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The renin-angiotensin system plays a crucial role in the regulation of blood pressure. Activation of the angiotensin II (Ang II)-Ang II type 1 receptor (AT1R) signaling pathway contributes to the pathogenesis of hypertension and subsequent organ damage. AT1R-associated protein (ATRAP) has been identified as an endogenous inhibitory protein of the AT1R pathological activation. We have shown that mouse Atrap (Atrap) represses various Ang II-AT1R-mediated pathologies, including hypertension in mice. The expression of human ATRAP (ATRAP)/Atrap can be altered in various pathological states in humans and mice, such as Ang II stimulation and serum starvation. However, the regulatory mechanisms of ATRAP/Atrap are not yet fully elucidated. miRNAs are 21 to 23 nucleotides of small RNAs that posttranscriptionally repress gene expression. Single miRNA can act on hundreds of target mRNAs, and numerous miRNAs have been identified as the Ang II-AT1R signaling-associated disease phenotype modulator, but nothing is known about the regulation of ATRAP/Atrap. In the present study, we identified miR-125a-5p/miR-125b-5p as the evolutionarily conserved miRNAs that potentially act on ATRAP/Atrap mRNA. Further analysis revealed that miR-125a-5p/miR-125b-5p can directly repress both ATRAP and Atrap. In addition, the inhibition of miR-125a-5p/miR-125b-5p resulted in the suppression of the Ang II-AT1R signaling in mouse distal convoluted tubule cells. Taken together, miR-125a-5p/miR-125b-5p activates Ang II-AT1R signaling by the suppression of ATRAP/Atrap. Our results provide new insights into the potential approaches for achieving the organ-protective effects by the repression of the miR-125 family associated with the enhancement of ATRAP/Atrap expression. [ABSTRACT FROM AUTHOR]

Aims: Large outcome studies demonstrated a reduction of heart failure hospitalization or cardiovascular death in patients with chronic heart failure (CHF). The renin–angiotensin system (RAS) is a key player in fluid and sodium regulation. The classic angiotensin‐converting enzyme–angiotensin II–angiotensin‐1 receptor axis (Ang I–ACE–Ang II receptor axis) is predominantly angiotensin II (Ang‐II) induced and promotes vasoconstriction. In contrast, the angiotensin‐converting‐enzyme‐2–angiotensin‐(1‐7)–Mas axis (Mas‐axis) is mediated by the metabolites angiotensin‐1‐7 (Ang‐(1‐7)) and angtiotensin‐1‐5 (Ang‐(1‐5)) and exerts cardioprotective effects. Methods: We previously investigated the effect of empagliflozin on the systemic haemodynamic in patients with stable CHF (NYHA II–III) in a randomized placebo‐controlled clinical trial 'Analysing the Effect of Empagliflozin on Reduction of Tissue Sodium Content in Patients With Chronic Heart Failure (ELSI)'. In a post hoc analysis, we now analysed whether empagliflozin has an effect on the RAS by measuring detailed RAS profiles (LC‐MS/MS‐based approach) in 72 patients from ELSI. We compared RAS parameters after 1‐month and 3‐months treatment with empagliflozin or placebo to baseline. The secondary goal was to analyse whether the effect of empagliflozin on RAS parameters was dependent on angiotensin‐receptor‐blocking (ARB) or angiotensin‐converting‐enzyme‐inhibitor (ACEI) co‐medication. Results: Empagliflozin medication induced a significant rise in Ang‐II [68.5 pmol/L (21.3–324.2) vs. 131.5 pmol/L (34.9–564.0), P = 0.001], angiotensin‐I (Ang‐I) [78.7 pmol/L (21.5–236.6) vs. 125.9 pmol/L (52.6–512.9), P < 0.001], Ang‐(1‐7) [3.0 pmol/L (3.0–15.0) vs. 10.1 pmol/L (3.0–31.3), P = 0.006], and Ang‐(1‐5) [5.4 pmol/L (2.0–22.9) vs. 9.9 pmol/L (2.8–36.4), P = 0.004], which was not observed in the placebo group (baseline to 3‐months treatment). A significant rise in Ang‐II (206.4 pmol/L (64.2–750.6) vs. 568.2 pmol/L (164.7–1616.4), P = 0.001), Ang‐(1‐7) (3.0 pmol/L (3.0–14.1) vs. 15.0 pmol/L (3.0–31.3), P = 0.017), and Ang‐(1‐5) [12.2 pmol/L (3.8–46.6) vs. 36.4 pmol/L (11.1–90.7), P = 0.001] under empagliflozin treatment was only seen in the subgroup of patients with ARB co‐medication, whereas no change of Ang‐II (16.7 pmol/L (2.0–60.8) vs. 26.4 pmol/L (10.7–63.4), P = 0.469), Ang‐(1‐7) (6.6 pmol/L (3.0–20.7) vs. 10.5 pmol/L (3.0–50.5), P = 0.221), and Ang‐(1‐5) (2.7 pmol/L (2.0–8.4) vs. 2.8 pmol/L (2.0–6.9), P = 0.851) was observed in patients with empagliflozin that were on ACEI co‐medication (baseline to 3‐months treatment). Conclusions: Our data indicate that empagliflozin might lead to an activation of both the Ang I–ACE–Ang II receptor axis and the Mas‐axis pathway. Activation of the Ang I–ACE–Ang II receptor axis and the protective Mas‐axis pathway after initiating treatment with empagliflozin was only seen in patients with ARB co‐medication, in contrast to co‐medication with ACEI. [ABSTRACT FROM AUTHOR]

Angiotensin Converting Enzyme-2 (ACE2), an important enzyme in the Renin Angiotensin Aldosterone System, degrades Angiotensin II (Ang II) into Angiotensin-(1-7) (Ang-(1-7)), whose actions are opposite to that of Ang II. Interestingly, SARS CoV-2 virus entry into human cells is mediated by ACE2. ACE2 receptors that are widely expressed in lungs and various other organs. Ang-(1-7) seems to have favorable effects on lungs, by preventing fibrosis in lung inflammation models, and exerts a similar action in cardiac and renal pathologies as well. Thus, modulation of Ang-(1-7) can be of potential benefit in chronic as well as acute inflammatory diseases affecting lungs and other organs. Upregulation of ACE2 by statins in different organs, and its consequent beneficial effects, have been demonstrated in many experimental studies, and also in a few clinical ones. This review aims at probing the role of ACE2 and its therapeutic modulation in pulmonary and extra pulmonary diseases, including COVID-19. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Are renal functional responses to intrarenal angiotensin 1–7 (Ang (1–7)) infusion dependent on the level of the endogenous renin–angiotensin system (RAS) in the two‐kidney one‐clip (2K1C) and deoxycorticosterone acetate (DOCA)‐salt animal models of hypertension?What is the main finding and its importance?The renal actions of Ang (1–7) are dependent on the relative endogenous levels of each arm of the classical angiotensin II–angiotensin II type 1 receptor (AT1R) axis and those of the Ang (1–7)–Mas receptor axis. These findings support the hypothesis that a balance exists between the intrarenal classical and novel arms of the RAS, and in particular the relative abundance of AT1R to Mas receptor, which may to a large extent determine the renal excretory response to Ang (1–7) infusion. This study investigated the action of angiotensin 1–7 (Ang (1–7)) on renal haemodynamic and excretory function in the two‐kidney one‐clip (2K1C) and deoxycorticosterone acetate (DOCA)‐salt rat models of hypertension, in which the endogenous renin–angiotensin system (RAS) activity was likely to be raised or lowered, respectively. Rats were anaesthetised and prepared for the measurement of mean arterial pressure and kidney function during renal interstitial infusion of Ang (1–7) or saline. Kidney tissue concentrations of angiotensin II (Ang II) and Ang (1–7) were determined. Intrarenal infusion of Ang (1–7) into the clipped kidney of 2K1C rats increased urine flow (UV), absolute (UNaV) and fractional sodium (FENa) excretions by 110%, 214% and 147%, respectively. Renal Ang II concentrations of the clipped kidney were increased with no major changes in Ang (1–7) concentration. By contrast, Ang (1–7) infusion decreased UV, UNaV, and FENa by 27%, 24% and 21%, respectively in the non‐clipped kidney in which tissue Ang (1–7) concentrations were increased, but renal Ang II concentrations were unchanged compared to sham animals. Ang (1–7) infusion in DOCA‐salt rats had minimal effects on glomerular filtration rate but significantly decreased UV, UNaV and FENa by ∼30%. Renal Ang (1–7) concentrations were higher and Ang II concentrations were lower in DOCA‐salt rats compared to sham rats. These findings demonstrate that the intrarenal infusion of exogenous Ang (1–7) elicits different renal excretory responses the magnitude of which is dependent on the balance between the endogenous renal Ang II–AT1 receptor axis and Ang (1–7)–Mas receptor axis. [ABSTRACT FROM AUTHOR]

Thoracic aortic aneurysm (TAA) involves extracellular matrix (ECM) remodeling of the aortic wall, leading to reduced biomechanical support with risk of aortic dissection and rupture. Activation of the renin-angiotensin system, and resultant angiotensin (Ang) II synthesis, is critically involved in the onset and progression of TAA. The current study investigated the effects of angiotensin (Ang) 1-7 on a murine model of TAA. Male 8–10-week-old ApoEKO mice were infused with Ang II (1.44 mg/kg/day) and treated with Ang 1-7 (0.576 mg/kg/day). ApoEKO mice developed advanced TAA in response to four weeks of Ang II infusion. Echocardiographic and histological analyses demonstrated increased aortic dilatation, excessive structural remodelling, perivascular fibrosis, and inflammation in the thoracic aorta. Ang 1-7 infusion led to attenuation of pathological phenotypic alterations associated with Ang II-induced TAA. Smooth muscle cells (SMCs) isolated from adult murine thoracic aorta exhibited excessive mitochondrial fission, oxidative stress, and hyperproliferation in response to Ang II. Treatment with Ang 1-7 resulted in inhibition of mitochondrial fragmentation, ROS generation, and hyperproliferation. Gene expression profiling used for characterization of the contractile and synthetic phenotypes of thoracic aortic SMCs revealed preservation of the contractile phenotype with Ang 1-7 treatment. In conclusion, Ang 1-7 prevented Ang II-induced vascular remodeling and the development of TAA. Enhancing Ang 1-7 actions may provide a novel therapeutic strategy to prevent or delay the progression of TAA. [ABSTRACT FROM AUTHOR]

Lymphangioleiomyomatosis (LAM) is a multisystem disease occurring in women of child-bearing age manifested by uncontrolled proliferation of smooth muscle-like "LAM" cells in the lungs. LAM cells bear loss-of-function mutations in tuberous sclerosis complex (TSC) genes TSC1 and/or TSC2, causing hyperactivation of the proliferation promoting mammalian/mechanistic target of Rapamycin complex 1 pathway. Additionally, LAM-specific active renin-angiotensin system (RAS) has been identified in LAM nodules, suggesting this system potentially contributes to neoplastic properties of LAM cells; however, the role of this renin-angiotensin signaling is unclear. Here, we report that TSC2-deficient cells are sensitive to the blockade of angiotensin II receptor type 1 (Agtr1). We show that treatment of these cells with the AGTR1 inhibitor losartan or silencing of the Agtr1 gene leads to increased cell death in vitro and attenuates tumor progression in vivo. Notably, we found the effect of Agtr1 blockade is specific to TSC2-deficient cells. Mechanistically, we demonstrate that cell death induced by Agtr1 inhibition is mediated by an increased expression of Klotho. In TSC2-deficient cells, we showed overexpression of Klotho or treatment with recombinant (soluble) Klotho mirrored the cytocidal effect of angiotensin blockade. Furthermore, Klotho treatment decreased the phosphorylation of AKT, potentially leading to this cytocidal effect. Conversely, silencing of Klotho rescued TSC2-deficient cells from cell death induced by Agtr1 inhibition. Therefore, we conclude that Agtr1 and Klotho are important for TSC2-deficient cell survival. These findings further illuminate the role of the RAS in LAM and the potential of targeting Agtr1 inhibition in TSC2-deficient cells. [ABSTRACT FROM AUTHOR]

The objective of our study was to contribute to the characterization of monocrotaline-induced pulmonary arterial hypertension (PAH) in a rat model, with emphasis on the renin–angiotensin–aldosterone system, parameters of oxidative stress, the activity of matrix metalloproteinases, and erythrocyte parameters. Moreover, we aimed to analyze the effects of bosentan. Experiments were performed on 12-week-old male Wistar rats randomly assigned to 3 groups: control, monocrotaline-treated (60 mg/kg), and monocrotaline combined with bosentan (300 mg/kg/day). Our study confirmed the well-known effects of monocrotaline administration on lungs and the right ventricle, as well as pulmonary arterial pressure. In addition, we observed activation of the alternative pathway of the renin–angiotensin system, namely an increase in angiotensin (Ang) 1–7 and Ang 1-5 together with an increase in Ang I, but without any change in Ang II level, and downregulation of aldosterone 4 weeks after monocrotaline administration. For the first time, modifications of erythrocyte Na,K-ATPase enzyme kinetics were demonstrated as well. Our observations do not support data obtained in PAH patients showing an increase in Ang II levels, increase in oxidative stress, and deterioration in RBC deformability. Although bosentan primarily targets the vascular smooth muscle, our study confirmed its antioxidant effect. The obtained data suggest that besides the known action of bosentan, it decreases heart rate and increases erythrocyte deformability, and hence could have a beneficial hemodynamic effect in the PAH condition. [ABSTRACT FROM AUTHOR]

The renin‐angiotensin system (RAS) contributes to vascular disease with multiple cardiovascular risk factors including hypertension. As a major effector within the RAS, angiotensin II (Ang II) activates diverse signaling mechanisms that affect vascular biology. Despite the impact of such vascular pathophysiology, our understanding of the effects of Ang II in relation to the function of endothelial cells is incomplete. Because genetic background and biological sex can be determinants of vascular disease, we performed studies examining the direct effects of Ang II using carotid arteries from male and female mice on two genetic backgrounds, C57BL/6J and FVB/NJ. Although FVB/NJ mice are much less susceptible to atherosclerosis than C57BL/6J, the effects of Ang II on endothelial cells in FVB/NJ are poorly defined. Overnight incubation of isolated arteries with Ang II (10 nmol/L), impaired endothelial function in both strains and sexes by approximately one‐half (p < 0.05). To examine the potential mechanistic contribution of Rho kinase (ROCK), we treated arteries with SLX‐2119, an inhibitor with high selectivity for ROCK2. In both male and female mice of both strains, SLX‐2119 largely restored endothelial function to normal, compared to vessels treated with vehicle. Thus, Ang II‐induced endothelial dysfunction was observed in both FVB/NJ and C57BL/6J mice. This effect was sex‐independent. In all groups, effects of Ang II were reversed by inhibition of ROCK2 with SLX‐2119. These studies provide the first evidence that ROCK2 may be a key contributor to Ang II‐induced endothelial dysfunction in both sexes and in mouse strains that differ in relation to other major aspects of vascular disease. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is frequently associated with type 2 diabetes. However, there is no specific medical therapy to treat this condition. Angiotensin‐converting enzyme 2 (ACE2) of the protective renin angiotensin system generates the antifibrotic peptide angiotensin‐(1‐7) from profibrotic angiotensin II peptide. In this study, we investigated the therapeutic potential of ACE2 in diabetic NAFLD mice fed a high‐fat (20%), high‐cholesterol (2%) diet for 40 weeks. Mice were given a single intraperitoneal injection of ACE2 using an adeno‐associated viral vector at 30 weeks of high‐fat, high‐cholesterol diet (15 weeks after induction of diabetes) and sacrificed 10 weeks later. ACE2 significantly reduced liver injury and fibrosis in diabetic NAFLD mice compared with the control vector injected mice. This was accompanied by reductions in proinflammatory cytokine expressions, hepatic stellate cell activation, and collagen 1 expression. Moreover, ACE2 therapy significantly increased islet numbers, leading to an increased insulin protein content in β‐cells and plasma insulin levels with subsequent reduction in plasma glucose levels compared with controls. Conclusion: We conclude that ACE2 gene therapy reduces liver fibrosis and hyperglycemia in diabetic NAFLD mice and has potential as a therapy for patients with NAFLD with diabetes. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters cells through angiotensin converting enzyme 2 (ACE2), which expression of its gene increases during pregnancy that is resulted in an enhanced level of the ACE2 enzyme. It might enhance the risk of SARS-CoV-2 infection and its complications in the pregnant women. Although, pregnancy hypertensive disorders and severe infection with SARS-CoV-2 are correlated with high comorbidity, these two entities should be discriminated from each other. Also, there is a concern about the risk of preeclampsia and consequently severe coronavirus disease 2019 (COVID-19) development in the pregnant women. So, to answer these questions, in the present review the literature was surveyed. It seems there is higher severity of COVID-19 among pregnant women than non-pregnant women and more adverse pregnancy outcomes among pregnant women infected with SARS-CoV-2. In addition, an association between COVID-19 with preeclampsia and the role of preeclampsia and gestational hypertension as risk factors for SARS-CoV-2 infection and its complications is suggested. However, infection of the placenta and the SARS-CoV-2 vertical transmission is rare. Various mechanisms could explain the role of COVID-19 in the risk of preeclampsia and association between preeclampsia and COVID-19. Suggested mechanisms are included decreased ACE2 activity and imbalance between Ang II and Ang-(1-7) in preeclampsia, association of both of severe forms of COVID-19 and pregnancy hypertensive disorders with comorbidity, and interaction between immune system, inflammatory cytokines and the renin angiotensin aldosterone system and its contribution to the hypertension pathogenesis. It is concluded that preeclampsia and gestational hypertension might be risk factors for SARS-CoV-2 infection and its complications. [ABSTRACT FROM AUTHOR]

Myocardial remodeling is one of the main lesions in the late stage of chronic heart failure and seriously affects the prognosis of patients. Continuous activation of the renin-angiotensin-aldosterone system (RAAS) contributes to the development of myocardial remodeling greatly, and angiotensin II (Ang II), its main constituent, can directly lead to cardiac remodeling through an inflammatory response and oxidative stress. Since Ang II-induced myocardial remodeling is closely related to inflammation, we tried to explore whether the anti-inflammatory drug oridonin (Ori) can reverse this process and its possible mechanism. Our study investigated that hypertrophy and fibrosis can be induced after being treated with Ang II in cardiomyocytes (H9c2 cells and primary rat cardiomyocytes) and C57BL/6J mice. The anti-inflammatory drug oridonin could effectively attenuate the degree of cardiac remodeling both in vivo and vitro by inhibiting GSDMD, a key protein of intracellular inflammation which can further activate kinds of inflammation factors such as IL-1β and IL-18. We illustrated that oridonin reversed cardiac remodeling by inhibiting the process of inflammatory signaling through GSDMD. After inhibiting the expression of GSDMD in cardiomyocytes by siRNA, it was found that Ang II-induced hypertrophy was attenuated. These results suggest that oridonin is proved to be a potential protective drug against GSDMD-mediated inflammation and myocardial remodeling. [ABSTRACT FROM AUTHOR]

Mechanical ventilation (MV) is a life‐saving instrument used to provide ventilatory support for critically ill patients and patients undergoing surgery. Unfortunately, an unintended consequence of prolonged MV is the development of inspiratory weakness due to both diaphragmatic atrophy and contractile dysfunction; this syndrome is labeled ventilator‐induced diaphragm dysfunction (VIDD). VIDD is clinically important because diaphragmatic weakness is an important contributor to problems in weaning patients from MV. Investigations into the pathogenesis of VIDD reveal that oxidative stress is essential for the rapid development of VIDD as redox disturbances in diaphragm fibers promote accelerated proteolysis. Currently, no standard treatment exists to prevent VIDD and, therefore, developing a strategy to avert VIDD is vital. Guided by evidence indicating that activation of the classical axis of the renin‐angiotensin system (RAS) in diaphragm fibers promotes oxidative stress and VIDD, we hypothesized that activation of the nonclassical RAS signaling pathway via angiotensin 1‐7 (Ang1‐7) will protect against VIDD. Using an established animal model of prolonged MV, our results disclose that infusion of Ang1‐7 protects the diaphragm against MV‐induced contractile dysfunction and fiber atrophy in both fast and slow muscle fibers. Further, Ang1‐7 shielded diaphragm fibers against MV‐induced mitochondrial damage, oxidative stress, and protease activation. Collectively, these results reveal that treatment with Ang1‐7 protects against VIDD, in part, due to diminishing oxidative stress and protease activation. These important findings provide robust evidence that Ang1‐7 has the therapeutic potential to protect against VIDD by preventing MV‐induced contractile dysfunction and atrophy of both slow and fast muscle fibers. [ABSTRACT FROM AUTHOR]

We investigated the role of the interaction between hypertension and the renin-angiotensin system in the pathophysiology of myocardial ischemia/reperfusion injury. We hypothesized that in the early phase of angiotensin II (ANG II)-dependent hypertension with developed left ventricular hypertrophy, cardioprotective mechanism(s) are fully activated. The experiments were performed in transgenic rats with inducible hypertension, noninduced rats served as controls. The early phase of ANG II-dependent hypertension was induced by five-days (5 days) dietary indole-3-carbinol administration. Cardiac hypertrophy, ANG II and ANG 1–7 levels, protein expression of their receptors and enzymes were determined. Separate groups were subjected to acute myocardial ischemia/reperfusion injury, and infarct size and ventricular arrhythmias were assessed. Induced rats developed marked cardiac hypertrophy accompanied by elevated ANG levels. Ischemia/reperfusion mortality was significantly higher in induced than noninduced rats (52.1 and 25%, respectively). The blockade of AT1 receptors with losartan significantly increased survival rate in both groups. Myocardial infarct size was significantly reduced after 5 days induction (by 11%), without changes after losartan treatment. In conclusion, we confirmed improved cardiac tolerance to ischemia/reperfusion injury in hypertensive cardiohypertrophied rats and found that activation of AT1 receptors by locally produced ANG II in the heart was not the mechanism underlying infarct size reduction. [ABSTRACT FROM AUTHOR]

The benefit of antagonizing the effect of the renin angiotensin aldosterone system (RAAS), notably by the use of angiotensin-converting enzyme inhibitor (ACEi) and angiotensin II type 1 receptor blocker (ARB) for coronary artery disease (CAD), has been demonstrated in multiple studies, which may be attributed to their ability to inhibit the deleterious effect of RAAS to the cardiovascular system. It is well known that angiotensin II (Ang II) plays a vital role in atheromatous plaque formation and progression through multiple pathways, including inflammatory and arterial remodeling aspects. Significant coronary atheromatous plaque regression has been previously demonstrated in various studies using statin agents. Similar results have been reported in different studies using angiotensin inhibitor agents, notably ARB agents. Analysis from various trials utilizing ARB showed a significant plaque regression using olmesartan and telmisartan as evaluated by IVUS studies. In contrary, the use of ACEi did not demonstrated significant plaque regression, which may be attributed to the heavy plaque calcification in respective studies. On this review, we aim to present the basic mechanism on the role of RAAS in plaque modulation and its arterial remodeling aspect, which is then integrated with the clinical evidence based on the available intravascular ultrasonography (IVUS) studies on coronary arteries. [ABSTRACT FROM AUTHOR]

Introduction: The renin–angiotensin–aldosterone system (RAAS), a metabolic cascade regulating pressure and circulating blood volume, has been considered the main system involved in the pathogenesis of severe lung injury and organs decline in COVID-19 patients. The angiotensin I-converting enzyme (ACE1), angiotensin-converting enzyme 2 (ACE2), angiotensinogen (AGT) and receptors angiotensin II receptor type 1 (AGTR1) are key factors for SARS-CoV-2 entering in the cells, sodium and water retention with an increase blood pressure, promotion of fibrotic and inflammatory phenomena resulting in a cytokine storm. Methods: In this pilot study, the frequencies of six polymorphisms in the ACE1, ACE2, AGT and AGTR1 genes were analysed in symptomatic patients affected by COVID-19 and compared with the results obtained from asymptomatic subjects. Results: Thus, we have identified that rs2074192 (ACE2), rs1799752 (ACE1) and rs699 (AGT) SNPs could potentially be a valuable tool for predicting the clinical outcome of SARS-CoV-2 infected patients. A genetic predisposition may be prospected for severe internal organ damages and poor prognosis in patients with COVID-19 disease, as observed in symptomatic vs asymptomatic. Conclusion: This study provides evidence that analysis of RAAS polymorphisms could be considered the key point in understanding and predicting the SARS-CoV-2 course infection. [ABSTRACT FROM AUTHOR]

Environmental stress during early life is an important factor that affects the postnatal renal development. We have previously shown that male rats exposed to maternal separation (MatSep), a model of early life stress, are normotensive but display a sex-specific reduced renal function and exacerbated angiotensin II (AngII)-mediated vascular responses as adults. Since optimal AngII levels during postnatal life are required for normal maturation of the kidney, this study was designed to investigate both short- and long-term effect of MatSep on (1) the renal vascular architecture and function, (2) the intrarenal renin-angiotensin system (RAS) components status, and (3) the genome-wide expression of genes in isolated renal vasculature. Renal tissue and plasma were collected from male rats at different postnatal days (P) for intrarenal RAS components mRNA and protein expression measurements at P2, 6, 10, 14, 21, and 90 and microCT analysis at P21 and 90. Although with similar body weight and renal mass trajectories from P2 to P90, MatSep rats displayed decreased renal filtration capacity at P90, while increased microvascular density at both P21 and P90 (p < 0.05). MatSep increased renal expression of renin, and angiotensin type 1 (AT1) and type 2 (AT2) receptors (p < 0.05), but reduced ACE2 mRNA expression and activity from P2-14 compared to controls. However, intrarenal levels of AngII peptide were reduced (p < 0.05) possible due to the increased degradation to AngIII by aminopeptidase A. In isolated renal vasculature from neonates, Enriched Biological Pathways functional clusters (EBPfc) from genes changed by MatSep reported to modulate extracellular structure organization, inflammation, and pro-angiogenic transcription factors. Our data suggest that male neonates exposed to MatSep could display permanent changes in the renal microvascular architecture in response to intrarenal RAS imbalance in the context of the atypical upregulation of angiogenic factors. [ABSTRACT FROM AUTHOR]

Severe acute respiratory-syndrome coronavirus-2 (SARS-CoV-2) host cell infection is mediated by binding to angiotensin-converting enzyme 2 (ACE2). Systemic dysregulation observed in SARS-CoV was previously postulated to be due to ACE2/angiotensin 1-7 (Ang1-7)/Mas axis downregulation; increased ACE2 activity was shown to mediate disease protection. Because angiotensin II receptor blockers, ACE inhibitors, and mineralocorticoid receptor antagonists increase ACE2 receptor expression, it has been tacitly believed that the use of these agents may facilitate viral disease; thus, they should not be used in high-risk patients with cardiovascular disease. Based on the anti-inflammatory benefits of the upregulation of the ACE2/Ang1-7/Mas axis and previously demonstrated benefits of lung function improvement in SARS-CoV infections, it has been hypothesized that the benefits of treatment with renin-angiotensin system inhibitors in SARS-CoV-2 may outweigh the risks and at the very least should not be withheld. • COVID-19 has been associated with cardiac involvement. SARS-CoV-2 requires binding to ACE2 in the RAS. • The ACE2/Ang1-7/Mas pathway counterbalances the RAS, which results in activation of anti-inflammatory pathways. • ACE inhibitors, ARBs, and MRAs upregulate ACE2 activity and expression. • More data are required to determine if regulation of ACE2 in patients with cardiovascular disease and COVID-19 would help improve clinical outcomes. [ABSTRACT FROM AUTHOR]

Background and Purpose: Damage to the vasculature caused by chronic iron-overload in both humans and animal models, is characterized by endothelial dysfunction and reduced compliance. In vitro, blockade of the angiotensin II AT1 receptors reversed functional vascular changes induced by chronic iron-overload. In this study, the effect of chronic AT1 receptor blockade on aorta stiffening was assessed in iron-overloaded rats.Experimental Approach: Male Wistar rats were treated for 15 days with saline as control group, iron dextran 200 mg·kg-1 ·day-1 , 5 days a week (iron-overload group), losartan (20 mg·kg-1 ·day-1 in drinking water), and iron dextran plus losartan. Mechanical properties of the aorta were assessed in vivo. In vitro, aortic geometry and biochemical composition were assessed with morphometric and histological methods.Key Results: Thoracoabdominal aortic pulse wave velocity (PWV) increased significantly, indicating a decrease in aortic compliance. Co-treatment with losartan prevented changes on PWV, β-index, and elastic modulus in iron-overloaded rats. This iron-related increase in PWV was not related to changes in aortic geometry and wall stress. but to increased elastic modulus/wall stress ratio, suggesting that a change in the composition of the wall was responsible for the stiffness. Losartan treatment also ameliorated the increase in aorta collagen content of the iron-overload group, without affecting circulating iron or vascular deposits.Conclusions and Implications: Losartan prevented the structural and functional indices of aortic stiffness in iron-overloaded rats, implying that inhibition of the renin-angiotensin system would limit the vascular remodelling in chronic iron-overload. [ABSTRACT FROM AUTHOR]

In angiotensin II (Ang II)-dependent hypertensive rats there is an increased expression of proximal tubule angiotensinogen (AGT), collecting duct renin and angiotensin converting enzyme (ACE), which contributes to intratubular Ang II formation. Ang II acts on Ang II type 1 receptors promoting sodium retention and vasoconstriction. However concurrently, the ACE2-Ang-(1–7) axis and the expression of kallikrein and medullary prostaglandins counteract the effects of Ang II, promoting natriuresis and vasodilation. Human studies demonstrate that dietary potassium (K+) intake lowers blood pressure. In this report we evaluate the expression of AGT, ACE, medullary prorenin/renin, ACE2, kallikrein and cyclooxygenase-2 (COX-2) in Ang II-infused rats fed with high K+ diet (2%) for 14 days. Dietary K+ enhances diuresis in non-infused and in Ang II-infused rats. The rise in systolic blood pressure in Ang II-infused rats was attenuated by dietary K+. Ang II-infused rats showed increased renal protein levels of AGT, ACE and medullary prorenin and renin. This effect was attenuated in the Ang II + K+ group. Ang II infusion decreased ACE2 compared to the control group; however, K+ diet prevented this effect in the renal medulla. Furthermore, medullary COX-2 was dramatically induced by K+ diet in non-infused and in Ang II infused rats. Dietary K+ greatly increased kallikrein immunostaining in normotensive rats and in Ang II-hypertensive rats. These results indicate that a high K+ diet attenuates Ang II-dependent hypertension by preventing the induction of ACE, AGT and collecting duct renin and by enhancing medullary COX-2 and ACE2 protein expression in the kidney. [ABSTRACT FROM AUTHOR]

The tissue renin-angiotensin system (RAS) plays an important role in the development and progression of many diseases. It has been confirmed that angiotensin II (ANG II) participates in the proliferation and angiogenesis of breast cancer. Moreover, some RAS dysregulations in cancer have been observed. Recent studies on the role of two opposite axes of angiotensinogen metabolism - ACE (angiotensin-converting enzyme)/ANGII/AT1R (angiotensin receptor type 1) and ACE-2/ANG 1-7/MAS (mitochondrial assembly) - indicate their importance in tumor growth and invasion, but studies describing the metabolic pathways in breast cancer and the role of newer angiotensins, such as ANG 1-12, remain lacking. In this study, the metabolism of angiotensinogen fragments in three breast cancer lines, namely, MDA-MB-231, MCF-7, and T-47D, compared with normal breast tissue cells (PCS-600) was estimated. Incubation of the cancer cells with angiotensinogen resulted in the prevalent formation of ANG 1-7. A difference in the ability to form ANG II was observed between cell lines. In normal breast cells, the strong predominance of the ACE-2/ANG 1-7/MAS pathway was detected. In cancer cells, differences in angiotensinogen metabolism depending on cancer line were observed; the prevalence of the ACE/ANG II/AT1R pathway was shown. Expressions of the RAS component were dysregulated in cancer cells and differed between cell lines. In conclusion, the ability of breast cancer cells to produce numerous angiotensin peptide metabolites was demonstrated. The metabolism of angiotensinogen differed between various types of breast cancer cells. The obtained results indicate the greater importance of the classical pathway - ACE/ANG II/AT1R - in breast cancer cells. The production of ANG 1-12 seems to be marginal in breast tissue, but a tendency for the higher formation of this peptide in cancer cells was observed. The production of ANG 1-7 was significantly lower in cancer cells, whereas the expression of MAS receptor was higher than that in the control. This finding suggests that substances with MAS receptor agonist activity could be useful in the treatment of breast cancer, but this requires further investigations. [ABSTRACT FROM AUTHOR]

Background: To explore the effects of chronic intermittent hypoxia (CIH), which mimics sleep apnea syndrome, on the cardiac renin angiotensin system (RAS), and to investigate the cardiac protection of an angiotensin receptor blocker (ARB)telmisartan (TERT) against CIH.Methods: 32 healthy male C57B6J mice were randomly divided into CIH, ARB, blank and air control groups. CIH lasted for 12 weeks. Cardiac angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE 2) and angiotensin II (Ang II) were evaluated by immunohistochemistry. Myocardial apoptosis were assessed by TUNEL assay and myocardial cell ultrastructure were observed under transmission electron microscope.Results: Cardiac ACE expression was higher in the CIH group than in blank and air control groups, which was decreased with TERT treatment. TERT treatment elevated the expression of cardiac ACE 2 and Ang II compared with CIH group. Myocardial cell and capillary endothelial cell apoptosis, mitochondrial injury were most severe in CIH groups, which were mitigated with TERT treatment.Conclusions: CIH changes the expression of cardiac ACE, ACE2 and Ang II, which may cause myocardial damage. TERT protects mice from CIH-linked cardiac damage via modulating the activity of RAS in the hearts. [ABSTRACT FROM AUTHOR]

Background: Anti-angiotensin II type 1 receptor antibodies (AT1R-Abs) have been suggested as a risk factor for graft failure and acute rejection (AR). However, the prevalence and clinical significance of pretransplant AT1R-Abs have seldom been evaluated in Asia. Methods: In this multicenter, observational cohort study, we tested the AT1R-Abs in pretransplant serum samples obtained from 166 kidney transplant recipients. Statistical analysis was used to set a threshold AT1R-Abs level at 9.05 U/mL. Results: Pretransplant AT1R-Abs were detected in 98/166 (59.0%) of the analyzed recipients. No graft loss or patient death was reported during the study period. AT1R-Abs (+) patients had a significantly higher incidence of biopsy-proven AR than AT1R-Abs (-) patients (27.6 versus 10.3%, P = 0.007). Recipients with pretransplant AT1R-Abs had a 3.2-fold higher risk of AR within a year of transplantation (P = 0.006). Five study subjects developed microcirculation inflammation (score ≥2). Four of them were presensitized to AT1R-Abs. In particular, three patients had a high titer of anti-AT1R-Abs (>22.7 U/mL). Conclusions: Pretransplant AT1R-Abs is an independent risk factor for AR, especially acute cellular rejection, and is possibly associated with the risk of antibody-mediated injury. Pretransplant assessment of AT1R-Abs may be useful for stratifying immunologic risks. [ABSTRACT FROM AUTHOR]

Angiotensins are a group of hormonal peptides and include angiotensin II and angiotensin 1-7 produced by the renin angiotensin system. The biology, pharmacology and biochemistry of the receptors for angiotensins were extensively reviewed recently. In the review, the receptor nomenclature committee was not emphatic on designating MAS1 as the angiotensin 1-7 receptor on the basis of lack of classical G protein signalling and desensitization in response to angiotensin 1-7, as well as a lack of consensus on confirmatory ligand pharmacological analyses. A review of recent publications (2013-2016) on the rapidly progressing research on angiotensin 1-7 revealed that MAS1 and two additional receptors can function as 'angiotensin 1-7 receptors', and this deserves further consideration. In this review we have summarized the information on angiotensin 1-7 receptors and their crosstalk with classical angiotensin II receptors in the context of the functions of the renin angiotensin system. It was concluded that the receptors for angiotensin II and angiotensin 1-7 make up a sophisticated cross-regulated signalling network that modulates the endogenous protective and pathogenic facets of the renin angiotensin system. [ABSTRACT FROM AUTHOR]

Introduction: Tonin is an enzyme that is able to generate angiotensin II (Ang II) from angiotensin I (Ang I) or directly from angiotensinogen. Our goal was to characterize the renal renin-angiotensin system in transgenic mice that express rat tonin (TGM`(rTon)).Materials and Methods: Mice were euthanized and the kidneys removed for analysis. Tonin activity was evaluated by radioimmunoassay and angiotensin I-converting enzyme (ACE) activity by HPLC. Tonin, ACE and angiotensin II-converting enzyme (ACE2) expression was analyzed by Western blotting.Results: Tonin activity was significantly increased in TGM`(rTon) compared to their respective wild-type (WT) littermates (1.7 ± 0.21 vs 0.11 ± 0.02 nmol of Ang II/min/mg of protein). Tonin activity had a strong positive correlation with tonin expression in both TGM`(rTon) and their respective wild-type littermates. The ACE activity and expression levels of 65-kDa N-domain angiotensin I-converting enzyme isoform were significantly increased in the TGM`(rTon) when compared with WT. ACE2 expression levels were statistically significantly higher in the TGM`(rTon) when compared with WT. Angiotensin 1-7 (Ang(1-7)) and Ang I levels were significantly lower in the TGM`(rTon).Conclusions: We suggest that the environment of tonin abundance may increase N-domain ACE activity liberated by a secretase able to cleave somatic ACE. [ABSTRACT FROM AUTHOR]

Introduction: Isolated nuclei of sheep proximal tubules express angiotensin (Ang) receptors as well as angiotensinogen (AGT) and renin. The present study characterized the NRK-52E tubular epithelial cell line for the intracellular expression of renin-angiotensin system (RAS) components.Methods: RAS components were visualized by immunofluorescent staining in intact cells and protein expression in isolated nuclei.Results: An antibody to the angiotensin I (Ang I) sequence of AGT (AI-AGT) revealed only cytosolic staining, while an antibody to an internal sequence of AGT (Int-AGT) revealed primarily nuclear staining. Immunoblots of nuclear and cytosolic fractions confirmed the differential cell staining of AGT. Immunostaining for renin was present on nuclei of intact cells. Nuclear renin activity averaged 0.77±0.05 nmol/mg protein/h that was reduced by aliskiren (0.13±0.01 nmol/mg/h, n=3, p<0.01); trypsin activation increased activity three-fold. Peptide staining localized angiotensin II (Ang II) and Ang-(1-7) to the nucleus and peptide content averaged 59±2 and 57±22 fmol/mg (n=4), respectively. Peptide metabolism in isolated nuclei revealed the processing of Ang I to Ang-(1-7) by thimet oligopeptidase.Conclusion: We conclude that the NRK-52E cells express an intracellular RAS localized to the nucleus and may be an appropriate cell model to elucidate the functional relevance of this system. [ABSTRACT FROM AUTHOR]