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Sepsis and septic shock are global healthcare problems associated with mortality rates of up to 40% despite optimal standard-of-care therapy and constitute the primary cause of death in intensive care units worldwide. Circulating biomarkers of septic shock severity may represent a clinically relevant approach to individualize those patients at risk for worse outcomes early in the course of the disease, which may facilitate early and more precise interventions to improve the clinical course. However, currently used septic shock biomarkers, including lactate, may be non-specific and have variable impact on prognosis and/or disease management. Activation of the renin-angiotensin-aldosterone system (RAAS) is likely an early event in septic shock, and studies suggest that an elevated level of renin, the early and committed step in the RAAS cascade, is a better predictor of worse outcomes in septic shock, including mortality, than the current standard-of-care measure of lactate. Despite a robust increase in renin, other elements of the RAAS, including endogenous levels of Ang II, may fail to sufficiently increase to maintain blood pressure, tissue perfusion, and protective immune responses in septic shock patients. We review the current clinical literature regarding the dysfunction of the RAAS in septic shock and potential therapeutic approaches to improve clinical outcomes. • We summarize clinical and experimental data on the possible dysfunction of the RAAS in septic shock. • RAAS dysfunction may reflect reduced ACE and Angiotensinogen but increased ACE2 and DPP3. • Septic shock may induce an imbalance in the RAAS with reduced Ang II but higher Ang-(1-7). • High circulating levels of active renin may be a predictor of disease severity in septic shock. [ABSTRACT FROM AUTHOR]

Pressure overload can result in significant changes to the structure of blood vessels, a process known as vascular remodeling. High levels of tension can cause vascular inflammation, fibrosis, and structural alterations to the vascular wall. Prior research from our team has demonstrated that the oral administration of alamandine can promote vasculoprotective effects in mice aorta that have undergone transverse aortic constriction (TAC). Furthermore, changes in local hemodynamics can affect the right and left carotid arteries differently after TAC. Thus, in this study, we aimed to assess the effects of alamandine treatment on right carotid remodeling and the expression of oxidative stress-related substances induced by TAC. Male C57BL/6 mice were categorized into three groups: Sham, TAC, and TAC treated with alamandine (TAC+ALA). Alamandine treatment was administered orally by gavage (30 µg/kg/day), starting three days before the surgery, and continuing for a period of fourteen days. Morphometric analysis of hematoxylin and eosin-stained sections revealed that TAC induced hypertrophic and positive remodeling in the right carotid artery. Picrosirius Red staining also demonstrated an increase in total collagen deposition in the right carotid artery due to TAC-induced vascular changes. Alamandine treatment effectively prevented the increase in reactive oxygen species production and depletion of nitric oxide levels, which were induced by TAC. Finally, alamandine treatment was also shown to prevent the increased expression of nuclear factor erythroid 2-related factor 2 and 3-nitrotyrosine that were induced by TAC. Our results suggest that alamandine can effectively attenuate pathophysiological stress in the right carotid artery of animals subjected to TAC. • Transverse aortic constriction (TAC) promotes a hypertrophic remodeling and oxidative stress in the right carotid of mice. • Alamandine prevents the rise of superoxide anion and the depletion of nitric oxide after TAC in the right carotid vascular wall. • Alamandine protects the right carotid from the exacerbation of oxidative stress, regulating NRF2 levels after TAC. [ABSTRACT FROM AUTHOR]

Highlights • Angiotensin II contractile responses are preserved in cirrhotic human splanchnic vessels. • Angiotensin II contractile responses of cirrhotic human splanchnic vessels are attenuated by angiotensin-(1–7). • Angiotensin II contractile responses of cirrhotic human splanchnic vessels are not augmented when AT2R is inhibited. Abstract Evidence suggests that the renin angiotensin system (RAS) may play a role in the pathological splanchnic vasodilatation that leads to a hyperdynamic circulation in cirrhosis. An impaired contractile response to the angiotensin II peptide of the classical RAS system has been described in animal models of cirrhosis and in vivo in cirrhotic subjects. Furthermore, in experimental cirrhosis, the so-called alternate arm of the RAS was found to be upregulated and its effector peptide, angiotensin-(1–7) was shown to attenuate splanchnic vascular tone. The aim of this study was to explore the relevance of these findings to human disease. Omental arteries from cirrhotic and controls subjects were studied in isolation using a wire myograph. Varied protocols to evaluate the vasoactivity of RAS mediators were enacted. The contractile response to angiotensin II was comparable in cirrhotic vs control splanchnic arteries (61 ± 9 vs 68 ± 11% KPSS, respectively). Despite this, however, arterial contractility of the cirrhotic vessels correlated negatively with Child Pugh score (p = 0.0003, r=-0.83) and there was evidence that angiotensin II-induced contractility was increased in early cirrhosis. Angiotensin II-induced contractility was attenuated by angiotensin-(1–7) in cirrhotic and control arteries, however, adrenergic responses were not affected by angiotensin-(1–7). Contractile responses to angiotensin II are preserved in narrow lumen human cirrhotic splanchnic arteries and are comparatively augmented in early disease. Angiotensin-(1–7) had no vasodilatory effect on adrenergic tone, however, attenuated angiotensin II-induced contractility, possibly through an Ang-(1–7)-AT1R interaction, and thus may contribute to pathological vasodilatation in human cirrhosis. [ABSTRACT FROM AUTHOR]

Sepsis is a serious syndrome, characterized by the excessive release of inflammatory mediators and thermoregulatory changes, being fever the most common sign. However, despite the importance of Angiotensin (Ang)-(1−7) in controlling the inflammation, the role of the peptide in the febrile response and mortality in animals submitted to experimental model of sepsis is still not clear. In this way, we evaluate the effect of continuous infusion of Ang-(1−7) in inflammatory response, thermoregulation and in mortality of Wistar male rats submitted to colonic ligation puncture (CLP). Before CLP surgery, the infusion pumps (Ang-(1−7), 1.5 mg/mL or saline) were inserted into the abdominal cavity and maintained for 24 h. CLP rats showed a febrile response starting from 3 h after and persisted until the 24th hour of experiment. Continuous treatment with Ang-(1−7) attenuated the febrile response and reestablished the euthermia 11 h after CLP, until the end of experiment, which coincided with an increased heat loss index (HLI). This effect was associated with a decrease in production of pro-inflammatory mediators in liver, white adipose tissue (WAT) and hypothalamus. Moreover, an increase in norepinephrine (NE) content in interscapular brown adipose tissue (iBAT) was observed in CLP animals, which was attenuated with treatment with Ang-(1−7), and decreased mortality in CLP animals treated with Ang-(1−7). Taken together, the present study demonstrates that continuous infusion treatment with Ang-(1−7) can promote a global anti-inflammatory effect, reestablishing the tail skin heat loss as a key thermo-effector function, resulting in an increased survival of animals submitted to experimental sepsis. • Treatment with Ang-(1−7) improves the survival of rats with polymicrobial sepsis. • Ang-(1−7) promotes neuroinflammation by peripheral inflammatory attenuation. • The thermoregulatory effect of Ang-(1−7) is independent of central PGE 2 production. • Ang-(1−7) controls fever via iBAT and tail vasculature modulating in septic animals. • Ang-(1−7) promotes direct action on the cutaneous vasculature of the tail. [ABSTRACT FROM AUTHOR]

Highlights • Genetic deletion of Angiotensin (1–7) receptor Mas promotes a reduced ovulatory outcome. • Knockout (Mas-KO) mice exhibit reduced follicularpool. • Mas receptor deletion promotes a lower IGF-1 expression in the ovary. Abstract Angiotensin-(1–7) [Ang-(1–7)] is a component of Renin-Angiotensin System (RAS) that acts through activation of the G-protein-coupled receptor Mas. Recent studies highlight Ang-(1–7) as an intermediate of gonadotropin in ovarian physiology. Genetically Mas-deficient mice allow the investigation of Ang-(1–7) in the ovulatory process. Therefore, the present study aimed to analyze the effects of Mas gene deletion on ovulation to confirm our hypothesis that Mas Knockout (Mas-KO) mice exhibit impairment in the ovulatory outcome. First, we evaluated the breeding data from our animal facilities and from a breeding experiment. The ovulation was observed directly from oviducts after a superovulation protocol and in the estrus morning. We also checked the follicular pool and mRNA expression of Insulin-like growth factor-1 (IGF-1) in ovaries to investigate a possible reason underlying the reduced ovulation. Mas-KO mice showed a reduced litter size and decreased spontaneous ovulatory rate. Ovarian stimulation by gonadotropins reversed ovulation outcome in Mas-KO mice. Mas deficiency also promoted a reduced ovarian follicular pool and lower IGF-1 mRNA levels, suggesting that Mas receptor plays a role in the survival of ovarian follicle. The reduction of ovulatory rate highlights the relevance of Ang-(1–7)/Mas axis in female reproduction, probably through a reduction of IGF-1 mRNA levels. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) involves a complex network of precursors, peptides, enzymes and receptors comprising a systemic (endocrine) and a local (paracrine/autocrine) system. The local RAS plays important roles in tissue modulation and may operate independently of or in close interaction with the circulatory RAS, acting in a complementary fashion. Angiotensin (Ang) II, its receptor AT 1 and Ang-(1-7) expression in the endometrium vary with menstrual cycle, and stromal cell decidualization in vitro is accompanied by local synthesis of angiotensinogen and prorenin. Mas receptor is unlikely to undergo marked changes accompanying the cyclic ovarian steroid hormone fluctuations. Studies investigating the functional relevance of the RAS in the non-gravid uterus show a number of paracrine effects beyond circulation and suggest that RAS peptides may be involved in the pathophysiology of proliferative and fibrotic diseases. Endometrial cancer is associated with increased expression of Ang II, Ang-converting enzyme 1 and AT 1 in the tumoral tissue compared to neighboring non-neoplastic endometrium, and also with a gene polymorphism that enhances AT 1 signal. Ang II induces human endometrial cells to transdifferentiate into cells with myofibroblast phenotype and to synthetize extracellular matrix components that might contribute to endometrial fibrosis. Altogether, these findings point to a fully operating RAS within the uterus, but since many concepts rely on preliminary evidence further studies are needed to clarify the role of the local RAS in uterine physiology and pathophysiology. [ABSTRACT FROM AUTHOR]

Hyperglycemia (HG) impairs the renin-angiotensin system (RAS), which may contribute to vascular dysfunction. Besides, hydrogen sulfide (H 2 S) exerts beneficial cardiovascular effects in metabolic diseases. Therefore, our study aimed to determine the effects of chronic administration of sodium hydrosulfide (NaHS; inorganic H 2 S donor) and DL-Propargylglycine [DL-PAG; cystathionine-ץ-lyase (CSE) inhibitor] on the RAS-mediated vascular responses impairments observed in thoracic aortas from male diabetic Wistar rats. For that purpose, neonatal rats were divided into two groups that received: 1) citrate buffer (n = 12) or 2) streptozotocin (STZ, 70 mg/kg; n = 48) on the third postnatal day. After 12 weeks, diabetic animals were divided into 4 subgroups (n = 12 each) that received daily i.p. injections during 4 weeks of: 1) non-treatment; 2) vehicle (PBS, 1 mL/kg); 3) NaHS (5.6 mg/kg); and 4) DL-PAG (10 mg/kg). After treatments (16 weeks), blood glucose, angiotensin-(1−7) [Ang-(1−7)], and angiotensin II (Ang II) levels, vascular responses to Ang-(1−7) and Ang II, and the expression of angiotensin AT 1 , AT 2 , and Mas receptors, angiotensin converting enzyme (ACE) and ACE type 2 (ACE2) were determined. HG induced: 1) increased blood glucose levels and expression of angiotensin II AT 1 receptor; 2) impaired Ang-(1−7) and Ang II mediated vascular responses; 3) decreased angiotensin levels and expression of angiotensin II AT 2 and angiotensin-(1−7) Mas receptors, and ACE2; and 4) no changes in ACE expression. Interestingly, NaHS, but not DL-PAG, reversed HG-induced impairments, except for blood glucose level changes. These results suggest that NaHS restores vascular function in streptozotocin-induced HG through RAS modulation. H 2 S improves vascular responses to Ang-(1−7) and Ang II impaired by HG. H 2 S restores Ang-(1−7) and Ang II serum levels during HG. H 2 S reestablishes ACE2 and angiotensin-(1−7) Mas receptor expression. H 2 S avoids changes in angiotensin II AT 1 and AT 2 receptors expression. [ABSTRACT FROM AUTHOR]

Background: Angiotensin-converting enzyme 2 (ACE2) plays a vital role in the pathogenesis of hypertension-induced cardiac remodeling and exhibits cardioprotective properties in hypertensive animal models. Evidence that ACE2 is an important regulator of hypertensive cardiac remodeling in humans has not been addressed directly yet. Methods: A total of 161 patients with essential hypertension and 47 age- and sex-matched normotensive healthy subjects were consecutively recruited. Serum concentration levels of ACE2 were determined by enzyme-linked immunosorbent assay. Cardiac structural and functional parameters were measured by echocardiography. Results: Serum ACE2 concentrations were higher in hypertensive patients compared to healthy subjects (170.31 [83.50-707.12] pg/ml in patients versus 59.28 [39.71-81.81] pg/ml in healthy subjects, P < 0.001). After adjustment for confounders, including age, sex, body mass index, snoring, smoking, duration of hypertension, comorbidities, medication use, mean arterial pressure and N-terminal pro-brain natriuretic peptide, serum ACE2 concentrations were positively correlated with left atrial diameter, left ventricular end-diastolic diameter and left ventricular mass in hypertensive patients. Moreover, multiple regression analyses adjusting for covariates revealed that serum ACE2 concentrations were also independently associated with left ventricular ejection fraction and late diastolic filling velocities of the mitral inflow. Conclusions: This study reveals an elevated serum concentration of ACE2 and independent associations between serum ACE2 and echocardiographic parameters in hypertensive patients. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system modulates insulin action. Angiotensin type 1 receptor exerts a deleterious effects while the angiotensin type 2 receptor (AT2R) appears to have beneficial effects providing protection against insulin resistance and type 2 diabetes. Although recent reports indicate that agonism of AT2R ameliorates diabetes and insulin resistance, the phenotype of AT2R-knockout mice seems to be controversial relating this aspect. Thus, in this study we have explored the role of AT2R in the control of insulin action. To that end, C57Bl/6 mice were administered the synthetic AT2R antagonist PD123319 for 21 days (10 mg/kg/day ip); vehicle treated animals were used as control. Glucose tolerance, metabolic parameters, in vivo insulin signaling in main insulin-target tissues as well as levels of adiponectin, TNF-α, MCP-1 and IL-6 in adipose tissue were assessed. AT2R blockade with PD123319 induced a marginal effect on glucose homeostasis but an important reduction in the insulin-induced phosphorylation of the insulin receptor and Akt in both liver and adipose tissue. Insulin signaling in skeletal muscle remained unaltered after treatment with PD123319, which could explain the minimal effect on glucose homeostasis induced by PD123319. Our current results reinforce the notion that the AT2R has a physiological role in the conservation of insulin action. [ABSTRACT FROM AUTHOR]

The renin-angiotensin-system is an important component of cardiovascular control and is up-regulated under various conditions, including hypertension and menopause. The aim of this study was to evaluate the effects of swimming training and estrogen therapy (ET) on angiotensin-II (ANG II)-induced vasoconstriction and angiotensin-(1-7) [ANG-(1-7)]-induced vasorelaxation in aortic rings from ovariectomized spontaneously hypertensive rats. Animals were divided into Sham (SH), Ovariectomized (OVX), Ovariectomized treated with E2 (OE2), Ovariectomized plus swimming (OSW) and Ovariectomized treated with E2 plus swimming (OE2 + SW) groups. ET entailed the administration of 5 μg of 17β-Estradiol three times per week. Swimming was undertaken for sixty minutes each day, five times per week. Both, training and ET were initiated seven days following ovariectomy. Forty-eight hours after the last treatment or training session, the animals’ systolic blood pressures were measured, and blood samples were collected to measure plasma ANG II and ANG-(1-7) levels via radioimmunoassay. In aortic rings, the vascular reactivity to ANG II and ANG-(1-7) was assessed. Expression of ANG-(1-7) in aortic wall was analyzed by immunohistochemistry. The results showed that both exercise and ET increased plasma ANG II levels despite attenuating systolic blood pressure. Ovariectomy increased constrictor responses to ANG II and decreased dilatory responses to ANG-(1-7), which were reversed by swimming independently of ET. Moreover, it was observed an apparent increase in ANG-(1-7) content in the aorta of the groups subjected to training and ET. Exercise training may play a cardioprotective role independently of ET and may be an alternative to ET in hypertensive postmenopausal women. [ABSTRACT FROM AUTHOR]

Accruing evidence have confirmed that the fetal programming in response to adverse environmental in utero factors plays essential roles in the pathogenesis of hypertension in later life. High sugar intake has been accepted worldwide in everyday life diet and becomes the critical public health issue. Our previous studies indicated that intake of high sucrose (HS) during pregnancy could change the vascular reactivity and dipsogenic behavior closely associated with abnormal renin-angiotensin system (RAS), to increase the risk of hypertension in adult offspring. In the present study, we tested the hypothesis that maternal HS intake in pregnancy may further deteriorate the Ang II-induced cardiovascular responses in the aged offspring. HS intake was provided to pregnant rats throughout the gestation. Blood pressure (BP) in conscious state and vascular contractility in vitro were measured in 22-month-old aged offspring rats. In addition, mRNA and protein expressions and epigenetic changes of Ang II type 1 receptor (AT 1 R) gene in blood vessels were determined with the methods of real-time RT-PCR, Western blotting, and Chromatin Immunoprecipitation Assay (CHIP). Results showed that, in the aged offspring, maternal HS intake during gestation would cause the elevation of basal BP which could be diminished by losartan. Although the circulatory Ang II was not changed, levels of local Ang II were significantly increased in blood vessels. In addition, prenatal HS exposure would significantly enhance the AT 1 R-mediated vasoconstrictions in both aorta and mesenteric arteries of the aged offspring. Moreover, in the aged offspring of prenatal HS exposure, mRNA and protein expressions of AT 1 R gene in both large and small blood vessels were significantly increased, which should be closely associated with the changes of epigenetic mechanisms such as histone modifications. Collectively, we proposed that maternal HS intake during gestation would cause abnormal BP responses mediated via the enhancement of vascular RAS, together with the increased expression of AT 1 R gene related to the its epigenetic changes, which would actually lead to the overt phenotype of hypertension in the aged offspring. [ABSTRACT FROM AUTHOR]

Angiotensin-(1-5) [Ang-(1-5)], which is a metabolite of Angiotensin-(1-7) [Ang-(1-7)] catalyzed by angiotensin-converting enzyme (ACE), is a pentapeptide of the renin-angiotensin system (RAS). It has been reported that Ang-(1-7) and Ang-(1-9) stimulate the secretion of atrial natriuretic peptide (ANP) via Mas receptor (Mas R) and Ang II type 2 receptor (AT 2 R), respectively. However, it still remains unknown whether Ang-(1-5) has a similar function to Ang-(1-7). We investigated the effect of Ang-(1-5) on ANP secretion and to define its signaling pathway using isolated perfused beating rat atria. Ang-(1-5) (0.3, 3, 10 μM) stimulated high pacing frequency-induced ANP secretion in a dose-dependent manner. Ang-(1-5)-induced ANP secretion (3 μM) was attenuated by the pretreatment with an antagonist of Mas R (A-779) but not by an antagonist of AT 1 R (losartan) or AT 2 R (PD123,319). An inhibitor for phosphatidylinositol 3-kinase (PI3K; wortmannin), protein kinase B (Akt; API-2), or nitric oxide synthase (NOS; L-NAME) also attenuated the augmentation of ANP secretion induced by Ang-(1-5). Ang-(1-5)-induced ANP secretion was markedly attenuated in isoproterenol-treated hypertrophied atria. The secretagogue effect of Ang-(1-5) on ANP secretion was similar to those induced by Ang-(1-9) and Ang-(1-7). These results suggest that Ang-(1-5) is an active mediator of renin-angiotensin system to stimulate ANP secretion via Mas R and PI3K-Akt-NOS pathway. [ABSTRACT FROM AUTHOR]

Previous studies have suggested that the Angiotensin-(1−7) [(Ang-(1−7)] can change cardiac function by modulating the autonomic nervous system. However, it is unknown whether the Ang-(1−7) can modulate the effect of acetylcholine (ACh) in ventricular contractility. Thus, this study aimed to investigate whether Ang-(1−7) modifies the amplitude of the cardiac cholinergic effects and if these effects are intrinsic to the heart. In anesthetized Wistar rats, Ang-(1−7) attenuated the effect of ACh in decreasing the left ventricular end-systolic pressure (LVESP), dP/dt max , and dP/dt min , but did not modify the hypotensive effect of ACh. Similarly, Ang-(1−7) attenuated the reduction of the LVESP, dP/dt max , and dP/dt min evoked by ACh in isolated hearts. These effects were blocked by the Mas receptor antagonist, A-779, but not by the adenylyl cyclase inhibitor MDL-12,330 A. Ang-(1−7) also attenuated the reduction in the maximum contraction and relaxation speeds and the shortening promoted by ACh in isolated cardiomyocytes. These data show that Ang-(1−7) acting through Mas receptor counter-regulates the myocardial contractile response to ACh in an arterial pressure and heart rate-independent manner. • Ang-(1−7) modulates the myocardial contractile response to ACh in anesthetized rats. • This effect was independent of changes in heart rate and blood pressure. • Ang-(1−7) also modulates the ACh effects in isolated hearts and cardiomyocytes. • The effect of Ang-(1−7) was mediated by the Mas receptor activation. [ABSTRACT FROM AUTHOR]

Studies have shown that the renin-angiotensin system (RAS) might play an essential role in intervertebral disc degeneration (IDD). The study aimed to investigate the relationship between serum angiotensin-converting enzyme (ACE) concentration and IDD and its predictive value for severe disc degeneration. 245 patients who came to our hospital for low back pain were recruited, and blood samples were collected for routine examination. Descriptive data and demographic parameters were collected. The cumulative grade 1 was calculated by summing up the Pfirrmann grade of all lumbar discs. ACE concentration grouping was determined via tertile split. Correlation analysis and multivariable linear regression analysis were performed to determine the relationship between ACE and IDD. The receiver's degree of disc degeneration (ROC) curve determined the ACE's predictive value. Results indicated that there was no significant difference in demographic parameters among groups. Correlation analysis and multivariate linear analysis showed that ACE was an independent risk factor for IDD. The cumulative grade 1 increased significantly with the increase in ACE concentration, which was consistent with the correlation analysis. Average Pfirrmann grade < 4 indicates mild to moderate degeneration, and grade ≥ 4 indicates severe degeneration in terms of an individual disc. From L1/2 to L5/S1, the mean plasma ACE concentration was significantly higher in the severe degeneration group than in the mild to moderate degeneration group. According to the ROC curve, the cut-off value of ACE levels was 22.5. patients with ACE > 22.5 had severe degeneration. The sensitivity and specificity were 0.762 and 0.521, respectively. • Local tissue renin-angiotensin system (tRAS) has been shown to exist in intervertebral disc tissue. • Tissue renin-angiotensin system (tRAS) was excessively activated in the human degenerated disc tissue. • The tissue renin-angiotensin system (tRAS) is composed of renin, angiotensin-converting enzyme (ACE), and angiotensinogen. • The serum ACE can be used to predict the disc degeneration severity, deepening its clinical significance. [ABSTRACT FROM AUTHOR]

Angiotensin (Ang) II, the main active member of the renin angiotensin system (RAS), is essential for the maintenance of cardiovascular homeostasis. However, hyperactivation of the RAS causes fibrotic diseases. Ang II has pro-inflammatory actions, and moreover activates interstitial fibroblasts and/or dysregulates extracellular matrix degradation. The discovery of new RAS pathways has revealed the complexity of this system. Among the RAS peptides, alamandine (ALA, Ala1 Ang 1–7) has been identified in humans, rats, and mice, with protective actions in different pathological conditions. ALA has similar effects to its well-known congener, Ang-(1–7), as a vasodilator, anti-inflammatory, and antifibrotic. Its protective role against cardiovascular diseases is well-reviewed in the literature. However, the protective actions of ALA in fibrotic conditions have been little explored. Therefore, in this article, we review the ability of ALA to modulate the inflammatory process and collagen deposition, to serve as an antioxidant, and to mediate protection against functional disorders. In this scenario, we also explore ALA as a promising therapy for pulmonary fibrosis after COVID-19 infection. • Pulmonary fibrosis (PF) is a restrictive disease with no cure. • The lack of effective treatment for PF results in high rates of mortality. • Alamandine (ALA) attenuates inflammation, oxidative stress, and collagen deposition. • ALA improves respiratory function in experimental PF. • Effects of ALA can improve the prognosis of patients with PF from several causes. [ABSTRACT FROM AUTHOR]

Aortic stiffness is an independent risk factor for development of cardiovascular diseases. Activation of renin-angiotensin-aldosterone system (RAAS) including angiotensin converting enzyme (ACE) activity leads to overproduction of angiotensin II (ANGII) from its precursor angiotensin I (ANGI). ANGII leads to overexpression and activation of matrix metalloproteinase-2 (MMP2), which is critically associated with pathophysiology of aortic stiffness. We previously reported that the whey peptide Isoleucine-Tryptophan (IW) acts as a potent ACE inhibitor. Herein, we critically elucidate the mechanism of action by which IW causes inhibition of expression and activity of MMP2 in aortic tissue. Effects of IW on expression and activity of MMP2 were assessed on endothelial and smooth muscle cells (ECs and SMCs) in vitro and ex vivo (isolated rat aorta). As controls we used the pharmaceutical ACE inhibitor – captopril and the ANGII type 1 receptor blocker – losartan. In vitro , both ANGII and ANGI stimulation significantly ( P < 0.01) increased expression of MMP2 assessed with western blot. Similarly, to captopril IW significantly ( P < 0.05) inhibited ANGI, but not ANGII mediated increase in expression of MMP2, while losartan also blocked effects of ANGII. Signaling pathways regulating MMP2 expression in ECs and SMCs were similarly inhibited after treatment with IW or captopril. In ECs IW significantly ( P < 0.05) inhibited JNK pathway, whereas in SMCs JAK2/STAT3 pathway, assessed with western blot. In vitro findings were fully consistent with results in isolated rat aorta ex vivo . Moreover, IW not only inhibited the MMP2 expression, but also its activation assessed with gelatin zymography. Our findings demonstrate that IW effectively inhibits expression and activation of MMP2 in rat aorta by decreasing local conversion of ANGI to ANGII. Thus, similar to pharmaceutical ACE inhibitor captopril the dipeptide IW may effectively inhibit ACE activity and prevent the age and hypertension associated rise of aortic stiffness. [ABSTRACT FROM AUTHOR]

Alamandine is a novel component of the renin-angiotensin system (RAS) as well as an important biologically active peptide. It has predominantly been studied in cardiovascular context. However, its role in rheumatoid arthritis (RA) remains unknown. Here we illustrated its effects on inflammatory cytokines production by synovial fibroblasts from RA and pathological changes in collagen-induced arthritis (CIA) mice. Alamandine (0.1, 1 and 10 µg/ml) did not affect the survival of the synovial fibroblasts, but decreased the migration and proinflammatory cytokines expression in TNF-α (10 ng/ml) stimulated cells in vitro. Additionally, alamandine selectively decreased phosphorylated-JNK expression induced by TNF-a stimulation in RA FLS. DBA/1 J mice were induced arthritis by a primary injection with an emulsion of bovine type II collagen (CII) and complete Freund's adjuvant (day 0) and a booster injection of CII in incomplete Freund's adjuvant (day 21). Mice were then given alamandine intraperitoneally in saline (50 μg/kg/day) from days 21–42. Histology and multiplex immunobead assay showed that alamandine treatment inhibited the development of arthritis and reduced the joint damage. This effect was accompanied by the reduced inflammatory cytokines (IL-6, IL-23, IFN-γ) mRNA expression in local joints, the decreased TNF-α, IL-6, IL-17 and the increased IL-10 levels in the serum from alamandine administrated CIA mice. In conclusion, alamandine attenuates the development of arthritis by suppressing inflammatory cytokines expression in RA synovial fibroblasts via MAPK signaling pathway, suggesting a potential therapeutic role for RA. • Alamandine is a novel component of the renin-angiotensin system as well as an important biologically active peptide • Alamandine suppresses proinflammatory cytokines production in rheumatoid arthritis synovial fibroblasts • Alamandine inhibits arthritis incidence in collagen-induced arthritis mice [ABSTRACT FROM AUTHOR]

Renin-angiotensin system (RAS) is an important factor in the pathophysiology of hypertension. Mas receptor, Angiotensin-(1–7) [Ang-(1–7)]-activated receptor, is an important RAS component and exerts protective effects in the vasculature. Ang-(1–7) vascular effects and Mas receptor expression in carotid from renovascular hypertensive (2K-1C) rats is not clear. In the present study we investigated Mas receptor vasodilator response activated by Ang-(1–7) in the carotid rings from sham and 2K-1C rats. Changes in isometric tension were recorded on organ chamber. Mas receptors expression was investigated in carotid by Western blot. Nitric oxide production was evaluated by 2,3-diaminonaphthalene (DAN) and eNOS expression and activity by immunofluoresce and western blot, respectively. Ang-(1–7) induced concentration-dependent vasodilator effect in carotid rings from sham and 2K-1C, which the hypertension increased vasodilatation response. In the 2K-1C carotid rings, A-779 (Mas receptor antagonist) reduced but not abolish the vasodilator effect of Ang-(1–7). Corroborating, Mas receptor protein expression was significantly increased in the 2K-1C rats. L -NAME and ibuprofen decreased Ang-(1–7) vasodilator response and L -NAME plus ibuprofen practically abolish the remaining vasodilatation response. Nitric oxide production is increased due increased of eNOS expression and p Ser 1177 activity. Our results demonstrated that renovascular hypertension increased Mas receptors expression and nitric oxide production in the rats carotid which, consequently increased Ang-(1–7)-vasorelaxant response. [ABSTRACT FROM AUTHOR]

A functional receptor for renin and prorenin ((P)RR) was identified as a new component of the renin–angiotensin system. The precise localization of (P)RR in the kidney has not been clarified. The present study was designed to determine the localization of (P)RR in the rat nephron and to investigate the regulation of renal (P)RR expression by high salt (HS) intake. (P)RR mRNA levels in the kidney sections and isolated nephron segments were examined using reverse transcription and polymerase chain reaction (RT-PCR), and (P)RR protein levels were examined by immunoblot and immunohistochemical analyses. Renal (P)RR mRNA and protein levels in rats fed a HS diet for 4 weeks were also compared with those fed a normal salt diet. (P)RR mRNA was expressed in various nephron segments of the cortex and medulla; glomeruli (Glm), proximal tubules (PT), thick ascending limbs (TAL) and collecting ducts (CD). (P)RR protein was highly expressed in the PT, medullary TAL (MTAL) and inner medullary CD (IMCD), and lowly in the preglomerular arterioles (Art) and Glm. HS intake increased (P)RR protein levels in the Glm, PT and tubules of medullary rays. These results indicated that (P)RR is expressed throughout various nephron segments and Art, and that (P)RR protein is expressed predominantly in the PT, MTAL and IMCD. HS intake appears to upregulate the (P)RR expression in the Glm, PT and tubules of medullary rays, suggesting that (P)RR may be involved in the regulation of renal function and HS-induced disorders. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) is now recognized as an important modulator of body metabolic processes. The discovery of angiotensin-converting enzyme 2 (ACE2) has renewed interest in the potential therapeutic role of RAS modulation. Recent studies have pointed out the importance of the local balance between ACE/Ang-II/AT1 and ACE2/Ang-(1-7)/Mas arms to avoid liver metabolic diseases. Furthermore, non-alcoholic fatty liver disease is an increasing health problem that includes a spectrum of hepatic steatosis, steatohepatitis and fibrosis. Some new studies revealed that RAS imbalance appears to promote hepatic fibrogenesis; while the activation of ACE2/Ang-(1-7)/Mas counter-regulatory axis is able to prevent liver injuries. In this context, the aim of the present review is to discuss the importance of RAS in the development and prevention of liver disease. AT1 receptor activation by Ang II induces hepatic stellate cell contraction and proliferation, causes oxidative stress, endothelial dysfunction, cell growth and inflammation. In addition, both AT1 blocker administration and ACE inhibitors lead to a reduction in inflammation and improvement of hepatic fibrosis. Conversely, Ang-(1-7) infusion reduces fibrosis and proliferation mainly by suppression of hepatic stellate cell activation; Mas receptor antagonism aggravates liver fibrosis and severe liver steatosis. In conclusion, the use of ACE/Ang II/AT1 axis inhibitors associated with ACE2/Ang(1-7)/Mas axis activation is a promising new strategy serving as a novel therapeutic regimen to prevent and treat chronic liver diseases as well as acute liver injury. [ABSTRACT FROM AUTHOR]

Prolylcarboxypeptidase (PRCP), an endothelial cell membrane serine peptidase that inactivates angiotensin II and activates pre-kallikrein, is thought to have anti-hypertensive and anti-proliferative roles in cardiovascular homeostasis. We hypothesized that PRCP function may be altered in heart tissue under conditions that predispose to left ventricle hypertrophy (LVH) in rats. We therefore used real-time PCR and western-blotting to examine the mRNA and protein expression of PRCP in the hearts of spontaneously hypertensive rats (SHR) at pre-hypertensive (5-week-old) and hypertensive (16-week-old) stages compared with age-matched hypertensive (2 kidney-1 clip; 2K-1C) rats and normotensive Wistar rats. PRCP mRNA expression was significantly reduced in hearts of 5- and 16-week-old SHR compared with age-matched Wistar controls, 2K-1C hypertensive rats and sham-operated normotensive rats. There were no significant differences in the PRCP mRNA and protein expression levels in hearts from hypertensive renovascular and sham-operated normotensive rats. Prolonged treatment of SHR with the AT 1 receptor antagonist losartan (40 mg/kg, gavage for 8 weeks) reduced the left ventricular weight/body weight ratio (LVW/BW), as well as the mRNA expression of collagen type 1, collagen type 3 and MMP9 in left ventricular tissue, without affecting PRCP gene and protein expression. Our results suggest that diminished PRCP gene and protein expression might be constitutionally involved in the SHR phenotype. In addition, since neither the development of arterial hypertension in the 2K-1C model nor its successful treatment in SHR altered PRCP gene and protein expression in heart tissue, it appears unlikely that PRCP function is regulated by the renin–angiotensin system or by afterload conditions. [ABSTRACT FROM AUTHOR]

Angiotensin-(1–7) has been described as a new potential therapeutic tool for the treatment and prevention of metabolic disorders by regulating several pathways in visceral white adipose tissue (vWAT). The aim of this study was to access the proteins differentially regulated by Ang-(1–7) using proteomic analysis of visceral adipose tissue. Male mice were divided into three groups and fed for 60 days, with each group receiving one of the following diets: standard diet + HPβCD (ST), high fat diet + HPβCD (HFD) and high fat diet + Ang-(1–7)/HPβCD (HFD + Ang-(1–7)). Body weight, fat weight and food intake were measured. At the end of treatment, Ang-(1–7) induced a decrease in body and fat weight. Differential proteomic analysis using two-dimensional electrophoresis (2-DE) combined with mass spectrometry were performed. Results of protein mapping of mesenteric adipose tissue using 2-DE revealed the presence of about 450 spots in each gel ( n = 3/treatment) with great reproducibility (>70%). Image analysis and further statistical analysis allowed the detection and identification of eight proteins whose expression was modulated in response to HFD when compared to ST. Among these, two proteins showed a sensitive response to Ang-(1–7) treatment (eno1 and aldehyde dehydrogenase). In addition, three proteins were expressed statistically different between HFD + Ang-(1–7) and HFD groups, and four proteins were modulated compared to standard diet. In conclusion, comparative proteomic analysis of a mice model of diet-induced obesity allowed us to outline possible pathways involved in the response to Ang-(1–7), suggesting that Ang-(1–7) may be a useful tool for the treatment of metabolic disorders. [ABSTRACT FROM AUTHOR]

Angiotensin-(1−7) is a biologically active product of the renin-angiotensin system cascade and exerts inhibitory effects on inflammation, vascular and cellular growth mechanisms signaling through the G protein-coupled Mas receptor. The major purpose of the present study was to investigate the use of glucose and fatty acids by cardiac tissue in Mas knockout mice models. Serum levels of glucose, lipids, and insulin were measured in Mas -deficient and wild-type FVB/N mice. To investigate the cardiac use of lipids, the lipoprotein lipase, the gene expression of peroxisome proliferator-activated receptor alpha; carnitine palmitoyltransferase I and acyl-CoA oxidase were evaluated. To investigate the cardiac use of glucose, the insulin signaling through Akt/GLUT4 pathway, glucose-6-phosphate (G-6-P) and fructose-6-phosphate (F-6-P) glycolytic intermediates, in addition to ATP, lactate and the glycogen content were measured. Despite normal body weight, cholesterol and insulin, Mas -Knockout mice presented hyperglycemia and hypertriglyceridemia, impaired insulin signaling, through reduced phosphorylation of AKT and decreased translocation of GLUT4 in response to insulin, with subsequent decrease of the cardiac G-6-P and F-6-P. Lactate production and glycogen content were not altered in Mas -KO hearts. Mas -KO presented reduced cardiac lipoprotein lipase activity and decreased translocation of CD36 in response to insulin. The expression of peroxisome proliferator-activated receptor alpha and carnitine palmitoyltransferase I genes were lower in Mas -KO animals compared to wild-type animals. The ATP content of Mas -KO hearts was smaller than in wild-type. The present results suggest that genetic deletion of Mas produced a devastating effect on cardiac use of glucose and lipids, leading to lower energy efficiency in the heart. • The renin-angiotensin system modulates the use of fatty acids and glucose cardiac. • Genetic deletion of the Mas receptor in mice decreases cardiac energy efficiency. • Genetic deletion of the Mas receptor inhibits insulin-induced Akt activation. • Mas -KO hearts present reduced LPL and expression of the CD36 at cardiac membrane. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme-2, or ACE2, is primarily a zinc-dependent peptidase and ectoenzyme expressed in numerous cell types and functioning as a counterbalance to ACE in the renin-angiotensin system. It was discovered 21 years ago more than 40 years after the discovery of ACE itself. Its primary physiological activity is believed to be in the conversion of angiotensin II to the vasodilatory angiotensin-(1−7) acting through the Mas receptor. As such it has been implicated in numerous pathological conditions, largely in a protective mode which has led to the search for ACE2 activatory mechanisms. ACE2 has a diverse substrate specificity allowing its participation in multiple peptide pathways. It also regulates aspects of amino acid transport through its homology with a membrane protein, collectrin. It also serves as a viral receptor for the SARS virus, and subsequently SARS-CoV2, driving the current COVID-19 pandemic. ACE2 therefore provides a therapeutic target for the treatment of COVID and understanding the biological events following viral binding can provide insight into the multiple pathologies caused by the virus, particularly inflammatory and vascular. In part this may relate to the ability of ACE2, like ACE, to be shed from the cell membrane. The shed form of ACE2 (sACE2) may be a factor in determining susceptibility to certain COVID pathologies. Hence, for just over 20 years, ACE2 has provided numerous surprises in the field of vasoactive peptides with, no doubt, more to come but it is its central role in COVID pathology that is producing the current intense interest in its biology. [Display omitted] • ACE2 is a multi-functional enzyme primarily metabolising regulatory peptides. • ACE2 counterbalances the actions of ACE through conversion of Ang II to Ang-(1−7). • ACE2 participates in intestinal amino acid transport. • ACE2 is the receptor for some coronaviruses, especially SARS-CoV-2. • ACE2 provides a key therapeutic target in the prevention and treatment of COVID-19. [ABSTRACT FROM AUTHOR]

Highlights: [•] Aging decreased Ang II and increased Ang 1-7 concentrations in Metabolic Syndrome rats. [•] Ang receptors in white adipose tissue (WAT) vary with MS during aging. [•] PPARγ levels decline with age in control rats but increase and remain high in MS. [•] Serum and WAT Ang 1-7 and adiponectin concentrations relate to PPARγ expression. [•] Ang 1-7/Mas is a target for therapeutical strategies in MS during aging. [ABSTRACT FROM AUTHOR]

Highlights: [•] Opiorphin induced an increase of mean arterial pressure in conscious rats. [•] Opiorphin evaluated the level of angiotensin II in serum. [•] Hypertension induced by opiorphin was inhibited by valsartan or captopril. [•] Opiorphin reversed hypotension induced by hypoxia. [Copyright &y& Elsevier]

Highlights: [•] Development of an orally active Ang(1–7) included compound and treatment of genetic hypertension. [•] HPB-CD/Ang-(1–7) reduces blood pressure and improves autonomic control in SHR. [•] HPB-CD/Ang-(1–7) decreases myocardium hypertrophy and improves cardiac function. [•] HPB-CD/Ang-(1–7) effects in the cardiovascular system are similar to exercise-training. [•] We report a potential therapeutic effect of the HPB-CD/Ang-(1–7) in hypertension. [ABSTRACT FROM AUTHOR]

Highlights: [•] Atenolol associated to Ang-(1–7) reduced cholesterol in SHR. [•] Atenolol associated to Ang-(1–7) improved the oral fat load tolerance in SHR. [•] Increased lipolytic response after association of Atenolol and Ang-(1–7). [Copyright &y& Elsevier]

Abstract: Angiotensin-(1-7) [Ang-(1-7)] is a new bioactive heptapeptide in the renin–angiotensin–aldosterone system (RAAS) with potent protective effects in cardiovascular diseases, opposing many actions of angiotensin II (Ang II) mediated by Ang II type 1 (AT1) receptor. It is produced mainly by the activity of angiotensin-converting enzyme 2 (ACE2) and acts through the Mas receptor. However, the role of Ang-(1-7) in vascular calcification (VC) is still unclear. In this study, we investigated the protective effects of Ang-(1-7) on VC in an in vivo rat VC model induced by vitamin D3 plus nicotine. The levels of ACE2 and the Mas receptor, as well as ACE, AT1 receptor, Ang II type 2 receptor and angiotensinogen, were significantly increased in calcified aortas, and Ang-(1-7) reversed the increased levels. Ang-(1-7) restored the reduced expression of lineage markers, including smooth muscle (SM) α-actin, SM22α, calponin and smoothelin, in vascular smooth muscle cells (VSMCs) and retarded the osteogenic transition of VSMCs by decreasing the expression of bone-associated proteins. It reduced alkaline phosphatase activity and calcium deposition in VC and alleviated the hemodynamic disorders of rats with VC. We provide the first in vivo evidence that Ang-(1-7) can inhibit the development of VC by inhibiting the osteogenic transition of VSMCs, at least in part by decreasing levels of the ACE/Ang II/AT1 axis. The increased expression of ACE2 and the Mas receptor in calcified aortas suggests the involvement of the ACE2/Ang-(1-7)/Mas axis during VC. Ang-(1-7) might be an efficient endogenous vasoprotective factor for VC. [Copyright &y& Elsevier]

Abstract: The renin–angiotensin system (RAS) is now regarded as an integral component in not only the development of hypertension, but also in physiologic and pathophysiologic mechanisms in multiple tissues and chronic disease states. While many of the endocrine (circulating), paracrine (cell-to-different cell) and autacrine (cell-to-same cell) effects of the RAS are believed to be mediated through the canonical extracellular RAS, a complete, independent and differentially regulated intracellular RAS (iRAS) has also been proposed. Angiotensinogen, the enzymes renin and angiotensin-converting enzyme (ACE) and the angiotensin peptides can all be synthesized and retained intracellularly. Angiotensin receptors (types I and 2) are also abundant intracellularly mainly at the nuclear and mitochondrial levels. The aim of this review is to focus on the most recent information concerning the subcellular localization, distribution and functions of the iRAS and to discuss the potential consequences of activation of the subcellular RAS on different organ systems. [Copyright &y& Elsevier]

Abstract: The renin–angiotensin system (RAS) is involved in the cardiac and vascular remodeling associated with cardiovascular diseases. Angiotensin (Ang) II/AT1 axis is known to promote cardiac hypertrophy and collagen deposition. In contrast, Ang-(1–7)/Mas axis opposes Ang II effects in the heart producing anti-trophic and anti-fibrotic effects. Exercise training is known to induce cardiac remodeling with physiological hypertrophy without fibrosis. We hypothesize that cardiac remodeling induced by chronic exercise depends on the action of Ang-(1–7)/Mas axis. Thus, we evaluated the effect of exercise training on collagen deposition and RAS components in the heart of FVB/N mice lacking Mas receptor (Mas-KO). Male wild-type and Mas-KO mice were subjected to a moderate-intense swimming exercise training for 6 weeks. The left ventricle (LV) of the animals was sectioned and submitted to qRT-PCR and histological analysis. Circulating and tissue angiotensin peptides were measured by RIA. Sedentary Mas-KO presented a higher circulating Ang II/Ang-(1–7) ratio and an increased ACE2 expression in the LV. Physical training induced in Mas-KO and WT a similar cardiac hypertrophy accompanied by a pronounced increase in collagen I and III mRNA expression. Trained Mas-KO and trained WT presented increased Ang-(1–7) in the blood. However, only in trained-WT there was an increase in Ang-(1–7) in the LV. In summary, we showed that deletion of Mas in FVB/N mice produced an unbalance in RAS equilibrium increasing Ang II/AT1 arm and inducing deleterious cardiac effects as deposition of extracellular matrix proteins. These data indicate that Ang-(1–7)/Mas axis is an important counter-regulatory mechanism in physical training mediate cardiac adaptations. [Copyright &y& Elsevier]

Abstract: The renin–angiotensin (Ang) system (RAS) plays an important role in the control of glucose metabolism and glycemia. Several studies demonstrated that the effects of angiotensin-(1-7) are mainly opposite to the actions of biological angiotensin II. Recent studies have demonstrated that rats with increased circulating angiotensin-(1-7), acting through the G protein coupled receptor Mas, have enhanced glucose tolerance and insulin sensitivity, presenting improved metabolic parameters. However, there is no data regarding the role of angiotensin-(1-7)–Mas axis in hepatic glycemic metabolism. In the present study, the gluconeogenesis and glycogenolysis was investigated in Sprague–Dawley (SD) and in TGR(A1-7)3292 (TGR) rats which present approximately twofold increase in plasma Ang-(1-7) levels compared to SD. The pyruvate administration in fasted rats showed a decreased synthesis of glucose in TGR compared to the SD rats, pointing to a downregulation of gluconeogenesis. Supporting this data, the mRNA evaluation of gluconeogenic enzymes showed a significant reduction in phosphoenolpyruvate carboxykinase reinforced by a significantly diminished expression of hepatocyte nuclear factor 4α (HNF-4α), responsible for the regulation of gluconeogenic enzymes. In conclusion our data show that the improved glucose metabolism induced by Ang-(1-7) could be due, at least in part, to a downregulation of hepatic gluconeogenesis. [Copyright &y& Elsevier]

Abstract: The renin–angiotensin system is known to enhance erythropoiesis. (Pro)renin receptor ((P)RR), a specific receptor for renin and prorenin, has recently been identified. However, expression of (P)RR in erythroid cells has not been studied. The aim of the present study is to clarify expression of (P)RR in erythroid cells, and the effects of erythropoietin, angiotensin II, transforming growth factor-β1 (TGF-β1), interferon-γ (IFN-γ) and interleukin-1β (IL-1β) on its expression. Western blot analysis showed that (P)RR protein was expressed in human cultured erythroid cell lines, YN-1 and YN-1-0-A (a clonal variant cell line of YN-1). Erythropoietin (1IU/ml) increased (P)RR mRNA expression levels in YN-1-0-A cells (1.7-fold increase compared with control), but angiotensin II did not. Treatment of YN-1-0-A cells with IFN-γ (10ng/ml) for 48h increased the expression levels of (P)RR protein significantly (1.4-fold increase compared with control), whereas it had no significant effects on expression levels of (P)RR mRNA. Treatment of YN-1-0-A cells with TGF-β1 or IL-1β for 24 or 48h had no significant effects on expression levels of (P)RR. The present study has shown for the first time expression of (P)RR in erythroid cells, raising the possibility that (P)RR may have a role in erythropoiesis and the pathophysiology of certain types of anemia. [Copyright &y& Elsevier]

Abstract: In the present review we examine the experimental and clinical evidence for the presence of a local renin–angiotensin system within the retina. Interest in a pathogenic role for the renin–angiotensin system in retinal disease originally stemmed from observations that components of the pathway were elevated in retina during the development of certain retinal pathologies. Since then, our knowledge about the contribution of the RAS to retinal disease has greatly expanded. We discuss the known functions of the renin–angiotensin system in retinopathy of prematurity and diabetic retinopathy. This includes the promotion of retinal neovascularization, inflammation, oxidative stress and neuronal and glial dysfunction. The contribution of specific components of the renin–angiotensin system is evaluated with a particular focus on angiotensin II and aldosterone and their cognate receptors. The therapeutic utility of inhibiting key components of the renin–angiotensin system is complex, but may hold promise for the prevention and improvement of vision threatening diseases. [Copyright &y& Elsevier]

Abstract: The Mas protooncogene encodes a G protein-coupled receptor that has been described as a functional receptor for the cardioprotective fragment of the renin-angiotensin system (RAS), Angiotensin (Ang)-(1-7). The aim of this current study was to evaluate the responsiveness of Mas expression in hearts during different physiological and pathological conditions in rats. Physical training was considered a physiological condition, while isoproterenol-induced hypertrophy, myocardial infarction and DOCA-salt model of hypertension were used as pathological models of heart injury. The expression of Mas was analyzed by western blotting. Although swim-trained rats presented significant cardiac hypertrophy, our physical training protocol was unable to induce changes in the expression of Mas. On the other hand, cardiac hypertrophy and damage elicited by isoproterenol treatment led to a reduction in Mas expression. Myocardial infarction also significantly decreased the expression of Mas after 21 days of myocardial ischemia. Additionally, Mas expression levels were increased in hearts of DOCA-salt rats. Our present data indicate that Mas expression is responsive to different pathological stimuli, thereby suggesting that Mas receptor is involved in the homeostasis of the heart, as well as in the establishment and progression of cardiac diseases. [Copyright &y& Elsevier]

Abstract: In the adrenal gland all components of the renin–angiotensin system (RAS) are expressed in both the adrenal cortex and the adrenal medulla. In this review evidence shall be presented that a local secretory RAS exists in the adrenal cortex that stimulates aldosterone production and serves as an amplification system for circulating angiotensin (ANG) II. The regulation of the secretory adrenal RAS clearly differs from the regulation of the circulatory RAS in terms of renin expression as well as of renin secretion. For example under potassium load the activity of the renal and circulatory RAS is suppressed whereas the activity of the adrenal RAS is stimulated. Thus the activity of the adrenal RAS but not of the circulating RAS correlates well with the regulation of aldosterone production by potassium. The present review also summarizes the knowledge about the expression and functions of an additional renin transcript that has recently been discovered. This transcript encodes for a non-secretory cytosolic renin isoform. The cytosolic renin may be a basis for the existence of an intracellular renin system in the adrenal gland that has long been proposed. The present state of knowledge shall be discussed indicating that such an intracellular system modulates cell survival and cell death such as apoptosis and necrosis or cell functions such as aldosterone production. [Copyright &y& Elsevier]

Abstract: The renin–angiotensin system is an important link between metabolic syndrome and cardiovascular diseases. Besides angiotensin II, other angiotensin peptides such as angiotensin-(1–7), have important biological activities. It has been demonstrated that angiotensin-(1–7), acting through the G protein-coupled receptor encoded by the Mas protooncogene have important actions on the cardiovascular system. However, the role of angiotensin-(1–7)-Mas axis in lipidic profile is not well established. In the present study, the adipocyte metabolism was investigated in wild type and FVB/N Mas-deficient male mice. The gene expression of peroxisome proliferator-activated receptor gamma, acetyl-CoA carboxylase and the amount of fatty acid synthase protein were reduced in the Mas-knockout mice. Serum nonesterified fatty acids of Mas-knockout showed a 50% increase in relation to wild type group. Basal and isoproterenol-stimulated lipolysis was similar between the groups, however, a significant decrease of the glycerol release (lipolytic index) in response to insulin was observed in wild type animals, while no effect of the insulin action was observed in a Mas-knockout group. The data suggest that the lack of angiotensin-(1–7) action through Mas receptor alters the response of adipocytes to insulin action. These effects might be related to decreased expression of PPARγ. [Copyright &y& Elsevier]

Abstract: The renin–angiotensin system (RAS), critically involved in the control of blood pressure and volume homeostasis, is a dual system comprising a circulating component and a local tissue component. The rate limiting enzyme is renin, which in the circulating RAS derives from the kidney to generate Ang II, which in turn regulates cardiovascular function by binding to AT1 and AT2 receptors on cardiac, renal and vascular cells. The tissue RAS can operate independently of the circulating RAS and may be activated even when the circulating RAS is suppressed or normal. A functional tissue RAS has been identified in brain, kidney, heart, adipose tissue, hematopoietic tissue, gastrointestinal tract, liver, endocrine system and blood vessels. Whereas angiotensinsinogen, angiotensin converting enzyme (ACE), Ang I and Ang II are synthesized within these tissues, there is still controversy as to whether renin is produced locally or whether it is taken up from the circulation, possibly by the (pro)renin receptor. This is particularly true in the vascular wall, where expression of renin is very low. The exact function of the vascular RAS remains elusive, but may contribute to fine-tuning of vascular tone and arterial structure and may amplify vascular effects of the circulating RAS, particularly in pathological conditions, such as in hypertension, atherosclerosis and diabetes. New concepts relating to the vascular RAS have recently been elucidated including: (1) the presence of functionally active Ang-(1-7)-Mas axis in the vascular system, (2) the importance of the RAS in perivascular adipose tissue and cross talk with vessels, and (3) the contribution to vascular RAS of Ang II derived from immune and inflammatory cells within the vascular wall. The present review highlights recent progress in the RAS field, focusing on the tissue system and particularly on the vascular RAS. [Copyright &y& Elsevier]

Abstract: In the present review we reevaluated the experimental and clinical evidence that there is a local renin angiotensin system in the heart as well as the presence of a functional intracrine component which is activated during pathological conditions like heart failure and hypertension. The implications of these findings for cardiology were discussed. The novel finding that cell swelling impairs cell coupling and impulse propagation through activation of ionic channels with consequent generation of cardiac arrhythmias and the evidence that AT1 receptors are mechanosensors able to alter the heart function independently of Ang II were discussed. Particular attention was given to the role of salt loading on the activation of a local cardiac renin angiotensin and its consequences. [Copyright &y& Elsevier]

Abstract: Although renin, the rate-limiting enzyme of the renin-angiotensin system (RAS), was first discovered by Robert Tigerstedt and Bergman more than a century ago, the research on the RAS still remains stronger than ever. The RAS, once considered to be an endocrine system, is now widely recognized as dual (circulating and local/tissue) or multiple hormonal systems (endocrine, paracrine and intracrine). In addition to the classical renin/angiotensin I-converting enzyme (ACE)/angiotensin II (Ang II)/Ang II receptor (AT1/AT2) axis, the prorenin/(Pro)renin receptor (PRR)/MAP kinase axis, the ACE2/Ang (1–7)/Mas receptor axis, and the Ang IV/AT4/insulin-regulated aminopeptidase (IRAP) axis have recently been discovered. Furthermore, the roles of the evolving RAS have been extended far beyond blood pressure control, aldosterone synthesis, and body fluid and electrolyte homeostasis. Indeed, novel actions and underlying signaling mechanisms for each member of the RAS in physiology and diseases are continuously uncovered. However, many challenges still remain in the RAS research field despite of more than one century''s research effort. It is expected that the research on the expanded RAS will continue to play a prominent role in cardiovascular, renal and hypertension research. The purpose of this article is to review the progress recently being made in the RAS research, with special emphasis on the local RAS in the kidney and the newly discovered prorenin/PRR/MAP kinase axis, the ACE2/Ang (1–7)/Mas receptor axis, the Ang IV/AT4/IRAP axis, and intracrine/intracellular Ang II. The improved knowledge of the expanded RAS will help us better understand how the classical renin/ACE/Ang II/AT1 receptor axis, extracellular and/or intracellular origin, interacts with other novel RAS axes to regulate blood pressure and cardiovascular and kidney function in both physiological and diseased states. [Copyright &y& Elsevier]

Abstract: The ancient renin–angiotensin system (RAS) was discovered more than a hundred years ago by identifying the rate-limiting enzyme of the system and its relevance to blood pressure regulation. Forty years ago, Detlev Ganten et al. postulated the existence of a tissue RAS. In these forty years, he kept developing the knowledge of these systems either directly or by training or attracting the interest of many researchers. Through the present review, we try to highlight recent advancements that originated from the postulation of local brain RAS. Although a large amount of knowledge accumulated, this system continues to intrigue and stimulate the interest and imagination of many researchers. [Copyright &y& Elsevier]

Abstract: The traditional renin–angiotensin system (RAS) components have been studied extensively since the rate-limiting component of RAS, renin, was first characterized. The ongoing identification of various novel RAS components and signaling pathways continues to elaborate the complexity of this system. Regulation of RAS according to the conventional and contemporary views of its functions in various tissues under pathophysiological conditions is a main treatment strategy for many metabolic diseases. The local pancreatic RAS, first proposed to exist in pancreatic islets two decades ago, could regulate islet function and glycemic control via influences on islet cell mass, inflammation, and ion channels. Insulin secretion, the major function of pancreatic islets, is controlled by numerous factors. Among these factors and of particular interest are glucagon-like peptide-1 (GLP-1) and vitamin D, which may regulate islet function by directly binding receptors on islet beta cells. These factors may work with local RAS signaling in islets to protect and maintain islet function under diabetic and hyperglycemic conditions. In this concise review, the local islet RAS will be discussed with particular attention being paid to recent notable findings. [Copyright &y& Elsevier]

Abstract: Gap junction channels facilitate chemical and electrical communication between adjacent cells. Gap junction protein, connexin (Cx), is expressed in the endothelial cells of vessels, glomerulus, and renin-secreting cells of the kidney. The purpose of this study was to investigate the role of Cx in renin release using Cx-overexpressing As 4.1 cells. The adenovirus-induced Cx overexpression was conducted by using recombinant adenovirus containing the cDNA encoding Cx37, Cx40, Cx43 (Ad-Cx), and β-galactosidase (Ad-β-gal). In 40-overexpressing cells, basal renin release increased in a time-dependent manner but it was significantly lower than that in Ad-β-gal-treated cells. In Cx37- and Cx43-overexpressing cells, basal renin release was increased in a time-dependent manner, which was not different from control cells. 18-β glycyrrhetinic acid (GA), a gap junction blocker, stimulated renin release dose-dependently and increased intracellular Ca2+ in both Cx43-overexpressing cells and control cells. However, no significant differences were observed. An increase in renin release by 3,4,5-trimethoxybenzoic acid 8-(diethylamino)-octyl ester, a putative antagonist of Ca2+ release from intracellular sequestration sites, was also similar between two groups. These results suggest that Cx43 may unlikely alter the regulation of renin release and intracellular Ca2+ by gap junction blocker in As 4.1 cells. [Copyright &y& Elsevier]

Abstract: The renin–angiotensin system (RAS) is an essential regulator of the blood pressure and body fluid balance, but the processing cascade or role of the tissue RAS remains obscure. Proangiotensin-12 (proang-12), a novel angiotensin peptide recently discovered in rat tissues, is assumed to function as a factor of the tissue RAS. To investigate the tissue production of proang-12, we measured the circulating and tissue components of the RAS including proang-12 following low-, normal-, or high-salt feeding in rats. Twelve-week-old male Wistar rats were fed a low-salt 0.3% NaCl or high-salt 8% NaCl diet for 7 days and compared with those fed a normal-salt diet of 0.7% NaCl. Low-salt feeding elevated the plasma renin activity and aldosterone concentration, resulting in significant increases in Ang I and Ang II levels in the plasma or kidney tissue, as compared with the normal- or high-salt group. Despite the increases in plasma renin activity, Ang I, and Ang II, the proang-12 levels in plasma and various tissues including the kidneys, small intestine, cardiac ventricles, and brain remained unchanged following low-salt feeding. These results suggest that peptide levels of proang-12 in rat plasma and tissues are regulated in a manner independent of the circulating RAS. [Copyright &y& Elsevier]

Abstract: Recent studies have revealed that (pro)renin receptor ((P)RR), a newly identified member of the renin–angiotensin system, was associated with organ damage in the kidney. However, there has been little information for (P)RR in hearts. To investigate the regulation of (P)RR in heart failure, we examined the expression of (P)RR in hearts and kidneys of rats with congestive heart failure (CHF) due to coronary ligation by quantitative RT-PCR and immunohistochemistry. Significantly increased levels of (P)RR mRNA were found in the atrium, right ventricle, non-infarcted part of left ventricle, infarcted part of left ventricle and kidney of CHF rats, when compared with sham operated rats (about 1.6-fold, 1.4-fold, 1.6-fold, 1.7-fold and 1.5-fold, respectively). Expression levels of mRNAs encoding renin and angiotensinogen in these heart and kidney tissues were also increased in the CHF rats. Immunohistochemistry showed positive (P)RR immunostaining in the myocardium, the renal tubular cells, and vascular smooth muscle and endothelial cells in the heart and the kidney. The renal tubular cells were more intensely immunostained in CHF rats than in sham operated rats. These findings suggest that the expression of (P)RR is increased in the hearts and kidneys of rats with heart failure, and that (P)RR may contribute to heart failure. [Copyright &y& Elsevier]

Abstract: Two research groups in both North and South America independently discovered that renin released a novel vasopressor agent. The Argentine group named it hypertensin, and called its plasma protein substrate hypertensinogen. The group from the United States named it angiotonin. In 1958, Braun Menendez and Irvine Page suggested that the peptide should be named angiotensin. The combined name eventually became commonly used to avoid linguistic confusion. Research scientists and physicians today acknowledge that studies of the renin–angiotensin system (RAS) have greatly improved our understanding of several diseases. Certainly, medical practice profited significantly from the synthesis and application of numerous pharmacological agents that antagonize either the biosynthesis or pharmacological responses of endogenously generated angiotensin II. Ultimately, discovery of the renin–angiotensin system led to many studies that resulted in therapies for vascular disease. This article briefly reviews research related to the discovery of angiotensin and indicates the importance of additional studies related to the RAS. [Copyright &y& Elsevier]

Abstract: Angiotensin 1–7 is a bioactive heptapeptide of the renin–angiotensin system. Its cardiovascular actions have recently acquired growing relevance, mainly due to its counter-regulatory actions in the angiotensin cascade. The aim of the present study was to evaluate the actions of angiotensin 1–7 on myocardial function. Increasing concentrations of angiotensin 1–7 (10−9 to 10−5 M) were added to rabbit right papillary muscles: (1) in baseline conditions with intact endocardial endothelium (EE); (2) after selective removal of the EE with Triton X-100 (1s, 0.01%); (3) with intact EE in the presence of the Mas receptor antagonist A-779, the AT1 receptor antagonist ZD-7155, the AT2 receptor antagonist PD-123,319 or the nitric oxide synthesis inhibitor NG-nitro-l-arginine (l-NA). Concerning the effects on contractility, we observed a significant decrease on active tension, dT/dt max, peak shortening and dL/dt max of −10.5±3.6%, −8.0±3.0%, −5.3±2.6% and −5.7±2.3%, respectively. There was no change on relaxation parameters, namely dT/dt min or dL/dt min. Time to half relaxation was significantly decreased. The presence of ZD-7155 or PD-123,319 did not change these effects. However, angiotensin 1–7 effects on myocardial properties were abolished after selective EE removal and in the presence of A-779 or l-NA. In conclusion, in this animal species, angiotensin 1–7 through its binding to Mas receptor induces a negative inotropic effect modulated by the EE and nitric oxide and independent of AT1 or AT2 receptors activation. As the effects described in the present work were influenced by the endocardial endothelium, they may be disrupted in situations associated to endothelial dysfunction, as in heart failure or myocardial ischemia. [Copyright &y& Elsevier]

Abstract: The incidence of chronic kidney disease, such as diabetic nephropathy, is increasing throughout the world. Many biologically active peptides play important roles in the kidney. The classical example is the renin–angiotensin system (RAS). Angiotensin II plays critical roles in the progression of chronic kidney disease through its vasoconstrictor action, stimulatory action on cell proliferation, and reactive oxygen-generating activity. A renin inhibitor, aliskiren, has recently been shown to be a clinically effective drug to reduce proteinuria in patients with diabetic nephropathy. (Pro)renin receptor, a specific receptor for renin and prorenin, was newly identified as a member of the RAS. When bound to prorenin, (pro)renin receptor activates the angiotensin I-generating activity of prorenin in the absence of cleavage of the prosegment, and directly stimulates the pathway of mitogen-activated protein kinase independently from the RAS. The kidney peptides that antagonize the intrarenal RAS may have renoprotective actions. Adrenomedullins, potent vasodilator peptides, have been shown to have renoprotective actions. On the other hand, urotensin II, a potent vasoconstrictor peptide, may promote the renal dysfunction in chronic kidney disease together with the renal RAS. Thus, in addition to the renin inhibitor and (pro)renin receptor, adrenomedullins and urotensin II may be novel targets to develop therapeutic strategies against chronic kidney disease. [Copyright &y& Elsevier]

• Both acute and chronic exercise decreased allodynia in rats with neuropathic pain. • The MasR antagonist A779 prevented the analgesia induced by both exercise protocols. • Exercise did not change the plasma Ang II/Ang-(1-7) ratio in nerve-damaged rats. • Subcutaneous administration of Ang-(1-7) reversed neuropathic pain in rats. Exercise reduces neuropathic pain in animals and humans. Recent studies indicate that training exercise favors the synthesis and action of angiotensin-(1-7) (Ang-(1-7)), a vasoactive peptide of the renin-angiotensin system (RAS), in various tissues. Interestingly, Ang-(1-7) also relieves neuropathic pain; however, it remains to be elucidated whether exercise mitigates this type of pain through Ang-(1-7). In this study, we investigated the role of Ang-(1-7) in exercise-induced analgesia in a neuropathic pain model. Male Wistar rats were ligated of lumbar spinal nerves (L5 and L6) or sham-operated. Then, they were subjected to acute (2-h) or chronic (4-week) exercise protocols. Tactile allodynia was evaluated before and after each exercise intervention. Microosmotic pumps were implanted subcutaneously for the release of Ang-(1-7) or A779 (selective Mas receptor (MasR; Ang-(1-7) receptor) antagonist). Plasma levels of Ang II and Ang-(1-7) were quantified by HPLC. Spinal nerve ligation (SNL) produced tactile allodynia. Both acute and chronic exercise reversed this neuropathic behavior. A779 treatment prevented the antiallodynic effect induced by each exercise protocol. SNL increased the plasma Ang II/Ang-(1-7) ratio; however, exercise did not modify it. Acute treatment with Ang-(1-7) via MasR mimicked exercise-mediated antinociception. Collectively, these results suggest that activation of the Ang-(1-7)/MasR axis of the RAS represents a potential novel mechanism by which exercise attenuates neuropathic pain in rats. [ABSTRACT FROM AUTHOR]