronic Ang II elevation is reported to cause fibrosis and other pathophysiological alterations in AT1 receptor containing organs as well as pathophysiological alterations of the vasculature [30,34-43].
It is now known that Ang II, is proinflammatory [44] and promotes many different inflammatory processes in the vasculature, heart, brain, liver, kidney and lung [45-47]. These effects are modulated in a non-hemodynamic manner [44,48]. Ang II also functions as a growth factor and immune-modulator influencing cell proliferation, apoptosis and tissue fibrosis [49]. Additionally, it causes extracellular matrix remodeling, regulates expression of numerous inflammatory genes and activates other cell signaling pathways such as the Rho kinase system [50] and mTOR [51].
Stimulation of the AT1R by Ang II increases expression of many inflammatory mediators in a variety of cell types. In macrophages, there is in increase in C-C chemokine receptor type 2 (CCR2) and monocyte chemotactic peptide (MCP)-1 [52]. Stimulation of the AT1R by Ang II increases maturation, antigen uptake and migration in dendritic cells; increases activation, proliferation and production of chemokines/cytokines in T lymphocytes; increases expression of toll-like receptor (TLR)-4, reactive oxygen species (ROS) and apoptosis in mesangial cells, and increases expression of TLR-4 and increases in chemokines and cytokines in vascular smooth muscle cells [53].
Other inflammatory events include the proliferation and chemotaxis of vascular smooth muscle and endothelial cells, increased transcription of vascular endothelial growth factor (VEGF), [54,55] production of ROS [56,57] production of proinflammatory cytokines such as interleukin (IL) -6, IL-1α, and C-reactive protein [58]. Additionally, endothelial adhesion molecules such as selectins, vascular cell adhesion molecule (VCAM) and intercellular adhesion molecules (ICAMs) are induced [59]. It has been noted that AT2R is also up-regulated in injured tissue and during pathological processes [60].
Table 1 List of renin-angiotensin system components, primary sources and functions.
*See text for citations for pathways and functions


Kidney, constitutive release

Conversion of  Angiotensinogen (AGT) to angiotensin (Ang) I (when bound to the pro-renin receptor [(P)RR]), signaling via renin receptor


Pro-renin via proconvertase, cathepsin B

Conversion of AGT to Ang I, signaling via renin receptor


Liver, adipose tissue (in obesity)

Substrate for renin and prorenin precursor of Ang I

Ang I

(Ang 1-10)

AGT via renin or prorenin. Cathepsin G, tonin

Weak vasoconstrictor, precursor of Ang II

AGT via Ang 1-12

Ang II

(Ang 1-8)

Ang I via angiotensin converting enzyme (ACE)

AT1R binding:  vasoconstrictor, mitogenic, hypertrophic, aldosteronogenic and aldosterone-releasing, antinatriuretic, dipsogenic, halophilic, antidiuretic (via increased antidiuretic hormone release), proinflammatory, pro-oxidative stress, profibrotic, and prothrombotic

Ang I via chymase, cathepsin G

AT2R binding:  vasodilation, antiproliferative, pro-apoptotic, prenatal development,

AGT via cathepsin G, tissue-type plasminogen activator (t-PA), tonin, trypsin, chymotrypsin


Ang 2-10 via ACE

Effects are generally the same as Ang II on AT1R and AT2R

Ang II via aminopeptidase A (APA)

Ang IV

Ang III via APN, APB

Cell proliferation, inflammation, neuronal development, Nitric oxide (NO) synthesis, neuropeptide metabolism,

Ang II via dipeptidyl peptidase I or III

Ang 1-12

AGT via cathepsin G, t-PA, tonin, trypsin, chymotrypsin


Ang 2-10

Ang I via APA or aspartyl AP

Antagonism of the actions of Ang II and Ang III

Ang 1-9

Ang I via ACE-2

Substrate for formation of Ang (1-7) via ACE, activates bradykinin to increase NO formation

Ang 1-7

Ang I via ACE-2 & ACE, neprilysin, neurolysin prolyl endopeptidase& thimet oligopeptidase

Vasodilatory, NO-releasing, anti-inflammatory, antifibrotic, antithrombotic, antiproliferative

Ang 1-9 via ACE, neprilysin

Ang II via ACE-2, prolyl endopeptidases, prolyl carboxypeptidase

Ang 2-7

Ang III via ACE-2 (hypothesized)


Ang 1-5

Ang 1-7 via ACE


Ang 3-7

Ang 1-7 via AP, Ang II

Neuromodulatory:  learning and memory, blood pressure regulation

Table 1 List of renin-angiotensin system components, primary sources and functions.
*See text for citations for pathways and functions

Angiotensin II is also involved in wound healing and tissue repair [61], it has profibrotic effects leading to excess accumulation of extracellular matrix material [62]. Studies suggest a role for AT1R activation in the promotion of the atherosclerotic process [63]. Evidence also suggests that Ang II plays a role in autoimmune disease such as multiple sclerosis and in cognitive changes associated with aging [64]. Agonistic autoantibodies to the AT1R have been shown to contribute to the pre-eclamptic hypertension of pregnancy [65].
The primary transduction pathway of the AT1R is coupling to the G protein Gq with activation of the phospholipase-C cascade resulting in activation of protein kinase C (PKC) and release of Ca++ into the cytoplasm from the smooth endoplasmic reticulum. The AT1R also activates MAP kinases either directly via PKC, via transactivation of the epidermal growth factor (EGF) receptor, or via scaffolding of β-arrestin with MAP kinases [66-68]. The AT1R also signals directly through the ERK1/2 MAP kinase pathway causing phosphorylation of a variety of proteins and activation of transcriptional regulators [69]. This is mediated via formation of transforming growth factor beta (TGF-β), proinflammatory cytokines and the formation of ROS [46,70,71] as well as via ß-arrestin scaffolding [72].
  • The AT2 receptor subtype: From its initial discovery the AT2R has been an enigma and cause of confusion. As noted above, initial efforts to develop an antagonist radioligand binding assays to screen for compounds that competed with Ang II for its receptor. These assays used either human uterus or rodent tissue membrane binding assays in which DTT was added to protect the radio-iodinated Ang II from degradation. In 1989 reports from both DuPont-Merck and Ciba-Geigy described how DTT and other sulfhydryl reducing agents inactivated the AT1R while protecting and even possibly enhancing the ability of the AT2R to bind Ang II [28,29,73]. Both Ciba-Geigy and Parke-Davis succeeded in developing ligands for the AT2R, however, they were ineffective as antagonists of the pressor actions of Ang II. The lead compounds developed by these companies, CGP42112A (Ciba-Geigy) and PD123319 (Parke-Davis) are still known by these names today, while the DuPont-Merck compound DUP-753 went on to become losartan and Cozaar®. Although CGP42112A and PD123319 were unsuccessful as therapeutic agents, they have been widely used by the research community to study the RAS. CGP42112A, originally thought to be an AT2R antagonist, serves as an AT2R selective agonist, and PD123319 serves as an AT2 receptor-selective antagonist.
Initial attempts to determine the functionality of the AT2R were largely unsuccessful. It did not appear to cause any of the major physiological actions ascribed to Ang II, e.g. elevation of blood pressure, generation of thirst or sodium appetite, aldosterone release, sodium retention. Attempts to link it to known signaling pathways of G protein-coupled receptors (GCPR) were also unsuccessful. With the cloning of the AT2R in 1993 [74,75] it was clearly shown to be a member of the GPCR family, however, its behavior differed significantly from most other GPCRs in that guanosine triphosphate or its stable analogs did not affect its affinity for agonist ligands [75,76].
The earliest definitive demonstration of functionality of the AT2R showed that it opened a potassium (K+) channel that hyperpolarized neurons grown in a primary cell culture system [77]. Subsequent studies showed that AT2R mediated stimulation of protein phosphatase activity was required to activate the K+ channels [78]. Since protein phosphatases oppose the actions of protein kinases, this was the first indication that the effects of AT2R stimulation could antagonize the effects of AT1 R stimulation. The mutual antagonism of AT1 and AT2Rs was further documented by studies showing that the AT2R antagonized the mitogenic effects of AT1R stimulation of neo-intimal cells [16]. These studies also showed that transfected AT2Rs in cultured vascular smooth muscle cells inhibited the AT1R mediated increase in MAP kinase activity.
It is now well established that the actions of the AT2R oppose those of the AT1R [79-83] and there is an increasing interest in the potential therapeutic value of AT2R stimulation. Indeed, it can be argued that part of the beneficial actions of angiotensin receptor blockers (ARBs), the “sartans”, as AT1R selective antagonists, arise from the fact that there is an increased stimulation of AT2Rs. This arises from the loss of negative feedback inhibition of renin release from the kidney, mediated by AT1R stimulation. When the AT1Rs on the juxtaglomerular cells of the kidney are blocked, there is an increase in renin release with subsequent increases in the formation of Ang I and Ang II. The increased levels of circulating Ang II would then lead to a selective increase in AT2R stimulation.
The ability of the AT2R to counteract the actions of the AT1R has stimulated interest in the development of AT2R-selective agonists. While CGP42112A and p-aminophenylalanine6 Ang II are AT2R selective agonists [31,76], they are peptides that are not good drug candidates because they are not orally bioavailable. Development of non-peptide agonists of AT2Rs has been undertaken and an orally active AT2R-selective agonist, compound 21, is now being investigated as a possible therapeutic agent to reverse pathologies mediated by AT1Rs [84-86].
ACE-2/Ang-(1-7)/Mas axis
Several years ago a homologue of ACE, called ACE-2, was identified [20,21]. It is found in the plasma membranes of cells of virtually all organs as an ectoenzyme and is shed into the plasma and urine in an active soluble form [87]. Angiotensin converting enzyme-2 is highly expressed in cardiac blood vessels and tubular epithelia of the kidneys [88,89]. It has also been identified in testis [20,90,91], lung [92,93] and has recently been described in the brain [94]. This enzyme hydrolyzes Ang I into Ang (1-9) [20,22] and Ang II into Ang (1-7) [21,95]. Thus ACE-2 is effectively an inhibitor of the formation of Ang II by stimulating alternative pathways for Ang I metabolism and as a metabolic inactivator of Ang II. Angiotensin (1-9) has been shown to prevent cardiomyocyte hypertrophy after myocardial infarction [96], enhance the ability of bradykinin (BK) to generate nitric oxide (NO) and arachidonic acid [97] and also serve as a precursor of Ang (1-7) via conversion by ACE [20,21] or neprilysin [22]. ACE-2 can convert bioactive Ang II into Ang (1-7) which has vasorelaxing effects via its receptor Mas [23]. It has been suggested that ACE-2 is a physiologically important modulator of blood pressure [98]. It is not established whether ACE-2 converts Ang III into Ang (2-7) and Ang IV into Ang (3-7) whose physiological significance is still uncertain. Additionally, ACE-2, in contrast to ACE, does not metabolize BK [20]. Bradykinin dilates blood vessels via stimulation of NO and cGMP and also by the release of the vasodilators prostaglandin (PG) E2 and prostacyclin [99]. However, bradykinin also induces inflammation and increased vascular permeability [100,101]. Enhancement of ACE-2 activity in the lung has been shown to reverse pulmonary hypertension and bleomycin induced inflammatory damage [42]. Of note, membrane bound ACE-2 has been identified as the receptor for severe acute respiratory syndrome (SARS) virus [102,103]. In addition to ACE-2, another carboxypeptidase, prolyl carboxypeptidase has been shown to form Ang (1-7) from Ang II in the kidney under acidic conditions [104].
Angiotensin (1-7) acts as a major biologically active peptide product of the RAS [105]. As noted above, it is formed by the direct conversion of Ang II by the enzyme ACE-2 [21,106], prolyl carboxypeptidase (angiotensinase C) [107], and prolyl endopeptidase [108], or from Ang (1-10) via conversion to Ang (1-9) by ACE-2 and then to Ang (1-7) by ACE [20], and by direct conversion to Ang (1-7) by neprilysin [109], thimet oligopeptidase and neurolysin [110] and prolyl endopeptidase [111] The receptor for Ang (1-7) has been identified as the Mas protein [23]. Mas protein displays a G protein-coupled receptor motif and is encoded by the Mas oncogene [112]. It was once proposed to be the Ang II receptor [113], however, the pharmacological characteristics of this receptor did not properly match the profile of the Ang II receptor. Angiotensin (1-7) can induce cardiovascular changes, promoting the release of PGs from vascular endothelial and smooth muscle cells [114,115], release of nitric oxide (NO) [116,117], vasorelaxation [23], inhibition of vascular wall cell growth [118], and attenuation of Ang II-induced vasoconstriction [119]. It is neuroprotective in an animal model of stroke [120], reducing ischemia induced inflammation [121] Its effects are basically antagonistic to the effects of Ang II binding to AT1R and it is generally recognized as being a counter-regulator of AT1R mediated effects, akin to the AT2R. Additionally, Ang (1- 7) is reported to have weak antagonistic effects at the AT1R [122].
An interesting adjunct to the ACE2/Ang (1-7)/Mas axis is the discovery of a novel Ang II analog in the bloodstream with high affinity and efficacy for the mas receptor, angioprotectin (Pro1,Glu2 Ang II) [123]. Angioprotectin reportedly binds with higher affinity than Ang (1-7) at the Mas receptor [123]. Of note, commercial antibodies used to measure plasma Ang II, which are directed at the C-terminal domain of Ang II do not distinguish between angioprotectin and Ang II, thus casting into doubt the significance of plasma Ang II-like immunoreactive material measurements.
(Pro) Renin and other receptors
Additional receptors have also been identified, one being the (pro)renin receptor ((P)RR) [27,124]. It is now becoming clear that (P)RR is a multifunctional protein that is also involved in the control of intracellular and extracellular pH via its interaction with the V-ATPase, MAP kinase signaling, Wnt/beta catenin signaling as well as by its ability to activate prorenin to form Ang I from AGT and to enhance the affinity of renin for AGT [124]. Renin has profibrotic actions that appear to be independent of Ang II formation which may be mediated through the (P) RR-ERK1/2 pathway [125]. (Pro) Renin receptor knockdown with SiRNA decreases mRNA for and protein expression of the proinflammatory mediators TGFß and fibronectin, and mRNA for plasminogen activator inhibitor-1 (PAI-1) in cultured glomerular cells from nephritic rats [126]. The (P)RR is found in a variety of tissues and may be critical to local formation of Ang II in tissues in which the concentration of renin is low, e.g. brain [127,128]. As noted previously, AGT can exist in two different conformations in plasma depending upon the redox state [1] and oxidative stress. Oxidized AGT forms a sulfhydryl bridge (cys 18-cys 138) that has more than a 10-fold increase in affinity for (P)RR bound renin. (P)RR has been linked to renal disease and hypertension via increased Ang II formation in the kidney [43] and brain [127] [128]. However, the physiological significance of the (P)RR for the RAS has been questioned [124,129].
A putative receptor for des Asp1, des Arg2 Ang II (Ang IV) known as the AT4R has been shown to be the enzyme insulinregulated aminopeptidase (IRAP) [19], also known as oxytocinase or vasopressinase (E.C. This receptor may play a role in regulation of the central nervous system (CNS), extracellular matrix, glucose metabolism, as well as modulation of oxytocin and vasopressin metabolism and release [130-137]. The AT4R is reported to have vasorelaxant effects via activation of NO synthase [138], however, it is also reported to have proinflammatory, prothrombotic activity [139]. A second subtype of AT4R has been reported to be the c-met receptor for hepatocyte growth factor [140]. Ang IV competes with hepatocyte growth factor for binding to c-met thereby inhibiting its actions [141].
The peptide fragment Ang (3-7) is reported to have neuromodulatory effects when administered into the brain [142-144], however no specific receptor for this fragment has been identified. Similarly, the Ang (2-10) fragment of Ang I is reported to have effects that are antagonistic to those of Ang II at the AT1R, but no receptor for Ang (2-10) has been described, see review [26].
An additional binding site for Ang I, Ang II and Ang III has been reported in mouse, rat and human brain tissue [145-147]. This binding site has recently been identified as a membranebound variant of neurolysin [148]. While the function of neurolysin includes metabolism of Ang I and Ang II [149-151], the possibility of additional functionality of the protein has not yet been explored.
Tissue renin-angiotensin systems
In addition to the classical circulating RAS, tissue-specific RAS's have been well documented. The presence of a local system suggests tissue specific functions. To be identified as having a complete tissue specific RAS, the following criteria must be met: 1) mRNAs for all components necessary for biosynthesis of a biologically active product (e.g., Ang II) are present, 2) a biologically active product is synthesized, 3) receptors for the biologically active angiotensin are present, 4) the biologically active product in the tissue is regulated, independently of the systemic RAS, and 5) reduction or elimination of the action of the product produces a physiological response. Depending on the tissue, the local enzymes responsible for cleavage of AGT or Ang I into Ang II may be different from those found in the classical cascade referred to as renin-independent or ACE-independent pathways. These are described in the next section. This is a most important concern in view of the fact that some tissue RAS's have little or no ability to synthesize renin and may depend on angiotensin-forming enzymes other than renin [25] or may be able to use prorenin to synthesize Ang I via the (pro)renin receptor [152].
Locations of tissue-specific RAS's include the brain [153,154], heart [155], pancreas [156,157], kidney [43], adrenal gland [158], blood vessels [159], reproductive tracts [160,161], lymphatic system [162,163]; adipose tissue [164]; bone marrow [165] and eye [6,166,167]. For comprehensive reviews of tissue RAS's see [168,169]. The RAS also acts as a modulator of hormone functions as evidenced in the adrenal gland. Angiotensin II is one of the most important physiological stimulators for the secretion of aldosterone [170,171]. The importance of aldosterone in the pathogenesis of cardiovascular diseases, including hypertension, has been well documented [172,173]. Ang II also stimulates the release of epinephrine from the adrenal gland [174,175].
Alternate pathways for angiotensin peptide metabolism
Over the past few years, a number of alternative pathways of the RAS have provided additional cascades for this system (Figure 2). These involve enzymes not generally considered to be part of the RAS. The zinc metallopeptidase, neprilysin (EC, converts Ang I into Ang (1-7) [22]. Similar to ACE, neprilysin also converts Ang (1-9) into Ang (1-7). Neurolysin is an endopeptidase that acts as the soluble and membrane associated Ang II binding protein in the RAS. It hydrolyzes Ang I to Ang (1-7) and Ang II to Ang (1-4) and (5-8), but is better known for its role in metabolizing neurotensin and BK [176]. It has been identified in the CNS [177] and is associated with neurons expressing neurotensin [178]. Other enzymes that are involved angiotensin peptide metabolism are thimet oligopeptidase (EC and prolyl endopeptidase (EC These enzymatic processes appear to be tissue-specific with neprilysin being primarily responsible for Ang (1–7) production in the circulation and ascular endothelium; whereas the other enzymatic pathways, e.g., ACE-2, prolyl endopeptidase and prolyl carboxypeptidase may be more active in tissues such as the brain [179] and kidney [180,181].
Other enzymes that can contribute to the RAS cascades via conversion of Ang I to Ang II or angiotensinogen to Ang II include: cathepsin G (E.C. [182,183], a membrane bound protein expressed on neutrophils, which may play a role in the production of potent vasoactive proteins and chemoattractants in inflammation [184] and tonin [185] (see review [25]). Chymase (E.C., forms α and β, which is found in the heart, kidney, vascular smooth muscle and in the secretory granules of mast cells is also able to generate Ang II from Ang I [182]. The literature suggests that alternate pathway Ang II production is important in both physiological and pathological processes [24,186]. Chymase mediated Ang II formation may also be important in diabetic nephropathy [187], vasoproliferative diseases [188,189] and in myocardial infarction [189].
Intracellular “intracrine” renin-angiotensin system
An intracellular RAS has also recently been identified [190-193]. It is characterized by RAS components inside the cell along with the intracellular synthesis of Ang II [194,195]. Numerous studies have shown the presence of functional intracellular RAS's [196,197]. However, the physiological role and involvement in pathophysiological processes have not yet been clearly identified [191,198,199]. It has been recently shown to have blood pressure elevating, sodium retention and prothrombotic effects mediated by AT1Rs in rodent models [193,200,201].
Our understanding of the RAS has evolved dramatically since Tigerstedt and Bergman's seminal observation that a pressure raising substance “eine drucksteigernde Substanz” which they called renin, was secreted into the bloodstream from the kidney in 1898 [202]. In what might be an incredible turn of events, this initial characterization of renin as a hormonal substance was verified with the discovery of a receptor for renin [203] now known as the (pro)renin receptor [27,204], although the functional significance of renin is still primarily based upon its enzymatic activity leading to the formation of the pressor hormone Ang II.
Perhaps the greatest change in our understanding of the RAS is that it is not all bad. While the predominant receptor of the system, the AT1 receptor, mediates a host of pathophysiological actions ranging from elevation of blood pressure to stimulation of inflammatory cytokines and promotion of fibrosis, there are two other arms of the RAS that act to counteract the actions of Ang II at the AT1 receptor. The first arm is that of the AT2 receptor which is now recognized to have the opposite effects of the AT1 receptor. Indeed, initial concerns that selective AT1 receptor antagonists, the …sartans, might have harmful effects because they would block the inhibitory feedback on renin release from the kidney mediated by the AT1 receptor [205] leading to elevated levels of blood Ang II never materialized. Suddenly the AT1 receptor blockers gained an additional therapeutic effect: to increase AT2 receptor stimulation by Ang II. Currently there is considerable interest in development of AT2 agonists as therapeutic agents based upon their ability to protect against stroke [206], myocardial infarction induced damage [207] and renal damage [208] in rodent models of cardiovascular disease. Additionally a naturally occurring variant of Ang II angiotensin A (Ala1 Ang II) [209] has been discovered to have greater affinity for the AT2 receptor than for the AT1 receptor. This variant may be generated by a specific decarboxylase to reduce the pathophysiological actions of Ang II [209].
The other beneficial arm of the RAS is that of the ACE-2/Ang (1-7)/mas axis. Although the initial report of Ang (1-7) as an active hormone of the RAS indicated it to have AT1 receptor-like actions [210], it is now well established that Ang (1-7) exerts actions at its own receptor mas [23] which are largely antagonistic to the actions of Ang II at the AT1 receptor [211]. Key to this arm of the RAS is the enzyme ACE-2 (also initially characterized under the name ACEH [21] ), which forms Ang (1-7) from Ang II, thereby simultaneously inactivating the AT1 receptor agonist and forming the mas agonist. Initially identified as an Ang I metabolizing enzyme [20] it is now known that Ang II is the preferred substrate of ACE-2 [22]. When ACE-2 was first discovered Millenium Pharmaceuticals developed an effective small molecule inhibitor of ACE-2, MLN-4760 with a subnanomolar inhibition constant [212] . However, the drug was never developed in view of the ability of ACE-2 to counter the pathophysiological actions of Ang II at the AT1 receptor. In contrast to the ACE-2 inhibitor MLN-4760, agents have been discovered that enhance the activity of ACE-2 [213] lowering blood pressure in an animal model of hypertension and improving cardiac function in an animal model of diabetes [214]. Most recently, an antiparasitic agent, diminazene, was also found to enhance ACE-2 activity and attenuate experimental pulmonary hypertension in rats [215].
The new direction of research aimed at understanding the beneficial arms of the RAS with the goal of developing novel therapeutic agents is something that was not even imaginable 20 years ago, this begs the question: Where will the RAS lead us in the next 20 years?
A search of the entire PubMed database was conducted using various combinations of the key words, renin, prorenin, angiotensinogen, angiotensin, AT1, AT2, AT4 receptors, mas, ACE, ACE2, intracellular, signaling, including various combinations of the different RAS components. A Google search using the same variations of these words was also performed to identify any scientific publications related to these words such as PhD dissertations or abstracts not published but presented at scientific meetings.
Funding Acknowledgments: RCS is supported in part by the National Heart Lung and Blood Institute division of the National Institutes of Health: HL113905.

  1. Zhou A, Carrell RW, Murphy MP, Wei Z, Yan Y, Stanley PL, et al. A redox switch in angiotensinogen modulates angiotensin release. Nature. 2010; 468: 108-111.
  2. Ménard J, Bouhnik J, Clauser E, Richoux JP, Corvol P. Biochemistry and regulation of angiotensinogen. Clin Exp Hypertens A. 1983; 5: 1005-1019.
  3. Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J. Inflammation and angiotensin II. Int J Biochem Cell Biol. 2003; 35: 881-900.
  4. Luetscher JA, Kraemer FB, Wilson DM, Schwartz HC, Bryer-Ash M. Increased plasma inactive renin in diabetes mellitus. A marker of microvascular complications. N Engl J Med. 1985; 312: 1412-1417.
  5. Franken AA, Derkx FH, Schalekamp MA, Man in t'Veld AJ, Hop WC, van Rens EH, et al. Association of high plasma prorenin with diabetic retinopathy. J Hypertens Suppl. 1988; 6: S461-463.
  6. Danser AH, van den Dorpel MA, Deinum J, Derkx FH, Franken AA, Peperkamp E, et al. Renin, prorenin, and immunoreactive renin in vitreous fluid from eyes with and without diabetic retinopathy. J Clin Endocrinol Metab. 1989; 68: 160-167.
  7. Mäkimattila S, Summanen P, Matinlauri I, Mäntysaari M, Schlenzka A, Aalto M, et al. Serum total renin, an independent marker of the activity and severity of retinopathy in patients with IDDM. Br J Ophthalmol. 1998; 82: 939-944.
  8. Yokota H, Mori F, Kai K, Nagaoka T, Izumi N, Takahashi A, et al. Serum prorenin levels and diabetic retinopathy in type 2 diabetes: new method to measure serum level of prorenin using antibody activating direct kinetic assay. Br J Ophthalmol. 2005; 89: 871-3.
  9. Corvol P, Michaud A, Soubrier F, Williams TA. Recent advances in knowledge of the structure and function of the angiotensin I converting enzyme. J Hypertens Suppl. 1995; 13: S3-10.
  10. Parkin ET, Turner AJ, Hooper NM. Secretase-mediated cell surface shedding of the angiotensin-converting enzyme. Protein Pept Lett. 2004; 11: 423-432.
  11. Erreira SH. A Bradykinin-Potentiating Factor (BPF) Present in the Venom of Bothrops JARARCA. Br J Pharmacol Chemother. 1965; 24: 163-169.
  12. Soffer RL. Angiotensin-converting enzyme and the regulation of vasoactive peptides. Annu Rev Biochem. 1976; 45: 73-94.
  13. Davis JO, Freeman RH. The other angiotensins. Biochem Pharmacol. 1977; 26: 93-97.
  14. de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T. International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev. 2000; 52: 415-472.
  15. Scheuer DA, Perrone MH. Angiotensin type 2 receptors mediate depressor phase of biphasic pressure response to angiotensin. Am J Physiol. 1993; 264: R917-923.
  16. Nakajima M, Hutchinson HG, Fujinaga M, Hayashida W, Morishita R, Zhang L, et al. The angiotensin II type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor: gain-of-function study using gene transfer. Proc Natl Acad Sci U S A. 1995; 92: 10663-10667.
  17. Kaschina E, Grzesiak A, Li J, Foryst-Ludwig A, Timm M, Rompe F, et al. Angiotensin II type 2 receptor stimulation: a novel option of therapeutic interference with the renin-angiotensin system in myocardial infarction? Circulation. 2008; 118: 2523-2532.
  18. Harding JW, Cook VI, Miller-Wing AV, Hanesworth JM, Sardinia MF, Hall KL, et al. Identification of an AII(3-8) [AIV] binding site in guinea pig hippocampus. Brain Res. 1992; 583: 340-343.
  19. Albiston AL, McDowall SG, Matsacos D, Sim P, Clune E, Mustafa T, et al. Evidence that the angiotensin IV (AT(4)) receptor is the enzyme insulin-regulated aminopeptidase. J Biol Chem. 2001; 276: 48623-48626.
  20. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000; 87: E1-9.
  21. Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000; 275: 33238-33243.
  22. Rice GI, Thomas DA, Grant PJ, Turner AJ, Hooper NM. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J. 2004; 383: 45-51.
  23. Santos RA, Simoes e Silva AC, Maric C, Silva DM, Machado RP, de Buhr I, et al. Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci U S A. 2003; 100: 8258-8263.
  24. Urata H, Healy B, Stewart RW, Bumpus FM, Husain A. Angiotensin II-forming pathways in normal and failing human hearts. Circ Res. 1990; 66: 883-890.
  25. Karamyan VT, Speth RC. Enzymatic pathways of the brain renin-angiotensin system: unsolved problems and continuing challenges. Regul Pept. 2007; 143: 15-27.
  26. Ramírez-Sánchez M, Prieto I, Wangensteen R, Banegas I, Segarra AB, Villarejo AB, et al. The renin-angiotensin system: new insight into old therapies. Curr Med Chem. 2013; 20: 1313-1322.
  27. Nguyen G, Delarue F, Burcklé C, Bouzhir L, Giller T, Sraer JD. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest. 2002; 109: 1417-1427.
  28. Chiu AT, Herblin WF, McCall DE, Ardecky RJ, Carini DJ, Duncia JV, et al. Identification of angiotensin II receptor subtypes. Biochem Biophys Res Commun. 1989; 165: 196-203.
  29. Whitebread S, Mele M, Kamber B, de Gasparo M. Preliminary biochemical characterization of two angiotensin II receptor subtypes. Biochem Biophys Res Commun. 1989; 163: 284-91.
  30. Dudley DT, Panek RL, Major TC, Lu GH, Bruns RF, Klinkefus BA, et al. Subclasses of angiotensin II binding sites and their functional significance. Mol Pharmacol. 1990; 38: 370-377.
  31. Brechler V, Jones PW, Levens NR, de Gasparo M, Bottari SP. Agonistic and antagonistic properties of angiotensin analogs at the AT2 receptor in PC12W cells. Regul Pept. 1993; 44: 207-213.
  32. Bumpus FM, Catt KJ, Chiu AT, DeGasparo M, Goodfriend T, Husain A, et al. Nomenclature for angiotensin receptors. A report of the Nomenclature Committee of the Council for High Blood Pressure Research. Hypertension. 1991; 17: 720-721.
  33. Moreau P, d'Uscio LV, Shaw S, Takase H, Barton M, Lüscher TF. Angiotensin II increases tissue endothelin and induces vascular hypertrophy: reversal by ET(A)-receptor antagonist. Circulation. 1997; 96: 1593-1597.
  34. Holtz J. Pathophysiology of heart failure and the renin-angiotensin-system. Basic Res Cardiol. 1993; 88 Suppl 1: 183-201.
  35. Fyhrquist F, Metsärinne K, Tikkanen I. Role of angiotensin II in blood pressure regulation and in the pathophysiology of cardiovascular disorders. J Hum Hypertens. 1995; 9 Suppl 5: S19-24.
  36. Marshall RP, McAnulty RJ, Laurent GJ. Angiotensin II is mitogenic for human lung fibroblasts via activation of the type 1 receptor. Am J Respir Crit Care Med. 2000; 161: 1999-2004.
  37. Ruiz-Ortega M, Ruperez M, Esteban V, Egido J. Molecular mechanisms of angiotensin II-induced vascular injury. Curr Hypertens Rep. 2003; 5: 73-79.
  38. Yamada T, Kuno A, Masuda K, Ogawa K, Sogawa M, Nakamura S, et al. Candesartan, an angiotensin II receptor antagonist, suppresses pancreatic inflammation and fibrosis in rats. J Pharmacol Exp Ther. 2003; 307: 17-23.
  39. Kuno A, Yamada T, Masuda K, Ogawa K, Sogawa M, Nakamura S, et al. Angiotensin-converting enzyme inhibitor attenuates pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori rats. Gastroenterology. 2003; 124: 1010-9.
  40. Ikura Y, Ohsawa M, Shirai N, Sugama Y, Fukushima H, Suekane T, et al. Expression of angiotensin II type 1 receptor in human cirrhotic livers: Its relation to fibrosis and portal hypertension. Hepatol Res. 2005; 32: 107-116.
  41. Kaschina E, Scholz H, Steckelings UM, Sommerfeld M, Kemnitz UR, Artuc M, et al. Transition from atherosclerosis to aortic aneurysm in humans coincides with an increased expression of RAS components. Atherosclerosis. 2009; 205: 396-403.
  42. Shenoy V, Ferreira AJ, Qi Y, Fraga-Silva RA, Díez-Freire C, Dooies A, et al. The angiotensin-converting enzyme 2/angiogenesis-(1-7)/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension. Am J Respir Crit Care Med. 2010; 182: 1065-1072.
  43. Navar LG, Prieto MC, Satou R, Kobori H. Intrarenal angiotensin II and its contribution to the genesis of chronic hypertension. Curr Opin Pharmacol. 2011; 11: 180-186.
  44. Ruiz-Ortega M, Lorenzo O, Suzuki Y, Rupérez M, Egido J. Proinflammatory actions of angiotensins. Curr Opin Nephrol Hypertens. 2001; 10: 321-329.
  45. Candido R, Allen TJ, Lassila M, Cao Z, Thallas V, Cooper ME, et al. Irbesartan but not amlodipine suppresses diabetes-associated atherosclerosis. Circulation. 2004; 109: 1536-1542.
  46. Phillips MI, Kagiyama S. Angiotensin II as a pro-inflammatory mediator. Curr Opin Investig Drugs. 2002; 3: 569-577.
  47. Okamura A, Rakugi H, Ohishi M, Yanagitani Y, Takiuchi S, Moriguchi K, et al. Upregulation of renin-angiotensin system during differentiation of monocytes to macrophages. J Hypertens. 1999; 17: 537-545.
  48. Luft FC. Angiotensin, inflammation, hypertension, and cardiovascular disease. Curr Hypertens Rep. 2001; 3: 61-67.
  49. Mehta PK, Griendling KK. Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol. 2007; 292: C82-97.
  50. Rüster C, Wolf G. Renin-angiotensin-aldosterone system and progression of renal disease. J Am Soc Nephrol. 2006; 17: 2985-2991.
  51. Whaley-Connell A, Habibi J, Panfili Z, Hayden MR, Bagree S, Nistala R, et al. Angiotensin II activation of mTOR results in tubulointerstitial fibrosis through loss of N-cadherin. Am J Nephrol. 2011; 34: 115-125.
  52. Dai Q, Xu M, Yao M, Sun B. Angiotensin AT1 receptor antagonists exert anti-inflammatory effects in spontaneously hypertensive rats. Br J Pharmacol. 2007; 152: 1042-1048.
  53. Cui R, Tieu B, Recinos A, Tilton RG, Brasier AR. RhoA mediates angiotensin II-induced phospho-Ser536 nuclear factor kappaB/RelA subunit exchange on the interleukin-6 promoter in VSMCs. Circ Res. 2006; 99: 723-730.
  54. Tamarat R, Silvestre JS, Durie M, Levy BI. Angiotensin II angiogenic effect in vivo involves vascular endothelial growth factor- and inflammation-related pathways. Lab Invest. 2002; 82: 747-756.
  55. Kitayama H, Maeshima Y, Takazawa Y, Yamamoto Y, Wu Y, Ichinose K, et al. Regulation of angiogenic factors in angiotensin II infusion model in association with tubulointerstitial injuries. Am J Hypertens. 2006; 19: 718-727.
  56. Nickenig G, Harrison DG. The AT(1)-type angiotensin receptor in oxidative stress and atherogenesis: part I: oxidative stress and atherogenesis. Circulation. 2002; 105: 393-396.
  57. Nickenig G, Harrison DG. The AT(1)-type angiotensin receptor in oxidative stress and atherogenesis: Part II: AT(1) receptor regulation. Circulation. 2002; 105: 530-536.
  58. Granger DN, Vowinkel T, Petnehazy T. Modulation of the inflammatory response in cardiovascular disease. Hypertension. 2004; 43: 924-931.
  59. Pastore L, Tessitore A, Martinotti S, Toniato E, Alesse E, Bravi MC, et al. Angiotensin II stimulates intercellular adhesion molecule-1 (ICAM-1) expression by human vascular endothelial cells and increases soluble ICAM-1 release in vivo. Circulation. 1999; 100: 1646-1652.
  60. Steckelings UM, Kaschina E, Unger T. The AT2 receptor--a matter of love and hate. Peptides. 2005; 26: 1401-1409.
  61. Marchesi C, Paradis P, Schiffrin EL. Role of the renin-angiotensin system in vascular inflammation. Trends Pharmacol Sci. 2008; 29: 367-374.
  62. Mezzano SA, Ruiz-Ortega M, Egido J. Angiotensin II and renal fibrosis. Hypertension. 2001; 38: 635-638.
  63. Wassmann S, Nickenig G. Pathophysiological regulation of the AT1-receptor and implications for vascular disease. J Hypertens Suppl. 2006; 24: S15-21.
  64. Benigni A, Cassis P, Remuzzi G. Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol Med. 2010; 2: 247-257.
  65. Wallukat G, Homuth V, Fischer T, Lindschau C, Horstkamp B, Jüpner A, et al. Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J Clin Invest. 1999; 103: 945-952.
  66. Eguchi S, Numaguchi K, Iwasaki H, Matsumoto T, Yamakawa T, Utsunomiya H, et al. Calcium-dependent epidermal growth factor receptor transactivation mediates the angiotensin II-induced mitogen-activated protein kinase activation in vascular smooth muscle cells. J Biol Chem. 1998; 273: 8890-6.
  67. Smith JB, Smith L, Brown ER, Barnes D, Sabir MA, Davis JS, et al. Angiotensin II rapidly increases phosphatidate-phosphoinositide synthesis and phosphoinositide hydrolysis and mobilizes intracellular calcium in cultured arterial muscle cells. Proc Natl Acad Sci U S A. 1984; 81: 7812-6.
  68. Godin CM, Ferguson SS. Biased agonism of the angiotensin II type 1 receptor. Mini Rev Med Chem. 2012; 12: 812-816.
  69. Shenoy SK, Lefkowitz RJ. Angiotensin II-stimulated signaling through G proteins and beta-arrestin. Sci STKE. 2005.
  70. Gibbons GH, Pratt RE, Dzau VJ. Vascular smooth muscle cell hypertrophy vs. hyperplasia. Autocrine transforming growth factor-beta 1 expression determines growth response to angiotensin II. J Clin Invest. 1992; 90: 456-461.
  71. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994; 74: 1141-1148.
  72. Wei H, Ahn S, Shenoy SK, Karnik SS, Hunyady L, Luttrell LM, et al. Independent beta-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2. Proc Natl Acad Sci U S A. 2003; 100: 10782-10787.
  73. Chiu AT, McCall DE, Nguyen TT, Carini DJ, Duncia JV, Herblin WF, et al. Discrimination of angiotensin II receptor subtypes by dithiothreitol. Eur J Pharmacol. 1989; 170: 117-118.
  74. Kambayashi Y, Bardhan S, Takahashi K, Tsuzuki S, Inui H, Hamakubo T, et al. Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phosphatase inhibition. J Biol Chem. 1993; 268: 24543-24546.
  75. Mukoyama M, Nakajima M, Horiuchi M, Sasamura H, Pratt RE, Dzau VJ. Expression cloning of type 2 angiotensin II receptor reveals a unique class of seven-transmembrane receptors. J Biol Chem. 1993; 268: 24539-24542.
  76. Speth RC, Kim KH. Discrimination of two angiotensin II receptor subtypes with a selective agonist analogue of angiotensin II, p-aminophenylalanine6 angiotensin II. Biochem Biophys Res Commun. 1990; 169: 997-1006.
  77. Kang J, Sumners C, Posner P. Modulation of net outward current in cultured neurons by angiotensin II: involvement of AT1 and AT2 receptors. Brain Res. 1992; 580: 317-324.
  78. Kang J, Sumners C, Posner P. Angiotensin II type 2 receptor-modulated changes in potassium currents in cultured neurons. Am J Physiol. 1993; 265: C607-616.
  79. Chung O, Kühl H, Stoll M, Unger T. Physiological and pharmacological implications of AT1 versus AT2 receptors. Kidney Int Suppl. 1998; 67: S95-99.
  80. Matsubara H. Pathophysiological role of angiotensin II type 2 receptor in cardiovascular and renal diseases. Circ Res. 1998; 83: 1182-1191.
  81. Porrello ER, Delbridge LM, Thomas WG. The angiotensin II type 2 (AT2) receptor: an enigmatic seven transmembrane receptor. Front Biosci (Landmark Ed). 2009; 14: 958-972.
  82. Stegbauer J, Coffman TM. New insights into angiotensin receptor actions: from blood pressure to aging. Curr Opin Nephrol Hypertens. 2011; 20: 84-88.
  83. Gao L, Zucker IH. AT2 receptor signaling and sympathetic regulation. Curr Opin Pharmacol. 2011; 11: 124-130.
  84. Unger T, Dahlöf B. Compound 21, the first orally active, selective agonist of the angiotensin type 2 receptor (AT2): implications for AT2 receptor research and therapeutic potential. J Renin Angiotensin Aldosterone Syst. 2010; 11: 75-77.
  85. Steckelings UM, Paulis L, Namsolleck P, Unger T. AT2 receptor agonists: hypertension and beyond. Curr Opin Nephrol Hypertens. 2012; 21: 142-146.
  86. McCarthy CA, Widdop RE, Denton KM, Jones ES. Update on the angiotensin AT(2) receptor. Curr Hypertens Rep. 2013; 15: 25-30.
  87. Ferreira AJ, Raizada MK. Are we poised to target ACE2 for the next generation of antihypertensives? J Mol Med (Berl). 2008; 86: 685-690.
  88. Brosnihan KB, Neves LA, Joyner J, Averill DB, Chappell MC, Sarao R, et al. Enhanced renal immunocytochemical expression of ANG-(1-7) and ACE2 during pregnancy. Hypertension. 2003; 42: 749-753.
  89. Soler MJ, Wysocki J, Batlle D. Angiotensin-converting enzyme 2 and the kidney. Exp Physiol. 2008; 93: 549-556.
  90. Guy JL, Lambert DW, Warner FJ, Hooper NM, Turner AJ. Membrane-associated zinc peptidase families: comparing ACE and ACE2. Biochim Biophys Acta. 2005; 1751: 2-8.
  91. Douglas GC, O'Bryan MK, Hedger MP, Lee DK, Yarski MA, Smith AI, et al. The novel angiotensin-converting enzyme (ACE) homolog, ACE2, is selectively expressed by adult Leydig cells of the testis. Endocrinology. 2004; 145: 4703-4711.
  92. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004; 203: 631-637.
  93. Paizis G, Tikellis C, Cooper ME, Schembri JM, Lew RA, Smith AI, et al. Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2. Gut. 2005; 54: 1790-1796.
  94. Doobay MF, Talman LS, Obr TD, Tian X, Davisson RL, Lazartigues E. Differential expression of neuronal ACE2 in transgenic mice with overexpression of the brain renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol. 2007; 292: R373-381.
  95. Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J, et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem. 2002; 277: 14838-14843.
  96. Ocaranza MP, Lavandero S, Jalil JE, Moya J, Pinto M, Novoa U, et al. Angiotensin-(1-9) regulates cardiac hypertrophy in vivo and in vitro. J Hypertens. 2010; 28: 1054-1064.
  97. Jackman HL, Massad MG, Sekosan M, Tan F, Brovkovych V, Marcic BM, et al. Angiotensin 1-9 and 1-7 release in human heart: role of cathepsin A. Hypertension. 2002; 39: 976-981.
  98. Yagil Y, Yagil C. Hypothesis: ACE2 modulates blood pressure in the mammalian organism. Hypertension. 2003; 41: 871-873.
  99. Schmaier AH. The kallikrein-kinin and the renin-angiotensin systems have a multilayered interaction. Am J Physiol Regul Integr Comp Physiol. 2003; 285: R1-13.
  100. Marceau F, Regoli D. Bradykinin receptor ligands: therapeutic perspectives. Nat Rev Drug Discov. 2004; 3: 845-852.
  101. Maier-Hauff K, Baethmann AJ, Lange M, Schürer L, Unterberg A. The kallikrein-kinin system as mediator in vasogenic brain edema. Part 2: Studies on kinin formation in focal and perifocal brain tissue. J Neurosurg. 1984; 61: 97-106.
  102. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003; 426: 450-4.
  103. Li F, Li W, Farzan M, Harrison SC. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science. 2005; 309: 1864-1868.
  104. Grobe N, Weir NM, Leiva O, Ong FS, Bernstein KE, Schmaier AH, et al. Identification of prolyl carboxypeptidase as an alternative enzyme for processing of renal angiotensin II using mass spectrometry. Am J Physiol Cell Physiol. 2013; 304: C945-953.
  105. Santos RA, Campagnole-Santos MJ, Andrade SP. Angiotensin-(1-7): an update. Regul Pept. 2000; 91: 45-62.
  106. Ferrario CM, Chappell MC. Novel angiotensin peptides. Cell Mol Life Sci. 2004; 61: 2720-2727.
  107. Odya CE, Marinkovic DV, Hammon KJ, Stewart TA, Erdös EG. Purification and properties of prolylcarboxypeptidase (angiotensinase C) from human kidney. J Biol Chem. 1978; 253: 5927-5931.
  108. Cunningham DF, O'Connor B. A study of prolyl endopeptidase in bovine serum and its relevance to the tissue enzyme. Int J Biochem Cell Biol. 1998; 30: 99-114.
  109. Yamamoto K, Chappell MC, Brosnihan KB, Ferrario CM. In vivo metabolism of angiotensin I by neutral endopeptidase (EC in spontaneously hypertensive rats. Hypertension. 1992; 19: 692-696.
  110. Barelli H, Vincent JP, Checler F. Peripheral inactivation of neurotensin. Isolation and characterization of a metallopeptidase from rat ileum. Eur J Biochem. 1988; 175: 481-489.
  111. Welches WR, Santos RA, Chappell MC, Brosnihan KB, Greene LJ, Ferrario CM. Evidence that prolyl endopeptidase participates in the processing of brain angiotensin. J Hypertens. 1991; 9: 631-638.
  112. Young D, Waitches G, Birchmeier C, Fasano O, Wigler M. Isolation and characterization of a new cellular oncogene encoding a protein with multiple potential transmembrane domains. Cell. 1986; 45: 711-719.
  113. Jackson TR, Blair LA, Marshall J, Goedert M, Hanley MR. The mas oncogene encodes an angiotensin receptor. Nature. 1988; 335: 437-440.
  114. Muthalif MM, Benter IF, Uddin MR, Harper JL, Malik KU. Signal transduction mechanisms involved in angiotensin-(1-7)-stimulated arachidonic acid release and prostanoid synthesis in rabbit aortic smooth muscle cells. J Pharmacol Exp Ther. 1998; 284: 388-98.
  115. Jaiswal N, Diz DI, Chappell MC, Khosla MC, Ferrario CM. Stimulation of endothelial cell prostaglandin production by angiotensin peptides. Characterization of receptors. Hypertension. 1992; 19: II49-55.
  116. Brosnihan KB, Li P, Ferrario CM. Angiotensin-(1-7) dilates canine coronary arteries through kinins and nitric oxide. Hypertension. 1996; 27: 523-528.
  117. Li P, Chappell MC, Ferrario CM, Brosnihan KB. Angiotensin-(1-7) augments bradykinin-induced vasodilation by competing with ACE and releasing nitric oxide. Hypertension. 1997; 29: 394-400.
  118. Freeman EJ, Chisolm GM, Ferrario CM, Tallant EA. Angiotensin-(1-7) inhibits vascular smooth muscle cell growth. Hypertension. 1996; 28: 104-108.
  119. Feng Y, Xia H, Cai Y, Halabi CM, Becker LK, Santos RA, et al. Brain-selective overexpression of human Angiotensin-converting enzyme type 2 attenuates neurogenic hypertension. Circ Res. 2010; 106: 373-382.
  120. Mecca AP, Regenhardt RW, O'Connor TE, Joseph JP, Raizada MK, Katovich MJ, et al. Cerebroprotection by angiotensin-(1-7) in endothelin-1-induced ischaemic stroke. Exp Physiol. 2011; 96: 1084-1096.
  121. Regenhardt RW, Desland F, Mecca AP, Pioquinto DJ, Afzal A, Mocco J, et al. Anti-inflammatory effects of angiotensin-(1-7) in ischemic stroke. Neuropharmacology. 2013; 71: 154-163.
  122. Bovy PR, O'Neal JM, Olins GM, Patton DR, McMahon EG, Palomo M, et al. Structure-activity relationships for the carboxy-terminus truncated analogues of angiotension II, a new class of angiotensin II antagonists. J Med Chem. 1990; 33: 1477-1482.
  123. Jankowski V, Tölle M, Santos RA, Günthner T, Krause E, Beyermann M, et al. Angioprotectin: an angiotensin II-like peptide causing vasodilatory effects. FASEB J. 2011; 25: 2987-2995.
  124. Nguyen G. Renin, (pro)renin and receptor: an update. Clin Sci (Lond). 2011; 120: 169-178.
  125. Huang Y, Noble NA, Zhang J, Xu C, Border WA. Renin-stimulated TGF-beta1 expression is regulated by a mitogen-activated protein kinase in mesangial cells. Kidney Int. 2007; 72: 45-52.
  126. Zhang J, Gu C, Noble NA, Border WA, Huang Y. Combining angiotensin II blockade and renin receptor inhibition results in enhanced antifibrotic effect in experimental nephritis. Am J Physiol Renal Physiol. 2011; 301: F723-732.
  127. Shan Z, Shi P, Cuadra AE, Dong Y, Lamont GJ, Li Q, et al. Involvement of the brain (pro)renin receptor in cardiovascular homeostasis. Circ Res. 2010; 107: 934-938.
  128. Li W, Peng H, Cao T, Sato R, McDaniels SJ, Kobori H, et al. Brain-targeted (pro)renin receptor knockdown attenuates angiotensin II-dependent hypertension. Hypertension. 2012; 59: 1188-1194.
  129. Krop M, Lu X, Danser AH, Meima ME. The (pro)renin receptor. A decade of research: what have we learned? Pflugers Arch. 2013; 465: 87-97.
  130. Mustafa T, Chai SY, Mendelsohn FA, Moeller I, Albiston AL. Characterization of the AT(4) receptor in a human neuroblastoma cell line (SK-N-MC). J Neurochem. 2001; 76: 1679-1687.
  131. Albiston AL, Mustafa T, McDowall SG, Mendelsohn FA, Lee J, Chai SY. AT4 receptor is insulin-regulated membrane aminopeptidase: potential mechanisms of memory enhancement. Trends Endocrinol Metab. 2003; 14: 72-77.
  132. Keller SR. The insulin-regulated aminopeptidase: a companion and regulator of GLUT4. Front Biosci. 2003; 8: s410-420.
  133. Chai SY, Fernando R, Peck G, Ye SY, Mendelsohn FA, Jenkins TA, et al. The angiotensin IV/AT4 receptor. Cell Mol Life Sci. 2004; 61: 2728-2737.
  134. Davis CJ, Kramár EA, De A, Meighan PC, Simasko SM, Wright JW, et al. AT4 receptor activation increases intracellular calcium influx and induces a non-N-methyl-D-aspartate dependent form of long-term potentiation. Neuroscience. 2006; 137: 1369-1379.
  135. Beyer CE, Dwyer JM, Platt BJ, Neal S, Luo B, Ling HP, et al. Angiotensin IV elevates oxytocin levels in the rat amygdala and produces anxiolytic-like activity through subsequent oxytocin receptor activation. Psychopharmacology (Berl). 2010; 209: 303-311.
  136. Wright JW, Harding JW. Brain renin-angiotensin--a new look at an old system. Prog Neurobiol. 2011; 95: 49-67.
  137. Benoist CC, Wright JW, Zhu M, Appleyard SM, Wayman GA, Harding JW. Facilitation of hippocampal synaptogenesis and spatial memory by C-terminal truncated Nle1-angiotensin IV analogs. J Pharmacol Exp Ther. 2011; 339: 35-44.
  138. Patel JM, Martens JR, Li YD, Gelband CH, Raizada MK, Block ER. Angiotensin IV receptor-mediated activation of lung endothelial NOS is associated with vasorelaxation. Am J Physiol. 1998; 275: L1061-1068.
  139. Ruiz-Ortega M, Esteban V, Egido J. The regulation of the inflammatory response through nuclear factor-kappab pathway by angiotensin IV extends the role of the renin angiotensin system in cardiovascular diseases. Trends Cardiovasc Med. 2007; 17: 19-25.
  140. Yamamoto BJ, Elias PD, Masino JA, Hudson BD, McCoy AT, Anderson ZJ, et al. The angiotensin IV analog Nle-Tyr-Leu-psi-(CH2-NH2)3-4-His-Pro-Phe (norleual) can act as a hepatocyte growth factor/c-Met inhibitor. J Pharmacol Exp Ther. 2010; 333: 161-173.
  141. Kawas LH, Yamamoto BJ, Wright JW, Harding JW. Mimics of the dimerization domain of hepatocyte growth factor exhibit anti-Met and anticancer activity. J Pharmacol Exp Ther. 2011; 339: 509-518.
  142. Braszko JJ, Własienko J, Koziołkiewicz W, Janecka A, Wiśniewski K. The 3-7 fragment of angiotensin II is probably responsible for its psychoactive properties. Brain Res. 1991; 542: 49-54.
  143. Braszko JJ, Kułakowska A, Wiśniewski K. Angiotensin II and its 3-7 fragment improve recognition but not spatial memory in rats. Brain Res Bull. 1995; 37: 627-631.
  144. Ferreira PM, Souza Dos Santos RA, Campagnole-Santos MJ. Angiotensin-(3-7) pressor effect at the rostral ventrolateral medulla. Regul Pept. 2007; 141: 168-174.
  145. Rabey FM, Karamyan VT, Speth RC. Distribution of a novel binding site for angiotensins II and III in mouse tissues. Regul Pept. 2010; 162: 5-11.
  146. Karamyan VT, Speth RC. Identification of a novel non-AT1, non-AT2 angiotensin binding site in the rat brain. Brain Res. 2007; 1143: 83-91.
  147. Karamyan VT, Gembardt F, Rabey FM, Walther T, Speth RC. Characterization of the brain-specific non-AT(1), non-AT(2) angiotensin binding site in the mouse. Eur J Pharmacol. 2008; 590: 87-92.
  148. Wangler NJ, Santos KL, Schadock I, Hagen FK, Escher E, Bader M, et al. Identification of membrane-bound variant of metalloendopeptidase neurolysin (EC as the non-angiotensin type 1 (non-AT1), non-AT2 angiotensin binding site. J Biol Chem. 2012; 287: 114-122.
  149. Millican PE, Kenny AJ, Turner AJ. Purification and properties of a neurotensin-degrading endopeptidase from pig brain. Biochem J. 1991; 276 : 583-591.
  150. Dahms P, Mentlein R. Purification of the main somatostatin-degrading proteases from rat and pig brains, their action on other neuropeptides, and their identification as endopeptidases 24.15 and 24.16. Eur J Biochem. 1992; 208: 145-154.
  151. Barelli H, Vincent JP, Checler F. Rat kidney endopeptidase 24.16. Purification, physico-chemical characteristics and differential specificity towards opiates, tachykinins and neurotensin-related peptides. Eur J Biochem. 1993; 211: 79-90.
  152. Li W, Peng H, Seth DM, Feng Y. The Prorenin and (Pro)renin Receptor: New Players in the Brain Renin-Angiotensin System? Int J Hypertens. 2012; 2012: 290635.
  153. Phillips MI. Angiotensin in the brain. Neuroendocrinology. 1978; 25: 354-377.
  154. Moulik S, Speth RC, Turner BB, Rowe BP. Angiotensin II receptor subtype distribution in the rabbit brain. Exp Brain Res. 2002; 142: 275-283.
  155. van Kats JP, Danser AH, van Meegen JR, Sassen LM, Verdouw PD, Schalekamp MA. Angiotensin production by the heart: a quantitative study in pigs with the use of radiolabeled angiotensin infusions. Circulation. 1998; 98: 73-81.
  156. Leung PS. The physiology of a local renin-angiotensin system in the pancreas. J Physiol. 2007; 580: 31-37.
  157. Pérez-Díaz I, Guzmán C, Olivares-Reyes JA, Ramírez T, Gutierréz-Reyes G, Hiriart M, et al. Evidence of an intracellular angiotensin-generating system and non-AT1, non-AT2 binding site in a human pancreatic cell line. Pancreas. 2011; 40: 701-707.
  158. Husain A, DeSilva P, Speth RC, Bumpus FM. Regulation of angiotensin II in rat adrenal gland. Circ Res. 1987; 60: 640-648.
  159. Unger T, Gohlke P, Ganten D, Lang RE. Converting enzyme inhibitors and their effects on the renin-angiotensin system of the blood vessel wall. J Cardiovasc Pharmacol. 1989; 13 Suppl 3: S8-16.
  160. Speth RC, Daubert DL, Grove KL. Angiotensin II: a reproductive hormone too? Regul Pept. 1999; 79: 25-40.
  161. Leung PS, Sernia C. The renin-angiotensin system and male reproduction: new functions for old hormones. J Mol Endocrinol. 2003; 30: 263-270.
  162. Iwai N, Inagami T, Ohmichi N, Kinoshita M. Renin is expressed in rat macrophage/monocyte cells. Hypertension. 1996; 27: 399-403.
  163. Koca E, Haznedaroglu IC, Uner A, Sayinalp N, Saglam AE, Goker H, et al. Angiotensin-converting enzyme expression of the lymphoma-associated macrophages in the lymph nodes of Hodgkin's disease. J Natl Med Assoc. 2007; 99: 1243-1244, 1246-7.
  164. Karlsson C, Lindell K, Ottosson M, Sjöström L, Carlsson B, Carlsson LM. Human adipose tissue expresses angiotensinogen and enzymes required for its conversion to angiotensin II. J Clin Endocrinol Metab. 1998; 83: 3925-3929.
  165. Haznedaroglu IC, Beyazit Y. Pathobiological aspects of the local bone marrow renin-angiotensin system: a review. J Renin Angiotensin Aldosterone Syst. 2010; 11: 205-213.
  166. Wagner J, Jan Danser AH, Derkx FH, de Jong TV, Paul M, Mullins JJ, et al. Demonstration of renin mRNA, angiotensinogen mRNA, and angiotensin converting enzyme mRNA expression in the human eye: evidence for an intraocular renin-angiotensin system. Br J Ophthalmol. 1996; 80: 159-163.
  167. Sramek SJ, Wallow IH, Tewksbury DA, Brandt CR, Poulsen GL. An ocular renin-angiotensin system. Immunohistochemistry of angiotensinogen. Invest Ophthalmol Vis Sci. 1992; 33: 1627-1632.
  168. Campbell DJ. Circulating and tissue angiotensin systems. J Clin Invest. 1987; 79: 1-6.
  169. Paul M, Poyan Mehr A, Kreutz R. Physiology of local renin-angiotensin systems. Physiol Rev. 2006; 86: 747-803.
  170. DAVIS JO, HARTROFT PM, TITUS EO, CARPENTER CC, AYERS CR, SPIEGEL HE. The role of the renin-angiotensin system in the control of aldosterone secretion. J Clin Invest. 1962; 41: 378-389.
  171. Weir MR, Dzau VJ. The renin-angiotensin-aldosterone system: a specific target for hypertension management. Am J Hypertens. 1999; 12: 205S-213S.
  172. ALHOUN FP Jr. Pigmentary glaucoma and its relation to Krukenberg's spindles. Am J Ophthalmol. 1953; 36: 1398-1415.
  173. Calhoun FP Jr. An aid to the clinical diagnosis of epithelial downgrowth into the anterior chamber following cataract extraction. Am J Ophthalmol. 1966; 61: 1055-1059.
  175. Peach MJ. Adrenal medullary stimulation induced by angiotensin I, angiotensin II, and analogues. Circ Res. 1971; 28: Suppl 2:107-117.
  176. Rioli V, Kato A, Portaro FC, Cury GK, te Kaat K, Vincent B, et al. Neuropeptide specificity and inhibition of recombinant isoforms of the endopeptidase family: comparison with the related recombinant endopeptidase Biochem Biophys Res Commun. 1998; 250: 5-11.
  177. Checler F, Barelli H, Kitabgi P, Vincent JP. Neurotensin metabolism in various tissues of central and peripheral origins: ubiquitous involvement of a novel neurotensin degrading metalloendopeptidase. Biochimie. 1988; 70: 75-82.
  178. Rawlings ND, Barrett AJ. Evolutionary families of peptidases. Biochem J. 1993; 290 : 205-218.
  179. Feng Y, Xia H, Santos RA, Speth R, Lazartigues E. Angiotensin-converting enzyme 2: a new target for neurogenic hypertension. Exp Physiol. 2010; 95: 601-606.
  180. Grobe N, Elased KM, Cool DR, Morris M. Mass spectrometry for the molecular imaging of angiotensin metabolism in kidney. Am J Physiol Endocrinol Metab. 2012; 302: E1016-1024.
  181. Grobe N, Weir NM, Leiva O, Ong FS, Bernstein KE, Schmaier AH, et al. Identification of prolyl carboxypeptidase as an alternative enzyme for processing of renal angiotensin II using mass spectrometry. Am J Physiol Cell Physiol. 2013; 304: C945-953.
  182. Reilly CF, Tewksbury DA, Schechter NM, Travis J. Rapid conversion of angiotensin I to angiotensin II by neutrophil and mast cell proteinases. J Biol Chem. 1982; 257: 8619-8622.
  183. Tonnesen MG, Klempner MS, Austen KF, Wintroub BU. Identification of a human neutrophil angiotension II-generating protease as cathepsin G. J Clin Invest. 1982; 69: 25-30.
  184. Owen CA, Campbell EJ. Angiotensin II generation at the cell surface of activated neutrophils: novel cathepsin G-mediated catalytic activity that is resistant to inhibition. J Immunol. 1998; 160: 1436-1443.
  185. Grisé C, Boucher R, Thibault G, Genest J. Formation of angiotensin II by tonin from partially purified human angiotensinogen. Can J Biochem. 1981; 59: 250-255.
  186. Bacani C, Frishman WH. Chymase: a new pharmacologic target in cardiovascular disease. Cardiol Rev. 2006; 14: 187-193.
  187. Huang XR, Chen WY, Truong LD, Lan HY. Chymase is upregulated in diabetic nephropathy: implications for an alternative pathway of angiotensin II-mediated diabetic renal and vascular disease. J Am Soc Nephrol. 2003; 14: 1738-1747.
  188. Nishimoto M, Takai S, Kim S, Jin D, Yuda A, Sakaguchi M, et al. Significance of chymase-dependent angiotensin II-forming pathway in the development of vascular proliferation. Circulation. 2001; 104: 1274-1279.
  189. Jin D, Takai S, Yamada M, Sakaguchi M, Miyazaki M. Beneficial effects of cardiac chymase inhibition during the acute phase of myocardial infarction. Life Sci. 2002; 71: 437-446.
  190. Re R, Bryan SE. Functional intracellular renin-angiotensin systems may exist in multiple tissues. Clin Exp Hypertens A. 1984; 6: 1739-1742.
  191. Baker KM, Chernin MI, Schreiber T, Sanghi S, Haiderzaidi S, Booz GW, et al. Evidence of a novel intracrine mechanism in angiotensin II-induced cardiac hypertrophy. Regul Pept. 2004; 120: 5-13.
  192. Carey RM. Functional intracellular renin-angiotensin systems: potential for pathophysiology of disease. Am J Physiol Regul Integr Comp Physiol. 2012; 302: R479-481.
  193. Cook JL, Re RN. Lessons from in vitro studies and a related intracellular angiotensin II transgenic mouse model. Am J Physiol Regul Integr Comp Physiol. 2012; 302: R482-493.
  194. Kumar R, Boim MA. Diversity of pathways for intracellular angiotensin II synthesis. Curr Opin Nephrol Hypertens. 2009; 18: 33-39.
  195. Kumar R, Singh VP, Baker KM. The intracellular renin-angiotensin system: a new paradigm. Trends Endocrinol Metab. 2007; 18: 208-214.
  196. Re RN, Cook JL. The intracrine hypothesis: an update. Regul Pept. 2006; 133: 1-9.
  197. De Mello WC. Novel aspects of angiotensin II action in the heart. Implications to myocardial ischemia and heart failure. Regul Pept. 2011; 166: 9-14.
  198. Re RN, Cook JL. Noncanonical intracrine action. J Am Soc Hypertens. 2011; 5: 435-448.
  199. Navar LG, Harrison-Bernard LM, Nishiyama A, Kobori H. Regulation of intrarenal angiotensin II in hypertension. Hypertension. 2002; 39: 316-322.
  200. Redding KM, Chen BL, Singh A, Re RN, Navar LG, Seth DM, et al. Transgenic mice expressing an intracellular fluorescent fusion of angiotensin II demonstrate renal thrombotic microangiopathy and elevated blood pressure. Am J Physiol Heart Circ Physiol. 2010; 298: H1807-1818.
  201. Li XC, Cook JL, Rubera I, Tauc M, Zhang F, Zhuo JL. Intrarenal transfer of an intracellular fluorescent fusion of angiotensin II selectively in proximal tubules increases blood pressure in rats and mice. Am J Physiol Renal Physiol. 2011; 300: F1076-1088.
  202. Tigerstedt R, Bergman PG. Niere und Kreislauf. Skand Arch Physiol. 1898; 8: 223–271.
  203. Nguyen G, Delarue F, Berrou J, Rondeau E, Sraer JD. Specific receptor binding of renin on human mesangial cells in culture increases plasminogen activator inhibitor-1 antigen. Kidney Int. 1996; 50: 1897-1903.
  204. Nguyen G, Contrepas A. Physiology and pharmacology of the (pro)renin receptor. Curr Opin Pharmacol. 2008; 8: 127-132.
  205. Gibson RE, Thorpe HH, Cartwright ME, Frank JD, Schorn TW, Bunting PB, et al. Angiotensin II receptor subtypes in renal cortex of rats and rhesus monkeys. Am J Physiol. 1991; 261: F512-518.
  206. McCarthy CA, Vinh A, Callaway JK, Widdop RE. Angiotensin AT2 receptor stimulation causes neuroprotection in a conscious rat model of stroke. Stroke. 2009; 40: 1482-1489.
  207. Steckelings UM, Larhed M, Hallberg A, Widdop RE, Jones ES, Wallinder C, et al. Non-peptide AT2-receptor agonists. Curr Opin Pharmacol. 2011; 11: 187-192.
  208. Gelosa P, Pignieri A, Fändriks L, de Gasparo M, Hallberg A, Banfi C, et al. Stimulation of AT2 receptor exerts beneficial effects in stroke-prone rats: focus on renal damage. J Hypertens. 2009; 27: 2444-2451.
  209. Jankowski V, Vanholder R, van der Giet M, Tölle M, Karadogan S, Gobom J, et al. Mass-spectrometric identification of a novel angiotensin peptide in human plasma. Arterioscler Thromb Vasc Biol. 2007; 27: 297-302.
  210. Schiavone MT, Santos RA, Brosnihan KB, Khosla MC, Ferrario CM. Release of vasopressin from the rat hypothalamo-neurohypophysial system by angiotensin-(1-7) heptapeptide. Proc Natl Acad Sci U S A. 1988; 85: 4095-4098.
  211. Speth RC, Brown TE, Barnes RD, Wright JW. Brain angiotensinergic activity: the state of our current knowledge. Proc West Pharmacol Soc. 2003; 46: 11-15.
  212. Dales NA, Gould AE, Brown JA, Calderwood EF, Guan B, Minor CA, et al. Substrate-based design of the first class of angiotensin-converting enzyme-related carboxypeptidase (ACE2) inhibitors. J Am Chem Soc. 2002; 124: 11852-11853.
  213. Hernández Prada JA, Ferreira AJ, Katovich MJ, Shenoy V, Qi Y, Santos RA, et al. Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents. Hypertension. 2008; 51: 1312-1317.
  214. Murça TM, Almeida TC, Raizada MK, Ferreira AJ. Chronic activation of endogenous angiotensin-converting enzyme 2 protects diabetic rats from cardiovascular autonomic dysfunction. Exp Physiol. 2012; 97: 699-709.
  215. Shenoy V, Gjymishka A, Jarajapu YP, Qi Y, Afzal A, Rigatto K, et al. Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models. Am J Respir Crit Care Med. 2013; 187: 648-657.

Cite this article: Speth RC, Giese MJ (2013) Update on the Renin-Angiotensin System. J Pharmacol Clin Toxicol 1(1): 1004.
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Current Issue Vol.1.1
Review Article
Update on the Renin-Angiotensin System
Robert C. Speth* and Michael J. Giese
Profile of Suspect Adverse Drug Reactions in a Teaching Tertiary Care Hospital
Shubhatara Swamy1, Bhanuprakash2, Pratibha Nadig1*, Muralimohan3 and Manjula Shetty1
Immunomodulatory Activity of DPP4
Mamgain S*, Mathur S and Kothiyal P
Research Article
Leptin Up-Regulates HECTD1 to Promote Phosphoinositide Metabolism and Cell Migration and Invasion in Breast Cancer Cells
Qiaodan Zheng1,2#, Xiang Li2#, Manjula Sunkara3, Andrew J. Morris3, Wenyuan Wu1* and Cai Huang2,4*
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