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Recent years have seen a resurgence of interest for the renin–angiotensin–aldosterone system in critically ill patients. Emerging data suggest that this vital homeostatic system, which plays a crucial role in maintaining systemic and renal hemodynamics during stressful conditions, is altered in septic shock, ultimately leading to impaired angiotensin II—angiotensin II type 1 receptor signaling. Indeed, available evidence from both experimental models and human studies indicates that alterations in the renin–angiotensin–aldosterone system during septic shock can occur at three distinct levels: 1. Impaired generation of angiotensin II, possibly attributable to defects in angiotensin-converting enzyme activity; 2. Enhanced degradation of angiotensin II by peptidases; and/or 3. Unavailability of angiotensin II type 1 receptor due to internalization or reduced synthesis. These alterations can occur either independently or in combination, ultimately leading to an uncoupling between the renin–angiotensin–aldosterone system input and downstream angiotensin II type 1 receptor signaling. It remains unclear whether exogenous angiotensin II infusion can adequately address all these mechanisms, and additional interventions may be required. These observations open a new avenue of research and offer the potential for novel therapeutic strategies to improve patient prognosis. In the near future, a deeper understanding of renin–angiotensin–aldosterone system alterations in septic shock should help to decipher patients' phenotypes and to implement targeted interventions. [ABSTRACT FROM AUTHOR]

Background: Dipeptidyl peptidase 3 (DPP3) is a ubiquitous cytosolic enzyme released into the bloodstream after tissue injury, that can degrade angiotensin II. High concentrations of circulating DPP3 (cDPP3) have been associated with worse outcomes during sepsis. The aim of this study was to assess the effect of Procizumab (PCZ), a monoclonal antibody that neutralizes cDPP3, in an experimental model of septic shock. Methods: In this randomized, open-label, controlled study, 16 anesthetized and mechanically ventilated pigs with peritonitis were randomized to receive PCZ or standard treatment when the mean arterial pressure (MAP) dropped below 50 mmHg. Resuscitation with fluids, antimicrobial therapy, peritoneal lavage, and norepinephrine was initiated one hour later to maintain MAP between 65–75 mmHg for 12 h. Hemodynamic variables, tissue oxygenation indices, and measures of organ failure and myocardial injury were collected. Organ blood flow was assessed using isotopic assessment (99mtechnetium albumin). cDPP3 activity, equilibrium analysis of the renin–angiotensin system and circulating catecholamines were measured. Tissue mRNA expression of interleukin-6 and downregulation of adrenergic and angiotensin receptors were assessed on vascular and myocardial samples. Results: PCZ-treated animals had reduced cDPP3 levels and required less norepinephrine and fluid than septic control animals for similar organ perfusion and regional blood flow. PCZ-treated animals had less myocardial injury, and higher PaO2/FiO2 ratios. PCZ was associated with lower circulating catecholamine levels; higher circulating angiotensin II and higher angiotensin II receptor type 1 myocardial protein expression, and with lower myocardial and radial artery mRNA interleukin-6 expression. Conclusions: In an experimental model of septic shock, PCZ administration was associated with reduced fluid and catecholamine requirements, less myocardial injury and cardiovascular inflammation, along with preserved angiotensin II signaling. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) constitutes one of the principal mechanisms to maintain hemodynamic and fluid homeostasis. However, most research until now on RAS primarily focuses on its relationship with hypertension and its role in critically ill hypotensive populations is not well understood. With the approval of angiotensin II (Ang II) in the United States and Europe, following a phase 3 randomized controlled trial showing efficacy in catecholamine-resistant vasodilatory shock, there is growing interest in RAS in critically ill patients. Among the fundamental components of RAS, renin acts as the initial stimulus for the entire system. In the context of hypotension, its release increases in response to low blood pressure sensed by renal baroreceptors and attenuated negative Ang II feedback loop. Thus, elevated renin could reflect disease severity and predict poor outcomes. Studies investigating this hypothesis have validated the prognostic accuracy of renin in various critically ill populations, with several reports indicating its superiority to lactate for mortality prediction. Accordingly, renin reduction has been used to assess the effectiveness of Ang II administration. Furthermore, renin holds potential to identify patients who might benefit from Ang II treatment, potentially paving the way for personalized vasopressor management. Despite these promising data, most available evidence is derived from retrospective analysis and necessitates prospective confirmation. The absence of a rapid, point-of-care and reliable renin assay presents another hurdle to its integration into routine clinical practice. This narrative review aims to describe the current understanding and future directions of renin as a biomarker during resuscitation of critically ill patients. [ABSTRACT FROM AUTHOR]

Patients with septic shock who experience refractory hypotension despite adequate fluid resuscitation and high-dose noradrenaline have high mortality rates. To improve outcomes, evidence-based guidelines recommend starting a second vasopressor, such as vasopressin, if noradrenaline doses exceed 0.5 µg/kg/min. Recently, promising results have been observed in treating refractory hypotension with angiotensin II, which has been shown to increase mean arterial pressure and has been associated with improved outcomes. This narrative review aims to provide an overview of the pathophysiology of the renin-angiotensin system and the role of endogenous angiotensin II in vasodilatory shock with a focus on how angiotensin II treatment impacts clinical outcomes and on identifying the population that may benefit most from its use. [ABSTRACT FROM AUTHOR]

Background: The physiological effects of renin-angiotensin system modulation in acute respiratory distress syndrome (ARDS) remain controversial and have not been investigated in randomized trials. We sought to determine whether angiotensin-II treatment is associated with improved oxygenation in shock-associated ARDS. Methods: Post-hoc subgroup analysis of the Angiotensin Therapy for High Output Shock (ATHOS-3) trial. We studied patients who met modified Berlin ARDS criteria at enrollment. The primary outcome was PaO2/FiO2-ratio (P:F) at 48-h adjusted for baseline P:F. Secondary outcomes included oxygenation index, ventilatory ratio, PEEP, minute-ventilation, hemodynamic measures, patients alive and ventilator-free by day-7, and mortality. Results: Of 81 ARDS patients, 34 (42%) and 47 (58%) were randomized to angiotensin-II or placebo, respectively. In angiotensin-II patients, mean P:F increased from 155 mmHg (SD: 69) at baseline to 265 mmHg (SD: 160) at hour-48 compared with no change with placebo (148 mmHg (SD: 63) at baseline versus 164 mmHg (SD: 74) at hour-48)(baseline-adjusted difference: + 98.4 mmHg [95%CI 35.2–161.5], p = 0.0028). Similarly, oxygenation index decreased by − 6.0 cmH2O/mmHg at hour-48 with angiotensin-II versus − 0.4 cmH2O/mmHg with placebo (baseline-adjusted difference: -4.8 cmH2O/mmHg, [95%CI − 8.6 to − 1.1], p = 0.0273). There was no difference in PEEP, minute ventilation, or ventilatory ratio. Twenty-two (64.7%) angiotensin-II patients had sustained hemodynamic response to treatment at hour-3 versus 17 (36.2%) placebo patients (absolute risk-difference: 28.5% [95%CI 6.5–47.0%], p = 0.0120). At day-7, 7/34 (20.6%) angiotensin-II patients were alive and ventilator-free versus 5/47(10.6%) placebo patients. Day-28 mortality was 55.9% in the angiotensin-II group versus 68.1% in the placebo group. Conclusions: In post-hoc analysis of the ATHOS-3 trial, angiotensin-II was associated with improved oxygenation versus placebo among patients with ARDS and catecholamine-refractory vasodilatory shock. These findings provide a physiologic rationale for trials of angiotensin-II as treatment for ARDS with vasodilatory shock. Trial Registration: ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015). [ABSTRACT FROM AUTHOR]

T1D can be associated with metabolic disorders and several impaired pathways, including insulin signaling, and development of insulin resistance through the renin-angiotensin system (RAS). The main precursor of RAS is angiotensinogen (Agt) and this system is often linked to autophagy dysregulation. Dysregulated autophagy has been described in T1D and linked to impairments in both glucose metabolism, and leukotrienes (LTs) production. Here, we have investigated the role of RAS and LTs in both muscle and liver from T1D mice, and its effects on insulin and autophagy pathways. We have chemically induced T1D in 129sve and 129sve 5LO−/− mice (lacking LTs) with streptozotocin (STZ). To further inhibit ACE activity, mice were treated with captopril (Cap). In muscle of T1D mice, treatment with Cap increased the expression of RAS (angiotensinogen and angiotensin II receptor), insulin signaling, and autophagy markers, regardless of the genotype. In the liver of T1D mice, the treatment with Cap increased the expression of RAS and insulin signaling markers, mostly when LTs were absent. 5LO−/− T1D mice showed increased insulin sensitivity, and decreased NEFA, after the Cap treatment. Cap treatment impacted both insulin signaling and autophagy pathways at the mRNA levels in muscle and liver, indicating the potential role of ACE inhibition on insulin sensitivity and autophagy in T1D. [ABSTRACT FROM AUTHOR]

Autosomal Recessive Renal Tubular Dysgenesis (AR-RTD) is a fatal genetic disorder characterized by complete absence or severe depletion of proximal tubules (PT) in patients harboring pathogenic variants in genes involved in the Renin–Angiotensin–Aldosterone System. To uncover the pathomechanism of AR-RTD, differentiation of ACE-/- and AGTR1-/- induced pluripotent stem cells (iPSCs) and AR-RTD patient-derived iPSCs into kidney organoids is leveraged. Comprehensive marker analyses show that both mutant and control organoids generate indistinguishable PT in vitro under normoxic (21% O2) or hypoxic (2% O2) conditions. Fully differentiated (d24) AGTR1-/- and control organoids transplanted under the kidney capsule of immunodeficient mice engraft and mature well, as do renal vesicle stage (d14) control organoids. By contrast, d14 AGTR1-/- organoids fail to engraft due to insufficient pro-angiogenic VEGF-A expression. Notably, growth under hypoxic conditions induces VEGF-A expression and rescues engraftment of AGTR1-/- organoids at d14, as does ectopic expression of VEGF-A. We propose that PT dysgenesis in AR-RTD is primarily a non-autonomous consequence of delayed angiogenesis, starving PT at a critical time in their development. Autosomal Recessive Renal Tubular Dysgenesis (AR-RTD) arises from mutations in Angiotensin II sensing genes, but how they impact the kidney was unclear. This study reveals that delayed angiogenesis at a critical developmental window underlies AR-RTD. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) accompanied by an arterial pressure increase in the pulmonary circulation, remodeling of pulmonary arteries and a change in its sensitivity to regulatory factors; PAH is accompanied by activation of the sympathetic nervous system and renin-angiotensin-aldosterone system and increased production of atrial natriuretic peptide. The change in the sensitivity of the vessels of the systemic circulation (SC) to regulatory influences in PAH has not been investigated. Vasoconstrictor reactions in SC with monocrotaline (MCT) were studied in the work models of PAH in rats (Wistar, 350 ± 50 g, 4 months). Mean arterial pressure (MAP) was recorded against the background of a double autonomous blockade with the administration of the α1-adrenergic receptor agonist (α1-AR) phenylephrine (Phe) to conscious rats at the start of experiment, then 2 and 4 weeks after the induction of PAH with MCT or saline injection for control animals. Registration of MAP under the action of Phe was also performed during angiotensin-II (ATII) infusion. The maximal amplitude (Amax) of the change in MAP and the longest half-return time of MAP (TΔMAP1/2) to the baseline level in rats in response to the Phe injection were estimated. It was found that in response to Phe, Amax did not change in rats with PAH, whereas in control animals it significantly increased. In rats with PAH 2 (n = 6) and 4 weeks after the induction of PAH with MCT, TΔMAP1/2 is significantly less than in control rats. ATII leads to delayed changes in TΔMAP1/2 in both control rats and rats with PAH. In rats with PAH, the potentiation with angiotensin TΔMAP1/2 is significantly less than in control rats. Thus, in animals with PAH, the ability of the resistive arteries of the systemic circulation to maintain tone in response to the activation of α1-AR decreases. In addition, PAH suppresses the ability of ATII to stimulate sympathetic responses in the SC. Firstly, in vivo, it has been demonstrated remodeling and changing the functional state of the pulmonary circulation leads to changes in the regulation of vascular tone of the systemic circulation. [ABSTRACT FROM AUTHOR]

The role of taurine in the treatment of congestive heart failure (CHF) in dogs without systemic deficiency is unexplored. Taurine might have beneficial cardiac effects aside from deficit replacement. We hypothesized that oral taurine supplementation administered to dogs with naturally-occurring CHF would suppress the renin-angiotensin aldosterone system (RAAS). Oral taurine was administered to 14 dogs with stable CHF. Serum biochemical variables, blood taurine concentrations, and comprehensive analysis of RAAS variables were compared before and 2 weeks after taurine supplementation added to background furosemide and pimobendan therapy for CHF. Whole blood taurine concentrations increased after supplementation (median 408 nMol/mL, range 248–608 before and median 493 nMol/mL, range 396–690 after; P =.006). Aldosterone to angiotensin II ratio (AA2) was significantly decreased after taurine supplementation (median 1.00, range 0.03–7.05 before and median 0.65, range 0.01–3.63 after; P =.009), but no other RAAS components significantly differed between timepoints. A subset of dogs showed marked decreases in RAAS metabolites after supplementation and these dogs were more likely to have been recently hospitalized for CHF treatment than dogs that did not show marked decreases in classical RAAS metabolites. Overall, taurine only lowered AA2 in this group of dogs, however, response heterogeneity was noted, with some dogs showing RAAS suppression. [ABSTRACT FROM AUTHOR]

Background: Astragalus root is a commonly used herb in traditional Chinese medicine. Although renoprotective effects have been reported in some clinical and experimental studies, the details remain unknown. Methods: We used 5/6 nephrectomized rats as chronic kidney disease (CKD) models. At 10 weeks, they were divided into four groups, namely, CKD, low-dose astragalus (AR400), high-dose astragalus (AR800), and sham groups. At 14 weeks, they were sacrificed for the evaluation of blood, urine, mRNA expression in the kidney, and renal histopathology. Results: Kidney dysfunction was significantly improved following astragalus administration (creatinine clearance: sham group; 3.8 ± 0.3 mL/min, CKD group; 1.5 ± 0.1 mL/min, AR400 group; 2.5 ± 0.3 mL/min, AR800 group; 2.7 ± 0.1 mL/min). Blood pressure, urinary albumin, and urinary NGAL levels were significantly lower in the astragalus-treated groups than those in the CKD group. Excretion of urinary 8-OHdG, an oxidative stress marker, and intrarenal oxidative stress were lower in the astragalus-treated groups than those in the CKD group. Furthermore, the mRNA expression of NADPH p22 phox, NADPH p47 phox, Nox4, renin, angiotensin II type 1 receptor, and angiotensinogen in the kidney was lower in the astragalus-treated groups compared with the CKD group. Conclusion: This study suggests that astragalus root slowed CKD progression, possibly through the suppression of oxidative stress and the renin–angiotensin system. [ABSTRACT FROM AUTHOR]

Radiation pneumonitis (RP) affects both patients and physicians during radiation therapy for lung cancer. To date, there are no effective drugs for improving the clinical outcomes of RP. The activation of angiotensin-converting enzyme 2 (ACE2) improves experimental acute lung injury caused by severe acute respiratory syndrome coronavirus, acid inhalation, and sepsis. However, the effects and underlying mechanisms of ACE2 in RP remain unclear. Therefore, this study aimed to investigate the effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on RP and ACE2/angiotensin-(1–7)/Mas receptor pathway activation. We found that radiotherapy decreased the expression of ACE2 and that overexpression of ACE2 alleviated lung injury in an RP mouse model. Moreover, captopril and valsartan restored ACE2 activation; attenuated P38, ERK, and p65 phosphorylation; and effectively mitigated RP in the mouse model. Further systematic retrospective analysis illustrated that the incidence of RP in patients using renin-angiotensin system inhibitors (RASis) was lower than that in patients not using RASis (18.2% vs. 35.8% at 3 months, p = 0.0497). In conclusion, the current findings demonstrate that ACE2 plays a critical role in RP and suggest that RASis may be useful potential therapeutic drugs for RP. [ABSTRACT FROM AUTHOR]

Severe acute respiratory coronavirus 2 (SARS-CoV-2) infection in the young and healthy usually results in an asymptomatic or mild viral syndrome, possibly through an erythropoietin (EPO)-dependent, protective evolutionary landscape. In the old and in the presence of co-morbidities, however, a potentially lethal coronavirus disease 2019 (COVID-19) cytokine storm, through unrestrained renin-angiotensin aldosterone system (RAAS) hyperactivity, has been described. Multifunctional microRNA-155 (miR-155) elevation in malaria, dengue virus (DENV), the thalassemias, and SARS-CoV-1/2, plays critical antiviral and cardiovascular roles through its targeted translational repression of over 140 genes. In the present review, we propose a plausible miR-155-dependent mechanism whereby the translational repression of AGRT1, Arginase-2 and Ets-1, reshapes RAAS towards Angiotensin II (Ang II) type 2 (AT2R)-mediated balanced, tolerable, and SARS-CoV-2-protective cardiovascular phenotypes. In addition, it enhances EPO secretion and endothelial nitric oxide synthase activation and substrate availability, and negates proinflammatory Ang II effects. Disrupted miR-155 repression of AT1R + 1166C-allele, significantly associated with adverse cardiovascular and COVID-19 outcomes, manifests its decisive role in RAAS modulation. BACH1 and SOCS1 repression creates an anti-inflammatory and cytoprotective milieu, robustly inducing antiviral interferons. MiR-155 dysregulation in the elderly, and in comorbidities, allows unimpeded RAAS hyperactivity to progress towards a particularly aggressive COVID-19 course. Elevated miR-155 in thalassemia plausibly engenders a favorable cardiovascular profile and protection against malaria, DENV, and SARS-CoV-2. MiR-155 modulating pharmaceutical approaches could offer novel therapeutic options in COVID-19. [ABSTRACT FROM AUTHOR]

The brain angiotensin II acting via AT1 receptors is a prominent mechanism involved in physiological and behavioral responses during aversive situations. The AT2 receptor has also been implicated in stress responses, but its role was less explored. Despite these pieces of evidence, the brain sites related to control of the changes during aversive threats by the brain renin-angiotensin system (RAS) are poorly understood. The bed nucleus of the stria terminalis (BNST) is a limbic structure related to the cardiovascular responses by stress, and components of the RAS system were identified in this forebrain region. Therefore, we investigated the role of angiotensinergic neurotransmission present within the BNST acting via local AT1 and AT2 receptors in cardiovascular responses evoked by an acute session of restraint stress in rats. For this, rats were subjected to bilateral microinjection of either the angiotensin-converting enzyme inhibitor captopril, the selective AT1 receptor antagonist losartan, or the selective AT2 receptor antagonist PD123319 before they underwent the restraint stress session. We observed that BNST treatment with captopril reduced the decrease in tail skin temperature evoked by restraint stress, without affecting the pressor and tachycardic responses. Local AT2 receptor antagonism within the BNST reduced both the tachycardia and the drop in tail skin temperature during restraint. Bilateral microinjection of losartan into the BNST did not affect the restraint-evoked cardiovascular changes. Taken together, these data indicate an involvement of BNST angiotensinergic neurotransmission acting via local AT2 receptors in cardiovascular responses during stressful situations. [ABSTRACT FROM AUTHOR]

The sex differences of age-related changes in the functional activity and expression of receptor and regulatory proteins of the renin–angiotensin system (RAS) in the aorta and myocardium of rats is evaluated. It was found that, with age in females, the sensitivity of the aorta to the vasoconstriction action of angiotensin II increases, while in older males it remains unchanged. In the aorta of old females, a decrease in the mRNA levels of ACE, MasR, and ACE2 was revealed by 1.6, 1.8, and 4.4 times, respectively. It has been shown that during aging in the left ventricle of females, the level of MasR and ACE2 mRNA decreases; in males, on the contrary, the level of ACE and MasR mRNA increases. The results obtained indicate the sexual characteristics of age-related changes in RAS activity in the vessels and heart of rats. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) plays a pivotal role in the maintenance of volume homeostasis and blood pressure. In addition to the well-studied systemic RAS, local RAS have been documented in various tissues, including the kidney. Given the role of the intrarenal RAS in the pathogenesis of hypertension, a role established via various pharmacologic and genetic studies, substantial efforts have been made to unravel the processes that govern intrarenal RAS activity. In particular, several mechanisms have been proposed to explain the rise in intrarenal angiotensin II (Ang II) that accompanies Ang II infusion, including increased angiotensin type 1 receptor (AT1R)-mediated uptake of Ang II and enhanced intrarenal Ang II production. However, experimentally isolating their contribution to the intrarenal accumulation of Ang II in Ang II–induced hypertension is challenging, given that they are fundamentally connected. Computational modelling is advantageous because the feedback underlying each mechanism can be removed and the effect on intrarenal Ang II can be studied. In this work, the mechanisms governing the intrarenal accumulation of Ang II during Ang II infusion experiments are delineated and the role of the intrarenal RAS in Ang II-induced hypertension is studied. To accomplish this, a compartmental ODE model of the systemic and intrarenal RAS is developed and Ang II infusion experiments are simulated. Simulations indicate that AT1R-mediated uptake of Ang II is the primary mechanism by which Ang II accumulates in the kidney during Ang II infusion. Enhanced local Ang II production is unnecessary. The results demonstrate the role of the intrarenal RAS in the pathogenesis of Ang II-induced hypertension and consequently, clinical hypertension associated with an overactive RAS. [ABSTRACT FROM AUTHOR]

Endothelial apoptosis caused by activation of renin-angiotensin system (RAS) plays a vital part in the occurrence and progress of hypertension. Angiotensin-(1–9) (Ang-(1–9)) is a peptide of the counter-regulatory non-classical RAS with anti-hypertensive effects in vascular endothelial cells (ECs). However, the mechanism of action remains unclear. Considering that the endothelial apoptosis was closely related to endoplasmic reticulum stress (ERS) and mitochondrial function. Herein, we aimed to elucidate the effects of Ang-(1–9) on endothelial apoptosis and the underlying molecular mechanism in angiotensin II (Ang II) induced hypertension. In human umbilical vascular endothelial cells (HUVECs), we observed Ang-(1–9) inhibited Ang II-induced ERS associated endothelial apoptosis. Mechanically, Ang-(1–9) inhibited endothelial apoptosis by blocking CNPY2/PERK mediated CaMKII/Drp1-dependent mitochondrial fission and eIF2α/CHOP signal. Consistent with above effects in HUVECs, in Ang II-induced hypertensive mice, we found administration of exogenous Ang-(1–9) attenuated endothelial apoptosis and arterial blood pressure, which were mediated by CNPY2/PERK signaling pathway. Our study indicated Ang-(1–9) inhibited Ang II-induced hypertension through CNPY2/PERK pathway. These findings may provide new insights for prevention and treatment of hypertension in future. [ABSTRACT FROM AUTHOR]

The renin–angiotensin–aldosterone-systems (RAAS) play a central role in the pathophysiology of congestive heart failure (CHF), justifying the use of angiotensin converting enzyme inhibitors (ACEi) in dogs and humans with cardiac diseases. Seminal studies in canine CHF had suggested that the pharmacological action of benazepril was relatively independent of doses greater than 0.25 mg/kg P.O, thereby providing a rationale for the European labeled dose of benazepril in dogs with CHF. However, most of these earlier studies relied on measures of ACE activity, a sub-optimal endpoint to characterize the effect of ACEi on the RAAS. The objectives of this study were (i) to expand on previous mathematical modeling efforts of the dose-exposure–response relationship of benazepril on biomarkers of the RAAS which are relevant to CHF pathophysiology and disease prognosis; and (ii) to develop a software implementation capable of simulating clinical trials in benazepril in dogs bedside dose optimization. Our results suggest that 0.5 mg/kg PO q12h of benazepril produces the most robust reduction in angiotensin II and upregulation of RAAS alternative pathway biomarkers. This model will eventually be expanded to include relevant clinical endpoints, which will be evaluated in an upcoming prospective trial in canine patients with CHF. [ABSTRACT FROM AUTHOR]

We recently reported exacerbated endotoxic signs of neuroinflammation and autonomic defects in offspring of preeclamptic (PE) dams. Here, we investigated whether PE programming similarly modifies hemodynamic and renal vasoconstrictor responsiveness to endotoxemia in PE offspring and whether this interaction is modulated by gestational angiotensin 1–7 (Ang1-7). Preeclampsia was induced by gestational treatment with L-NAME. Adult offspring was challenged with lipopolysaccharides (LPS, 5 mg/kg) and systolic blood pressure (SBP) and renal vasoconstrictions were assessed 4 h later. Male, but not female, offspring of PE rats exhibited SBP elevations that were blunted by LPS. Renal vasoconstrictions induced by angiotensin II (Ang II), but not phenylephrine, were intensified in perfused kidneys of either sex. LPS blunted the heightened Ang II responses in male, but not female, kidneys. While renal expressions of AT1-receptors and angiotensin converting enzyme (ACE) were increased in PE offspring of both sexes, ACE2 was upregulated in female offspring only. These molecular effects were diminished by LPS in male offspring. Gestational Ang1-7 caused sex-unrelated attenuation of phenylephrine vasoconstrictions and preferentially downregulated Ang II responses and AT1-receptor and nuclear factor-kB (NFkB) expressions in females. Together, endotoxemia and Ang1-7 offset in sexually-related manners imbalances in renal vasoconstriction and AT1/ACE/ACE2 signaling in PE offspring. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is associated with morbidity, rehospitalization and polypharmacy. The incidence rate of mortality in HF patients with polypharmacy is poorly studied. We examine the association of polypharmacy with mortality risk in incident hospitalized HF patients with a primary diagnosis after discharge from the hospital using Quebec administrative databases, Canada from 1999 to 2015. Polypharmacy, cardiovascular (CV) polypharmacy and non-CV polypharmacy were respectively defined as exposure to ≥ 10 drugs, ≥ 5 CV drugs and ≥ 5 non-CV drugs within three months prior to the case or the control selection date. We conducted a nested case–control study to estimate rate ratios (RR) of all-cause mortality using a multivariate conditional logistic regression during one-year of follow-up. We identified 12,242 HF patients with a mean age of 81.6 years. Neither CV polypharmacy (RR 0.97, 95%CI 0.82–1.15) nor non-CV polypharmacy (RR 0.93, 95%CI 0.77–1.12) were associated with lower mortality risk. However, all polypharmacy (RR 1.31, 95%CI 1.07–1.61) showed an association with mortality risk. Myocardial infarction, valvular disease, peripheral artery disease, diabetes, major bleeding, chronic kidney disease, high comorbidity score, high Frailty score, hydralazine and spironolactone users were associated with increasing mortality risk, ranging from 15 to 61%, while use of angiotensin II inhibitors, beta-blockers, statins, anticoagulant, and antiplatelets were associated with lower risk, ranging from 23 to 32%. [ABSTRACT FROM AUTHOR]

Background: Telmisartan is a non-peptide angiotensin II receptor antagonist which acts by ACE/AngII/AT1 axis blockade (ARB). In the last years increasing evidence of its metabolic benefits pointed out this drug as the most promising ARB for nonalcoholic fatty liver disease (NAFLD) treatment. The aim of the present study was to investigate the Telmisartan effect on treating NAFLD in mice fed with a high-fat diet evaluating liver gene modulation. Twenty-four male mice were divided into four groups and fed for 60 days with a standard diet (ST), standard diet plus TEL (ST+TEL 5 mg/kg/day by gavage for 4 weeks), high-fat diet (HFD), or high-fat diet plus TEL (HFD+TEL 5 mg/kg/day by gavage for 4 weeks). Body weight, lipid profile, insulin, alanine transaminase, and aspartate aminotransferase were evaluated. Liver histology was analyzed. US imaging was performed to access liver dimension and echogenicity and also epididymal fat pad thickness. The expression of proinflammatory resistin/TRL4/MYD88 pathway was analyzed. Results: The main findings showed that TEL reduced the resistin, TRL4, and Myd88 liver expression in the HFD + TEL group when compared to the obese control group (HFD). Decreased hepatic steatosis in the HFD + TEL group demonstrated by US measurements of the liver longitudinal axis and echogenicity were observed. In addition, TEL reduced epididymal adipose pad thickness, body weight, transaminases, and improved glucose tolerance test and HDL cholesterol. Conclusions: We observed that Telmisartan treatment improved metabolism, decreasing NAFLD. Telmisartan improves metabolic and lipid profile and liver steatosis of obese mice [ABSTRACT FROM AUTHOR]

We examined urine excretion during primary acute sympathetic activation (PASA) in Wistar–Kyoto rats with myocardial infarction (MI). The rats underwent unilateral renal denervation (RDN) 7 weeks after coronary artery ligation. 4–10 days later, an acute experiment was performed under anesthetized conditions (n = 8 rats). Isolated carotid sinus pressure was changed stepwise from 60 to 180 mmHg, and the relationship between the arterial pressure (AP) and the normalized urine flow (nUF, urine flow normalized by the body weight) was examined. After obtaining the control data, an angiotensin II type 1 receptor blocker telmisartan (2.5 mg/kg) was intravenously administered. The effects of RDN, telmisartan, and heart weight (biventricular weight) on the relationship between AP and nUF were examined using multiple regression analyses. Regarding the slope of nUF versus AP (nUFslope), the constant term of the regression was positive (0.315 ± 0.069 μL·min−1·kg−1·mmHg−1), indicating that nUF increased with AP. The heart weight had a negative effect on nUFslope (P < 0.05), suggesting that the severity of MI was associated with the impairment of urine excretion. Telmisartan increased nUFslope by 0.358 ± 0.080 μL·min−1·kg−1·mmHg−1 (P < 0.001), whereas RDN had no significant effect on this parameter. The results indicate that unilateral RDN was unable to abolish the effect of the renin–angiotensin system on urine excretion during PASA. Circulating or locally produced angiotensin II, rather than ongoing renal sympathetic nerve activity, played a dominant role in the impairment of urine excretion during PASA in rats with chronic MI. [ABSTRACT FROM AUTHOR]

The renin–angiotensin system (RAS) plays a crucial role and coordinates multiple body functions through its hormonal mechanism. The RAS is supported in its function by numerous peptides such as angiotensin II (Ang II), Ang IV, Ang III, angiotensin (1-7) and (1-9). The system formed by ACE2/Ang(1-7)/MASr is a regulatory pathway within the RAS system and its functions are different from those of the ACE/Ang II/AT-1r system. Recently, it has been discovered that a key role of the RAS and the ACE2/Ang(1-7)/MASr system is in inflammatory processes such as cardiac hypertrophy and heart failure. Studies are ongoing to better understand and comprehend the function of the RAS in inflammation. Recent evidence associates AT-1r antagonists with a cardioprotective, anti-inflammatory, and anti-hypertrophic role. In this in vitro study, we demonstrate the protective role of treatment (50 and 200 μM) of an AT-1r antagonist, irbesartan, on hypoxia and inflammation-induced damage in cardiomyocytes. [ABSTRACT FROM AUTHOR]

Background: This study aimed to explore a correlation between plasma angiotensin II/(1–7) (Ang II/Ang-(1–7)) ratio, anti-ACE2 autoantibodies level and disease activity in rheumatoid arthritis (RA) patients. Methods: In a pilot study, the plasma level of Ang II, Ang-(1–7), and anti-ACE2 autoantibodies of twelve RA patients (five in active stage and seven in remission) were measured using an LC–MS/MS method and an ELISA kit, respectively. Results: The Ang-(1–7) level was significantly higher in the remission group than in the active RA patients (7.63 ± 2.61 vs. 1.29 ± 0.81 ng/mL). On the contrary, the Ang II level was higher in those with active RA compared to the remission group (5.43 ± 1.82 vs. 0.87 ± 0.16 ng/mL). The mean ELISA score of anti-ACE2 autoantibodies in patients with active RA was significantly higher than patients in remission (1.41 ± 0.11 vs. 1.81 ± 0.11, p < 0.05). Conclusion: This study result suggests that the angiotensin peptides concentration and anti-ACE2 autoantibodies levels can be used as biomarkers of RA. This will help clinicians evaluate better treatment success rates and disease prognosis to prevent long-term complications of RA. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD), an anxiety-related syndrome, is associated with increased risk for cardiovascular diseases. The present study investigated whether predator scent (PS) stress, a model of PTSD, induces sensitization of hypertension and anxiety-like behaviors and underlying mechanisms related to renin–angiotensin systems (RAS) and inflammation. Coyote urine, as a PS stressor, was used to model PTSD. After PS exposures, separate cohorts of rats were studied for hypertensive response sensitization (HTRS), anxiety-like behaviors, and changes in plasma levels and mRNA expression of several components of the RAS and proinflammatory cytokines (PICs) in the lamina terminalis (LT), paraventricular nucleus (PVN), and amygdala (AMY). Rats exposed to PS as compared to control animals exhibited (1) a significantly greater hypertensive response (i.e., HTRS) when challenged with a slow-pressor dose of angiotensin (ANG) II, (2) significant decrease in locomotor activity and increase in time spent in the closed arms of a plus maze as well as general immobility (i.e., behavioral signs of increased anxiety), (3) upregulated plasma levels of ANG II and interleukin-6, and (4) increased expression of message for components of the RAS and PICs in key brain nuclei. All the PS-induced adverse effects were blocked by pretreatment with either an angiotensin-converting enzyme antagonist or a tumor necrosis factor-α inhibitor. The results suggest that PS, used as an experimental model of PTSD, sensitizes ANG II-induced hypertension and produces behavioral signs of anxiety, probably through upregulation of RAS components and inflammatory markers in plasma and brain areas associated with anxiety and blood pressure control. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a serious public health problem, affecting 69 million people worldwide annually. Mild TBI (mTBI) comprises the majority of the cases and remains the most neglected TBI severity. Its intricate pathophysiology involves complex cellular and molecular processes that remain uncomprehended. Although the renin-angiotensin system (RAS) has its well-known roles in blood pressure regulation and fluid balance, accumulating evidence demonstrates its active expression and signaling in the central nervous system. Over the past years, pre-clinical studies have been supporting the role of RAS in mTBI. However, particularly for human TBI, evidence is still missing. Herein, we investigated peripheral levels of angiotensin II (Ang II) and angiotensin-converting enzyme (ACE), components of RAS classical axis, as well as angiotensin-(1-7) [Ang-(1-7)] and ACE2, components of RAS counter-regulatory axis, in 28 mTBI patients and 24 healthy controls. In the first 24 h, mTBI patients displayed lower ACE (p = 0.0004) and ACE2 (p = 0.0047) concentrations and an increase in Ang II (p = 0.0234) and Ang-(1-7) (p = 0.0225) levels compared to controls. Interestingly, at 30 days follow-up, mTBI patients increased the levels of ACE (p = 0.0415) and ACE2 (p = 0.0416) along with a decrease in Ang II (p = 0.0039) and Ang-(1-7) (p = 0.0015) concentrations compared with their measures at 24 h after TBI. Also, our receiver operating curve (ROC) analysis demonstrated that ACE concentration was a good predictor of mTBI diagnosis (AUC = 0.798, p < 0.0001). The current study provides the first clinical evidence of RAS molecule's involvement in mTBI and their possible role as discriminating biomarkers. [ABSTRACT FROM AUTHOR]

Hypertension is one of the most prevalent cardiovascular disorders worldwide, affecting 1.13 billion people, or 14% of the global population. Hypertension is the single biggest risk factor for cerebrovascular dysfunction. According to the American Heart Association, high blood pressure (BP), especially in middle-aged individuals (~ 40 to 60 years old), is associated with an increased risk of dementia, later in life. Alzheimer's disease and cerebrovascular disease are the two leading causes of dementia, accounting for around 80% of the total cases and usually combining mixed pathologies from both. Little is known regarding how hypertension affects cognitive function, so the impact of its treatment on cognitive impairment has been difficult to assess. The brain renin-angiotensin system (RAS) is essential for BP regulation and overactivity of this system has been established to precede the development and maintenance of hypertension. Angiotensin II (Ang-II), the main peptide within this system, induces vasoconstriction and impairs neuro-vascular coupling by acting on brain Ang-II type 1 receptors (AT1R). In this review, we systemically analyzed the association between RAS and biological mechanisms of cognitive impairment, from the perspective of AT1R located in the central nervous system. Additionally, the possible contribution of brain AT1R to global cognition decline in COVID-19 cases will be discussed as well. [ABSTRACT FROM AUTHOR]

Purpose: We investigated lower limb strength training (LLST)'s effect on the levels of renin angiotensin system (RAS) molecules in urine and serum. Methods: Twelve male volunteers with 23.4 ± 2.7 years old performed our LLST protocol for 10 weeks. The effect of LLST was evaluated based on urine and serum levels of RAS molecules, including Angiotensin II, Ang-(1–7), angiotensin converting enzyme ACE 1 and ACE 2, before and immediately after the first (S1) and the last (S30) training sessions. Results: The training protocol significantly reduced the percentage of fat and increased the total lean mass. Serum and urinary levels of Ang II were higher after the last session in comparison to levels before this session as well as if compared to values after the first exercise session. Levels of Ang-(1–7) significantly increased in serum and urine after first and last sessions and in the comparison to values before and after last session to those before and after first session, respectively. Levels of ACE1 and ACE2 did not modify in any condition. In addition, LLST seems to chronically shift the balance between both RAS axes toward the alternative axis based on the analysis of Ang-(1–7)/Ang II ratio. Conclusion: LLST acutely and chronically modified serum and urinary concentrations of Ang II and Ang-(1–7). [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) is a leading non-communicable disease with a high fatality rate worldwide. Hypertension, a common cardiovascular condition, is a significant risk factor for the development of heart failure because the activation of the renin-angiotensin system (RAS) is considered to be the major promoting reason behind myocardial fibrosis (MF). In this study, Angiotensin II (Ang II) stimulation-induced endothelial to mesenchymal transition (End-MT) in HCAECs, including the decrease of CD31 level, the increase of α-SMA, collagen I, slug, snail, and TGF-β1 levels, and the promotion of Smad2/3 phosphorylation. Meanwhile, the c-Ski level was reduced in Ang II-stimulated HCAECs. In HCAECs, Ang II-induced changes could be partially attenuated by c-Ski overexpression. miR-214-3p directly targeted c-Ski and inhibited c-Ski expression. Moreover, miR-214-3p inhibition reduced Ang II-caused End-MT in HCAECs. miR-214-3p overexpression further enhanced Ang II-induced End-MT, while c-Ski overexpression could markedly reverse the effects of miR-214-3p overexpression. In the Ang II-induced mouse cardiac hypertrophic model, Ang II-caused increase of cellular cross-sectional area and cardiac fibrosis were partially ameliorated by LV-c-Ski; when mice were co-treated with LV-c-Ski and agomir-214-3p, the beneficial effects of LV-c-Ski were reversed. In conclusion, the miR-214-3p/c-Ski axis modulated Ang II-induced End-MT in HCAECs and cardiac hypertrophy and fibrosis in the mice model. [ABSTRACT FROM AUTHOR]

Among numerous choices in cardiovascular therapies used for the management of hypertension and heart failure, drugs affecting the renin–angiotensin–aldosterone system (RAAS) hold substantial therapeutic roles. Therapies aimed at modifying the RAAS and its overactivation are employed for the management of various insidious disorders. In the pharmacologic perspective, RAAS is one of the frequently manipulated systems for the management of hypertension, heart failure, myocardial infarction, and renal disease. The RAAS pharmacologic interventions principally include the ACE inhibitors, the angiotensin II-AT1 receptor blockers, the mineralocorticoid receptor antagonists, and the direct renin inhibitors. In addition, therapeutic implication of ACE2/angiotensin (1–7)/Mas receptor activation using various ligands is being explored owing to their anti-inflammatory, anti-fibrotic, vasodilatory, and cardiovascular defensive roles. Moreover, being considered as the counter-regulatory arm of AT1 receptor, the potential role of AT2 receptor activation using selective AT2 receptor agonist is currently investigated for its efficacy in pulmonary complications. As an important regulator of fluid volume, blood pressure, and cardiovascular–renal function, the RAAS has been documented as a diversified intricate system with several therapeutic possibilities coupled with their fundamental structural and functional modulatory roles in cardiovascular, renal, and other systems. The RAAS possesses a number of regulatory, deregulatory, and counter-regulatory axes of physiopathologic importance in health and disease. The counter-regulatory arms of the RAAS might play an essential role in mitigating cardiovascular, renal, and pulmonary pathologies. In light of this background, we sought to explore the classical and counter-regulatory axes/arms of the RAAS and their imperative roles in physiologic functions and disease pathogenesis. [ABSTRACT FROM AUTHOR]

Renovascular hypertension is one of the most relevant causes of secondary hypertension, mostly caused by atherosclerotic renovascular stenosis or fibromuscular dysplasia. The increase in angiotensin II production, oxidative stress, and formation of peroxynitrite promotes the decrease in nitric oxide (NO) availability and the development of hypertension, renal and endothelial dysfunction, and cardiac and vascular remodeling. The NO produced by nitric oxide synthases (NOS) acts as a vasodilator; however, endothelial NOS uncoupling (eNOS) also contributes to NO reduced availability in renovascular hypertension. NO donors and NO-derived metabolites have been investigated in experimental renovascular hypertension and have shown promissory effects in attenuating blood pressure and organ damage in this condition. Therefore, understanding the role of decreased NO in the pathophysiology of renovascular hypertension promotes the study and development of NO donors and molecules that can be converted into NO (such as nitrate and nitrite), contributing for the treatment of this condition in the future. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) is involved in cardiovascular and hydroelectrolytic control, being associated with the development of hypertension. The restraint stress (RS) model is an aversive situation, which promotes a sustained increase in blood pressure and heart rate, and stimulation of the hypothalamic–pituitary–adrenal axis. Stress leads to an increase of angiotensin-II contents both in the circulation and the central nervous system (CNS), as well as an increased expression of AT-1 receptors in CNS structures related to stress. Stressful stimuli are associated with the modulation of autonomic nervous system, as well as baroreflex; changes in this adjustment mechanism are related to cardiovascular diseases. We hypothesized that RAS is involved in the modulation of autonomic, neuroendocrine, and functional RS-caused alterations. The intravenous (i.v) pretreatment of rats with lisinopril, an angiotensin-converting-enzyme inhibitor, reduced the RS-evoked pressor response. The doses of 0.1 and 0.3 mg/kg also reduced the RS-evoked tachycardia, while in the dose of 1 mg/kg of lisinopril potentiated the tachycardic one. Additionally, i.v. pretreatment with losartan, a selective AT-1 receptor antagonist, reduced the pressor and the tachycardic responses caused by RS. Pretreatment with lisinopril 0.3 mg/kg increased the power of the low frequency (LF) band of the systolic BP spectrum after the treatment without affecting this parameter during RS. The pretreatment with losartan 1 mg/kg increased the power of the high frequency (HF) band and reduced the LF (n.u.) and the LF/HF ratio of the pulse interval spectrum in the first hour of RS. Concerning baroreflex sensitiveness (SBR), pretreatments with losartan or lisinopril did not affect the gain of the baroreflex sequences. However, the pretreatment with losartan reduced the baroreflex effectiveness index of the total sequences in the third hour of the RS. These results indicate that Ang-II, via the AT-1 receptor, plays a facilitating influence on the cardiovascular response caused by RS; facilitates sympathetic activation and reduces parasympathetic activity related to RS; facilitates the baroreflex activation during RS and favors corticosterone release under this stress model. The impairment of Ang-II synthesis, as well as the blockade of AT-1 receptors, may constitute an important pharmacological strategy to treat cardiovascular consequences caused by stress. [ABSTRACT FROM AUTHOR]

Introduction: Angiotensin-converting enzyme 2 (ACE2) is a key enzyme of the renin-angiotensin system (RAS) that has been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). Enhancing ACE2 activity using GSK2586881, a recombinant form of human ACE2, could be beneficial in diseases such as ARDS but may blunt the hypoxic pulmonary vasoconstriction (HPV) response and potentially impact systemic and tissue oxygenation. This study aimed to evaluate the effect of GSK2586881 0.8 mg/kg on HPV response in healthy adult volunteers during exercise under hypoxic conditions. Methods: In this phase I, randomised, double-blind (sponsor open) study, GSK2586881 or placebo was administered as a single intravenous (IV) dose in a two-period crossover design. Treatment periods were separated by a washout period of 3–14 days. The primary endpoint was change from baseline in pulmonary artery systolic pressure (PASP) measured by echocardiography. Secondary endpoints included RAS peptides and oxygen saturation. Results: Seventeen adults aged 18–40 years were randomised to treatment. There were no clinically relevant differences (defined as a reduction of ≥ 5 mmHg) in change from baseline in PASP between GSK2586881 and placebo. GSK2586881 was well tolerated, with no serious adverse events, no worsening of hypoxaemia and no evidence of immunogenicity. The study was terminated early after review of the data, which showed that the predefined success criteria had not been met. Following GSK2586881 administration, levels of the RAS peptide angiotensin II decreased while angiotensin (1-7) increased, as expected, indicating that GSK2586881 was pharmacologically active. Conclusions: A single IV dose of GSK2586881 0.8 mg/kg was well tolerated but did not impact the acute HPV response in healthy volunteers. [ABSTRACT FROM AUTHOR]

Background: The renin–angiotensin system (RAS) is activated in inflammatory bowel disease (IBD), and vitamin D deficiency aggravates the development of colitis, but the relationship between the local colonic RAS and vitamin D is unclear with regard to the pathogenesis of IBD. Aims: To investigate whether vitamin D suppresses the local colonic RAS to prevent colonic mucosal inflammation in a mouse model of experimental colitis. Methods: C57BL/6 mice fed vitamin D-deficient (VDD) diet for 8 weeks were induced to colitis by 2,4,6-trinitrobenzenesulfonic acid (TNBS), with mice fed vitamin D-sufficient (VDS) diet as controls. Colitis severity was assessed by histology, and pro-inflammatory cytokines, RAS components, and signaling pathways were quantified by real-time RT-PCR and Western blotting. Results: C57BL/6 mice fed the VDD diet for 8 weeks exhibited significantly lower serum 25(OH)D3 concentrations compared to mice fed the VDS diet. When these VDD mice were induced to colitis by TNBS, they exhibited more severe colonic inflammation and developed more severe colitis compared to the VDS counterparts. VDD diet feeding resulted in higher production of mucosal pro-inflammatory cytokines, higher activation of the myosin light chain kinase-tight junction regulatory pathway, and greater increases in mucosal permeability. VDD diet feeding also enhanced colonic RAS activation. Treatment with angiotensin II receptor blocker losartan markedly alleviated colitis in TNBS-induced VDD mice. Conclusion: Vitamin D deficiency promotes colonic inflammation at least in part due to over activation of the local RAS in the colon. [ABSTRACT FROM AUTHOR]

The renin–angiotensin system is involved in the regulation of various heart diseases. The present study aimed to determine the effects of angiotensin (Ang)-(3–7) on cardiac remodeling and its downstream signaling pathways in neonatal rat cardiomyocytes (NRCMs) and neonatal rat cardiac fibroblasts (NRCFs). The administration of Ang-(3–7) alleviated isoprenaline (ISO)-induced cardiac hypertrophy and fibrosis of mice. ISO treatment increased the levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and beta-myosin heavy chain (β-MHC) in NRCMs, and reduced the levels of collagen I, collagen III, fibronectin, and alpha-smooth muscle actin (α-SMA) in NRCFs. These changes were inhibited by Ang-(3–7) administration. The levels of protein kinase A (PKA), phosphorylated phosphatidylinositol-3-kinase (p-PI3K), and phosphorylated protein kinase B (p-Akt) were increased in NRCMs and NRCFs treated with ISO. The increase of PKA, but not p-PI3K or p-Akt was attenuated by Ang-(3–7) treatment in NRCMs. The increases of p-PI3K and p-Akt, but not PKA were reversed by Ang-(3–7) treatment in NRCFs. Treatment with cAMP or PKA overexpression reversed the attenuating effects of Ang-(3–7) on ISO-induced hypertrophy of NRCMs. The administration of PI3K inhibitor or Akt inhibitor alleviated ISO-induced fibrosis of NRCFs. These results indicated that Ang-(3–7) could alleviate cardiac remodeling. The administration of Ang-(3–7) attenuated hypertrophy of NRCMs via inhibiting the cAMP/PKA signaling pathway, and alleviated fibrosis of NRCFs via inhibiting PI3K/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) alters brain function and is a crucial public health concern worldwide. TBI triggers the release of inflammatory mediators (cytokines) that aggravate cerebral damage, thereby affecting clinical prognosis. The renin angiotensin system (RAS) plays a critical role in TBI pathophysiology. RAS is widely expressed in many organs including the brain. Modulation of the RAS in the brain via angiotensin type 1 (AT1) and type 2 (AT2) receptor signaling affects many pathophysiological processes, including TBI. AT1R is highly expressed in neurons and astrocytes. The upregulation of AT1R mediates the effects of angiotensin II (ANG II) including release of proinflammatory cytokines, cell death, oxidative stress, and vasoconstriction. The AT2R, mainly expressed in the fetal brain during development, is also related to cognitive function. Activation of this receptor pathway decreases neuroinflammation and oxidative stress and improves overall cell survival. Numerous studies have illustrated the therapeutic potential of inhibiting AT1R and activating AT2R for treatment of TBI with variable outcomes. In this review, we summarize studies that describe the role of brain RAS signaling, through AT1R and AT2R in TBI, and its modulation with pharmacological approaches. [ABSTRACT FROM AUTHOR]

The intrarenal renin-angiotensin system is critical for the regulation of tubule sodium reabsorption, renal haemodynamics and blood pressure. The excretion of renin in urine can result from its increased filtration, the inhibition of renin reabsorption by megalin in the proximal tubule, or its secretion by the principal cells of the collecting duct. Modest increases in circulating or intrarenal angiotensin II (ANGII) stimulate the synthesis and secretion of angiotensinogen in the proximal tubule, which provides sufficient substrate for collecting duct-derived renin to form angiotensin I (ANGI). In models of ANGII-dependent hypertension, ANGII suppresses plasma renin, suggesting that urinary renin is not likely to be the result of increased filtered load. In the collecting duct, ANGII stimulates the synthesis and secretion of prorenin and renin through the activation of ANGII type 1 receptor (AT1R) expressed primarily by principal cells. The stimulation of collecting duct-derived renin is enhanced by paracrine factors including vasopressin, prostaglandin E2 and bradykinin. Furthermore, binding of prorenin and renin to the prorenin receptor in the collecting duct evokes a number of responses, including the non-proteolytic enzymatic activation of prorenin to produce ANGI from proximal tubule-derived angiotensinogen, which is then converted into ANGII by luminal angiotensin-converting enzyme; stimulation of the epithelial sodium channel (ENaC) in principal cells; and activation of intracellular pathways linked to the upregulation of cyclooxygenase 2 and profibrotic genes. These findings suggest that dysregulation of the renin-angiotensin system in the collecting duct contributes to the development of hypertension by enhancing sodium reabsorption and the progression of kidney injury. [ABSTRACT FROM AUTHOR]

Even though effective drugs for treating hypertension are available, a great percentage of patients have inadequate control of their blood pressure. Unwanted side effects and inappropriate oral drug adherence are important factors that contribute to the global problem of uncontrolled hypertension. Vaccination could provide a revolutionary therapy with long-lasting effects, increasing patient compliance and therefore better control of high blood pressure. Nowadays, current immunization approaches against hypertension target renin, angiotensin I, angiotensin II, and angiotensin II type 1 receptor, key elements of the renin-angiotensin system. This article reviews the different vaccination attempts with proteins and peptides against the different molecules of the renin-angiotensin system in the last two decades, safety issues, and other novel prospects biomarkers in hypertension, and summarizes the potential of this immunomodulatory approach in clinical practice. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 uses ACE2, an inhibitor of the Renin-Angiotensin-Aldosterone System (RAAS), for cellular entry. Studies indicate that RAAS imbalance worsens the prognosis in COVID-19. We present a consecutive retrospective COVID-19 cohort with findings of frequent pulmonary thromboembolism (17%), high pulmonary artery pressure (60%) and lung MRI perfusion disturbances. We demonstrate, in swine, that infusing angiotensin II or blocking ACE2 induces increased pulmonary artery pressure, reduces blood oxygenation, increases coagulation, disturbs lung perfusion, induces diffuse alveolar damage, and acute tubular necrosis compared to control animals. We further demonstrate that this imbalanced state can be ameliorated by infusion of an angiotensin receptor blocker and low-molecular-weight heparin. In this work, we show that a pathophysiological state in swine induced by RAAS imbalance shares several features with the clinical COVID-19 presentation. Therefore, we propose that severe COVID-19 could partially be driven by a RAAS imbalance. The SARS-CoV-2 receptor ACE2 is involved in the Renin-Angiotensin-Aldosterone System (RAAS). Over-activation of RAAS in swine results in a disease state similar to that of COVID-19 in human patients, suggesting that COVID-19 pathophysiology may be driven, at least in part, by an imbalance of this hormonal system. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review focuses on the associations between the renin-angiotensin system, hypertension, and severe acute respiratory syndrome (SARS-COV-2) infection. A brief prelude on the current state of affairs with COVID-19 is given. In addition to an overview of ACE2, Ang II, and Ang (1–7), this review presents a brief statement on hypertension, including the function of enzymes involved in the control of hypertension, cardiovascular disease, diabetes mellitus, and other malignancies. Recent Findings: There is currently no data in support of the concerns raised with the use of ACEIs/ARBs. Many researchers have voiced concerns that the use of ACEIs and ARBs may increase tissue ACE2 levels. These researchers therefore recommend that individuals on ACEIs/ARB's medications withhold such antihypertensive drugs, unless advised by their physicians to do so. Summary: SARS-CoV-2 uses ACE2 receptors as the port of entry to human hosts. ACE2 and ACE are different enzymes and ACE inhibitors do not inhibit ACE2. Therefore, the use of ARB's or ACEIs should not be discontinued if an individual is infected by SARS-CoV-2. Further studies are required to investigate the effect of ACEIs and ARBs on ACE2 expression and COVID-19. [ABSTRACT FROM AUTHOR]

The imbalance of the renin-angiotensin system is currently considered as a potentially important factor of the pathogenesis of COVID-19 disease. It has been shown previously in the murine model, that the expression of angiotensin-converting enzyme 2 (ACE2) on the cell surface is downregulated in response to the infection by SARS-CoV virus or recombinant spike protein (S protein) alone. In the case of natural infection, circulation of the S protein in a soluble form is unlikely. However, in SARS-CoV-2, a large fraction of S protein trimers is pre-processed during virion morphogenesis due to the presence of furin protease cleavage site between the S1 and S2 subunits. Therefore, S protein transition into the fusion conformation may be accompanied by the separation of the S1 subunits carrying the receptor-binding domains from the membrane-bound S2 subunits. The fate of the S1 particles shed due to the spontaneous "firing" of some S protein trimers exposed on the virions and on the surface of infected cells has been never investigated. We hypothesize that the soluble S1 subunits of the SARS-CoV-2 S protein shed from the infected cells and from the virions in vivo may bind to the ACE2 and downregulate cell surface expression of this protein. The decrease in the ACE2 activity on the background of constant or increased ACE activity in the lungs may lead to the prevalence of angiotensin II effects over those of angiotensin (1-7), thus promoting thrombosis, inflammation, and pulmonary damage. This hypothesis also suggests the association between less pronounced shedding of the S1 particles reported for the S protein carrying the D614G mutation (vs. the wild type D614 protein), and lack of increased severity of the COVID-19 infection caused by the mutant (D614G) SARS-CoV-2 strain, despite its higher infectivity and higher in vivo viral load. [ABSTRACT FROM AUTHOR]

The coronavirus disease (COVID-19) pandemic is a global health priority. Given that cardiovascular diseases (CVD) are the leading cause of morbidity around the world and that several trials have reported severe cardiovascular damage in patients infected with SARS-CoV-2, a substantial number of COVID-19 patients with underlying cardiovascular diseases need to continue their medications in order to improve myocardial contractility and to prevent the onset of major adverse cardiovascular events (MACEs), including heart failure. Some of the current life-saving medications may actually simultaneously expose patients to a higher risk of severe COVID-19. Angiotensin-converting enzyme 2 (ACE2), a key counter regulator of the renin-angiotensin system (RAS), is the main entry gate of SARS-CoV-2 into human host cells and an established drug target to prevent heart failure. In fact, ACE inhibitors, angiotensin II receptor blockers, and mineralocorticoid antagonists may augment ACE2 levels to protect organs from angiotensin II overload. Elevated ACE2 expression on the host cell surface might facilitate viral entrance, at the same time sudden nonadherence to these medications triggers MACEs. Hence, safety issues in the use of RAS inhibitors in COVID-19 patients with cardiac dysfunction remain an unsolved dilemma and need paramount attention. Although ACE2 generally plays an adaptive role in both healthy subjects and patients with systolic and/or diastolic dysfunction, we conducted a literature appraisal on its maladaptive role. Understanding the exact role of ACE2 in COVID-19 patients at risk of heart failure is needed to safely manage RAS inhibitors in frail and non-frail critically ill patients. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) remains a worldwide public health concern despite decades of research and the availability of numerous targeted therapies. While the intrinsic physiological mechanisms regulating cardiovascular function are similar between males and females, marked sex differences have been established in terms of CVD onset, pathophysiology, manifestation, susceptibility, prevalence, treatment responses and outcomes in animal models and clinical populations. Premenopausal females are generally protected from CVD in comparison to men of similar age, with females tending to develop cardiovascular complications later in life following menopause. Emerging evidence suggests this cardioprotection in females is, in part, attributed to sex differences in hormonal regulators, such as the renin–angiotensin system (RAS). To date, research has largely focused on canonical RAS pathways and shown that premenopausal females are protected from cardiovascular derangements produced by activation of angiotensin II pathways. More recently, a vasodilatory arm of the RAS has emerged that is characterized by angiotensin-(1-7) [(Ang-(1-7)], angiotensin-converting enzyme 2 and Mas receptors. Emerging studies provide evidence for a shift towards these cardioprotective Ang-(1-7) pathways in females, with effects modulated by interactions with estrogen. Despite well-established sex differences, female comparison studies on cardiovascular outcomes are lacking at both the preclinical and clinical levels. Furthermore, there are no specific guidelines in place for the treatment of cardiovascular disease in men versus women, including therapies targeting the RAS. This review summarizes current knowledge on sex differences in the cardiovascular actions of the RAS, focusing on interactions with gonadal hormones, emerging data for protective Ang-(1-7) pathways and potential clinical implications for established and novel therapies. [ABSTRACT FROM AUTHOR]

The article presents clinical reports on Acute bilateral vision loss in a toddler with stage 5 chronic kidney disease. Topics include impairment in blood pressure control by the autonomic nervous system or the renin–angiotensin–aldosterone system; and echocardiogram was completed to assess cardiac function and showed normal ventricular function with ejection fraction.

Objectives There are several types of research on the COVID-19 disease which have been conducting. It seems that prevailing over the pandemic would be achieved only by mastering over the virus pathophysiology. We tried to categorize the massive amount of available information for useful interpretation. Evidence acquisition We searched databases with different keywords and search strategies that focus on virulence and pathophysiology of COVID-19. The present review has aimed to gather and categorize all implemented drugs based on the susceptible virulence mechanisms, and the pathophysiological events in the host cells, discussing and suggesting treatments. Results As a result, the COVID-19 lifecycle were categorized as following steps: "Host Cell Attachment" which is mainly conducted with ACE2 receptors and TMPRSS2 from the host cell and Spike (S) protein, "Endocytosis Pathway" which is performed mainly by clathrin-mediated endocytosis, and "Viral Replication" which contains translation and replication of RNA viral genome. The virus pathogenicity is continued by "Inflammatory Reactions" which mainly caused moderate to severe COVID-19 disease. Besides, the possible effective therapeutics' mechanism and the pharmaceutical agents that had at least one experience as a preclinical or clinical study on COVID-19 were clearly defined. Conclusion The treatment protocol would be occasional based on the stage of the infection and the patient situation. The cocktail of medicines, which could affect almost all mentioned stages of COVID-19 disease, might be vital for patients with severe phenomena. [ABSTRACT FROM AUTHOR]

In this article the author talks about the dedication to the legendary physician and one of the most beloved value of Istanbul Medical Faculty, Professor Cemil Taşçıoğlu, who was actively working and sadly lost at Covid-19 pandemic in Turkey. It mentions that the SARS-CoV-2 is a respiratory pathogen sharing significant similarity with the SARS-CoV that caused an epidemic in 2002-2004 originated in China.

Excessive activation of the tissue renin–angiotensin system through angiotensin II (Ang II) type 1 receptor (AT1R) plays a pivotal role in the pathogenesis of hypertension and related organ injury. AT1R-associated protein (ATRAP/Agtrap) was identified as a molecule specifically interacting with the carboxyl- terminal domain of AT1R. The results of in vitro studies showed that ATRAP suppresses Ang II-mediated pathological responses in cardiovascular cells by promoting AT1R internalization. With respect to the tissue distribution and regulation of ATRAP expression in vivo, ATRAP is broadly expressed in many tissues as is AT1R including kidney. The results of in vivo study employing genetic engineered mice with modified ATRAP expression showed that ATRAP inhibits cardiovascular injuries provoked by Ang II-induced hypertension, along with preserving physiological AT1R signaling. In addition, we have shown that ATRAP functions as an endogenous modulator so as to prevent hypertension in response to pathological stimuli, by regulating renal sodium handling. Furthermore, ATRAP may have an AT1R-independent function of renal proximal tubule to protect aging and fibrosis. These results suggest the clinical potential benefit of an ATRAP activation strategy in the treatment of hypertension and cardiorenal and vascular diseases. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases have been implicated in diabetic microvascular complications. However, little is known about the pathophysiological links between MMP-10 and the renin-angiotensin system (RAS) in diabetic kidney disease (DKD). We tested the hypothesis that MMP-10 may be up-regulated in early stage DKD, and could be down-regulated by angiotensin II receptor blockade (telmisartan). Serum MMP-10 and TIMP-1 levels were measured in 268 type 2 diabetic subjects and 111 controls. Furthermore, histological and molecular analyses were performed to evaluate the renal expression of Mmp10 and Timp1 in a murine model of early type 2 DKD (db/db) after telmisartan treatment. MMP-10 (473 ± 274 pg/ml vs. 332 ± 151; p = 0.02) and TIMP-1 (573 ± 296 ng/ml vs. 375 ± 317; p < 0.001) levels were significantly increased in diabetic patients as compared to controls. An early increase in MMP-10 and TIMP-1 was observed and a further progressive elevation was found as DKD progressed to end-stage renal disease. Diabetic mice had 4-fold greater glomerular Mmp10 expression and significant albuminuria compared to wild-type, which was prevented by telmisartan. MMP-10 and TIMP-1 are increased from the early stages of type 2 diabetes. Prevention of MMP-10 upregulation observed in diabetic mice could be another protective mechanism of RAS blockade in DKD. [ABSTRACT FROM AUTHOR]

Epilepsy is one of the most prevalent neurological diseases and although numerous novel anticonvulsants have been approved, the proportion of patients who are refractory to medical treatment of seizures and have progressive co-morbidities such as cognitive impairment and depression remains at about 20-30%. In the last decade, extensive research has identified a therapeutic capacity of the components of the brain renin-angiotensin system (RAS) in seizure- and epilepsy-related phenomena. Alleviating the activity of RAS in the central nervous system is considered to be a potential adjuvant strategy for the treatment of numerous detrimental consequences of epileptogenesis. One of the main advantages of RAS is associated with its modulatory influence on different neurotransmitter systems, thereby exerting a fine-tuning control mechanism for brain excitability. The most recent scientific findings regarding the involvement of the components of brain RAS show that angiotensin II (Ang II), angiotensin-converting enzyme (ACE), Ang II type 1 (AT1) and type 2 (AT2) receptors are involved in the control of epilepsy and its accompanying complications, and therefore they are currently of therapeutic interest in the treatment of this disease. However, data on the role of different components of brain RAS on co-morbid conditions in epilepsy, including hypertension, are insufficient. Experimental and clinical findings related to the involvement of Ang II, ACE, AT1, and AT2 receptors in the control of epilepsy and accompanying complications may point to new therapeutic opportunities and adjuvants for the treatment of common co-morbid conditions of epilepsy. [ABSTRACT FROM AUTHOR]

Background: Hypertension causes the aorta to remodel and potentially stiffen. We aimed to compare the aortic remodelling response to hypertension as induced by adrenergic receptor activation versus renin-angiotensin-aldosterone system activation. Methods: Adult male C57BL/6 J mice were studied under seven conditions: untreated, and after 7/14/28-day subcutaneous infusion of 3880 ng/kg/min norepinephrine (NE) or 1000 ng/kg/min angiotensin II (AngII). After euthanasia, ascending/descending thoracic (ATA/DTA) and infrarenal abdominal (IAA) aortas were dissected, placed within a computer-controlled biaxial testing device, and subjected to isobaric (90 mmHg) vasoreactivity experiments to, among others, 1 μM phenylephrine + 1 mM L-NAME [1]. Under passive conditions, pressure-diameter tests were performed at 95/100/105% of the < i > in vivo axial stretch and axial force-length tests at 10/60/100/140 mmHg. Data were fit using a nonlinear constitutive model [1]. Results: Figure (bar charts, < i > n = 4-8 per group) shows passive metrics calculated at < i > in vivo axial stretch and groupspecific systolic blood pressures [2]. AngII caused larger increases in wall thickness than NE. Both NE and AngII led to significant structural arterial stiffening, driven by a combination of wall thickening and stiffening of the wall material. Figure also shows correlation of wall thickness with contractility (scatter plots, < i > n = 4-7 per group; symbols represent individual aortas). The stronger an individual aorta was able to contract (larger absolute stress change; to the left on < i > x -axis), the weaker its remodelling response. Conclusions: NE- and AngII-induced hypertension elicit distinct aortic remodelling responses. However, independent of the hypertensive stimulus, aortic contractile capacity emerged as protective against hypertensive arterial remodelling. [ABSTRACT FROM AUTHOR]

The renin-angiotensin-aldosterone system (RAAS) plays a major role in the regulation of blood pressure and homeostasis. Therefore, it is a commonly used target for pharmacotherapy of cardiovascular diseases in adults. However, the efficacy of this pharmacotherapy can only be limitedly derived into children. Comprehensive knowledge of the humoral parameters acting in the paediatric RAAS (e.g. angiotensin I, angiotensin II, angiotensin 1-7, angiotensin III, and angiotensin IV) might facilitate a more effective and rational pharmacotherapy in children. Therefore, this review aims to provide an overview of the maturing RAAS. Out of 925 identified records, 35 publications were classified as relevant. Physiological and pathophysiological concentrations of angiotensin peptides were compiled and categorised according to European Medicines Agency age groups. Age has a major impact on circulating angiotensin I, angiotensin II, and angiotensin 1-7, which is reflected in an age-dependent decrease during childhood. In contrast to data obtained in adults, no gender-related differences in angiotensin levels were identified. The observed increase in peptide concentrations regarding cardiac- and renal-diseased children is influenced by surgical repair, while evidence for a pharmacological impact is conflicting. A comprehensive set of angiotensin I, angiotensin II, and angiotensin 1-7 values from neonates up to adolescents was compiled. Indicating age as a strong effector. However, evidence about potential promising targets of the RAAS like angiotensin III and angiotensin IV is still lacking in children. [ABSTRACT FROM AUTHOR]