Angiotensin-converting enzyme 2 alleviates liver fibrosis through the renin-angiotensin system

The present letter to the editor is related to the study titled‘Angiotensin-converting enzyme 2 improves liver fibrosis in mice by regulating autophagy of hepatic stellate cells’.Angiotensin-converting enzyme 2 can alleviate liver fibrosis by regulating autophagy of hepatic stellate cells and affecting the renin-angiotensin system.

Impacts of angiotensin II on retinal artery changes in apolipoprotein E deficient mice

AIM:To investigate the impacts of angiotensin II(Ang II)on retinal artery changes in apolipoprotein E deficient(apoE^(-/-))mice.METHODS:ApoE^(-/-)male mice were infused by minipumps with Ang II at 1000 ng/kg·min(Ang II group)or saline(control group)for 28d.They were underwent ophthalmic fundus examination on day 0,14,and 28 of infusion.Histopathologic examination,ribonucleic acid(RNA)sequencing and local Ang II measurement of retinas were conducted.RESULTS:Ophthalmic fundus examination showed Ang II infusion promoted the formation of retinal arterial aneurysm-like lesions on day 28.Optical coherence tomography revealed the ganglion cell and inner plexiform layer(GCIPL)thickness in the control group was significantly thinner than that in Ang II group(P<0.001).Hematoxylin-eosin staining demonstrated diffused swelling of GCIPL layer and its disordered structure in Ang II group.Transmission electron microscopy showed Ang II infusion caused aggravation of atherosclerotic lesions,including increased swelling,roughness,disorganization of the retinal vasculature,and vacuoles formation.RNA-sequencing and gene ontology enrichment analysis demonstrated that the structure and function of cellular membrane might be disturbed and visual function might be compromised by Ang II.The local level of Ang II was higher in Ang II infusion group but did not show significant differences compared to the control group(P=0.086).CONCLUSION:Ang II infusion promotes the formation of retinal arterial aneurysm-like lesions in apoE^(-/-)mice,causing aggravation of atherosclerotic lesions,more severe disorganization of the retinal vasculature and disturbance of the cellular membrane.

Extracellular vesicles and angiotensin-converting enzyme 2 in COVID-19 disease

Extracellular vesicles(EVs)are membranous vesicular structures released from almost all eukaryotic cell types under different physiological or pathological conditions.Growing evidence demonstrates that EVs can serve as mediators of intercellular communication between donor and recipient cells or microorganism-infected and noninfected cells.Coronavirus disease 2019(COVID-19)disease is caused by infection of the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)of host cells in the respiratory system and various extra-pulmonary tissue/organs,resulting in complications of multiple organ systems.As the cell surface receptor,angiotensin-converting enzyme 2(ACE2)mediates cellular entry of SARS-CoV-2 into the host cells in patients with COVID-19.Recent studies have found that ACE2 can be released with EVs,which have been shown to interfere with the entry of the virus into host cells and thus may be involved in COVID-19 pathophysiology.In addition,ACE2,neprilysin(NEP),and thimet oligopeptidase(TOP)are the key enzymes that regulate angiotensin metabolism by converting angiotensin II or angiotensin I to angiotensin 1-7,the latter of which has protective effects in counterbalancing the harmful effects of angiotensin II in COVID-19 disease.This review summarizes the recent research progress regarding EV-associated ACE2,NEP,and TOP and the perspectives of their potential involvement in the pathophysiology of COVID-19 disease.

Biological function of miRNA-145-5p in angiotensin II induced renal inflammation

Objective:Chronic kidney disease(CKD)is a progressive disorder characterized by intricate structural and functional alterations in the kidneys,attributable to diverse causative factors.Notably,the therapeutic promise of miR-145-5p in addressing renal pathologies has been discerned.This investigation seeks to elucidate the functional role of miR-145-5p in injured kidneys by subjecting human glomerular mesangial cells(HGMCs)to stimulation with Angiotensin II(AngII).Materials and Methods:Cellular viability and the levels of inflammatory mediators were evaluated utilizing Cell Counting Kit-8(CCK-8),quantitative real-time polymerase chain reaction(qRT-PCR),and western blot methodologies,both in the presence of AngII incubation and in scenarios of miR-145p overexpression and downregulation.Furthermore,the cell cycle dynamics were elucidated through Fluorescence-activated Cell Sorting(FACS)analysis.Results:AngII incubation induced an upregulation of miR-145-5p and inflammatory factors including Intercellular Adhesion Molecule 1(ICAM-1),Interleukin 6(IL-6),Interleukin 8(IL-8),and Interleukin 1β(IL-1β).Additionally,it elevated the expression of Cyclin A2,Cyclin D1,and the G2/M cell cycle ratio.Conversely,inhibition of miR-145-5p heightened the levels of inflammatory factors and cell cycle regulators induced by AngII incubation.Reduced expression of miR-145-5p correlated with a downregulation of Interleukin 10(IL-10)expression,concurrently promoting HGMC proliferation under AngII stimulation.Moreover,ectopic miR-145-5p expression demonstrated a reduction in inflammatory factors,cell cyclin regulators,G2/M cell cycle ratio,and overall proliferation.Conclusion:MiR-145-5p exhibited inhibitory effects on the inflammatory response and proliferation induced by Angiotensin II in HGMCs,showcasing its potential as a therapeutic avenue for the treatment of kidney injury.

Role of angiotensin receptor-neprilysin inhibitor in diabetic complications

Diabetes mellitus is a prevalent disorder with multi-system manifestations,causing a significant burden in terms of disability and deaths globally.Angio-tensin receptor-neprilysin inhibitor(ARNI)belongs to a class of medications for treating heart failure,with the benefits of reducing hospitalization rates and mortality.This review mainly focuses on the clinical and basic investigations related to ARNI and diabetic complications,discussing possible physiological and molecular mechanisms,with insights for future applications.

Influence of Angiotensin II on α1-Adrenergic Receptors Function in Rat Aorta and Expression in Vascular Smooth Muscle Cells

Angiotensin II (Ang II) is the main mediator of the Renin-Angiotensin-System acting on AT1 and other AT receptors. It is regarded as a pleiotropic agent that induces many actions, including functioning as a growth factor, and as a contractile hormone, among others. The aim of this work was to examine the impact of Ang II on the expression and function of α1-adrenergic receptors (α1-ARs) in cultured rat aorta, and aorta-derived smooth muscle cells. Isolated Wistar rat aorta was incubated for 24 h in DMEM at 37˚C, then subjected to isometric tension and to the action of added norepinephrine, in concentration-response curves. Ang II was added (1 × 10−5 M), and in some experiments, 5-Methylurapidil (α1A-AR antagonist), AH11110A (α1B-AR antagonist), or BMY-7378 (α1D-AR antagonist), were used to identify the α1-AR involved in the response. Desensitization of the contractile response to norepinephrine was observed due to incubation time, and by the Ang II action. α1D-AR was protected from desensitization by BMY-7378;while RS-100329 and prazosin partially mitigated desensitization. In another set of experiments, isolated aorta-derived smooth muscle cells were exposed to Ang II and α1-ARs proteins were evaluated. α1D-AR increased at 30 and 60 min post Ang II exposure, the α1A-AR diminished from 1 to 4 h, while α1B-AR remained unchanged over 24 h of Ang II exposure. Ang II induced an increase of α1D-AR at short times, and BMY-7378 protected α1D-AR from desensitization.

Angiotensin II administration in severe thrombocytopenia and chronic venous thrombosis:A case report

BACKGROUND The initial trials on angiotensin II(AT II)administration indicated a high incidence of thrombocytopenia and thrombosis,as well as a positive correlation between hyperreninemia and response to the medication.CASE SUMMARY We describe a case of a patient presenting with catecholamine resistant septic shock,thrombocytopenia,deep vein thrombosis,and normal renin concentration who responded immediately to AT II treatment.We observed no worsening of thrombocytopenia and no progression of thrombosis or additional thromboses during treatment.CONCLUSION Our case underscores the need for individualized assessment of patients for potential therapy with AT II.

Association between renin-angiotensin system inhibitor and the risk of CMV pneumonia:a Mendelian randomization study

Background:Cytomegalovirus(CMV)reactivation is linked to a high mortality rate,especially among the elderly.Prior research suggests that renin-angiotensin system(RAS)inhibitors may influence both the onset and prognosis of pneumonia.This study aims to examine the causal relationship between RAS inhibitor use and the risk of CMV pneumonia using Mendelian randomization(MR)analysis.Methods:We conducted an analysis using data from two genome-wide association studies(GWAS)involving individuals of European ancestry.This dataset included individuals treated with RAS inhibitors and those with CMV pneumonia.We assessed the relationship between RAS inhibitor use and CMV pneumonia risk using the inverse variance weighted(IVW)method.The results were further evaluated for pleiotropy,heterogeneity,and robustness.Results:The Mendelian randomization(MR)analysis revealed a causal relationship between RAS inhibitor use and an increased risk of CMV pneumonia(IVW:odds ratio[OR]=2.73;95%confidence interval[CI]=1.11-6.73;P=0.028).Conclusions:Our finding indicate a positive causal relationship between the use of RAS inhibitors and the onset of CMV pneumonia.

MicroRNA-155 mediates endogenous angiotensin II type 1 receptor regulation:implications for innovative type 2 diabetes mellitus management

Type 2 diabetes mellitus(T2DM)is a lifelong condition and a threat to human health.Thorough understanding of its pathogenesis is acutely needed in order to devise innovative,preventative,and potentially curative pharmacological interventions.MicroRNAs(miRNA),are small,non-coding,one-stranded RNA molecules,that can target and silence around 60%of all human genes through translational repression.MiR-155 is an ancient,evolutionarily well-conserved miRNA,with distinct expression profiles and multifunctionality,and a target repertoire of over 241 genes involved in numerous physiological and pathological processes including hematopoietic lineage differentiation,immunity,inflammation,viral infections,cancer,cardiovascular conditions,and particularly diabetes mellitus.MiR-155 Levels are progressively reduced in aging,obesity,sarcopenia,and T2DM.Thus,the loss of coordinated repression of multiple miR-155 targets acting as negative regulators,such as C/EBPβ,HDAC4,and SOCS1 impacts insulin signaling,deteriorating glucose homeostasis,and causing insulin resistance(IR).Moreover,deranged regulation of the renin angiotensin aldosterone system(RAAS)through loss of Angiotensin II Type 1 receptor downregulation,and negated repression of ETS-1,results in unopposed detrimental Angiotensin II effects,further promoting IR.Finally,loss of BACH1 and SOCS1 repression abolishes cytoprotective,anti-oxidant,anti-apoptotic,and anti-inflam matory cellular pathways,and promotesβ-cell loss.In contrast to RAAS inhibitor treatments that further decrease already reduced miR-155 Levels,strategies to increase an ailing miR-155 production in T2DM,e.g.,the use of metformin,mineralocorticoid receptor blockers(spironolactone,eplerenone,finerenone),and verapamil,alone or in various combinations,represent current treatment options.In the future,direct tissue delivery of miRNA analogs is likely.

Ocular renin-angiotensin system with special reference in the anterior part of the eye

The renin-angiotensin system(RAS) regulates blood pressure(BP) homeostasis, systemic fluid volume and electrolyte balance. The RAS cascade includes over twenty peptidases, close to twenty angiotensin peptides and at least six receptors. Out of these, angiotensin Ⅱ, angiotensin converting enzyme 1 and angiotensin Ⅱ type 1 receptor(AngⅡ-ACE1-AT1R) together with angiotensin(1-7), angiotensin converting enzyme 2 and Mas receptor(Ang(1-7)-ACE2-Mas R) are regarded as the main components of RAS. In addition to circulating RAS, local RA-system exists in various organs. Local RA-systems are regarded as tissue-specific regulatory system accounting for local effects and long term changes in different organs. Many of the central components such as the two main axes of RAS: AngⅡ-ACE1-AT1 R and Ang(1-7)-ACE2-Mas R, have been identified in the human eye. Furthermore, it has been shown that systemic antihypertensive RAS- inhibiting medications lower intraocular pressure(IOP). These findings suggest the crucial role of RAS not only in the regulation of BP but also in the regulation of IOP, and RAS potentially plays a role in the development of glaucoma and antiglaucomatous drugs.

The Role for AVE0991 (MAS-Receptor Angiotensin II (1-7) Agonist) in Reducing Cisplatin-Induced Acute Kidney Injury on C57BL/6 Mice

Acute Kidney Injury (AKI) is a condition that causes nephrotoxicity in kidney tissues due to cisplatin-induced cancer treatments. Hence, it is proposed in this review that AVE0991 (a MAS-receptor Angiotensin II (1-7) agonist) may reduce cisplatin-induced acute kidney injury by promoting nitric oxide production.

Impact of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on the mortality in sepsis: A meta-analysis

BACKGROUND The effect of angiotensin-converting enzyme inhibitors(ACEIs)or angiotensin receptor blockers(ARBs)on the mortality of patients with sepsis is not well characterized.AIM To elucidate the association between prior ACEI or ARB exposure and mortality in sepsis.METHODS The PubMed,EMBASE,Web of Science,and Cochrane Library databases were searched for all studies of premorbid ACEI or ARB use and sepsis mortality until November 302019.Two reviewers independently assessed,selected,and ab-stracted data from studies reporting ACEIs or ARBs,sepsis,and mortality.The primary extracted data consisted of premorbid ACEI or ARB exposure,mortality,and general patient data.Two reviewers independently assessed the risk of bias and quality of evidence.RESULTS A total of six studies comprising 281238 patients with sepsis,including 49799 cases with premorbid ACEI or ARB exposure were eligible for analysis.Pre-morbid ACEIs or ARBs exposure decreased the 30-d mortality in patients with sepsis.Moreover,the use of ACEIs or ARBs was associated with approximately a 6%decreased risk of 30-d mortality.CONCLUSION The results of this systematic review suggest that ACEI or ARB exposure prior to sepsis may be associated with reduced mortality.Further high-quality cohort studies and molecular mechanism experiments are required to confirm our results.

Renin-angiotensin system in the pathogenesis of liver fibrosis

Hepatic fibrosis is considered a common response to many chronic hepatic injuries. It is a multifunctional process that involves several cell types, cytokines, chemokines and growth factors leading to a disruption of homeostatic mechanisms that maintain the liver ecosystem. In spite of many studies regarding the development of fibrosis, the understanding of the pathogenesis remains obscure. The hepatic tissue remodeling process is highly complex, resulting from the balance between collagen degradation and synthesis. Among the many mediators that take part in this process, the components of the Renin angiotensin system （RAS） have progressively assumed an important role. Angiotensin （Ang） II acts as a profibrotic mediator and Ang-（1-7）, the newly recognized RAS component, appears to exert a counter-regulatory role in liver tissue. We briefly review the liver fibrosis process and current aspects of the RAS. This review also aims to discuss some experimental evidence regarding the participation of RAS mediators in the pathogenesis of liver fibrosis, focusing on the putative role of the ACE2-Ang-（1-7）- Mas receptor axis.

Relationship between angiotensin-(1-7) and angiotensin Ⅱ correlates with hemodynamic changes in human liver cirrhosis

AIM： To measure circulating angiotensins at different stages of human cirrhosis and to further evaluate a possible relationship between renin angiotensin system （RAS） components and hemodynamic changes. METHODS： Patients were allocated into 4 groups： mild-to-moderate liver disease （MLD）, advanced liver disease （ALD）, patients undergoing liver transplantation, and healthy controls. Blood was collected to determine plasma renin activity （PRA）, angiotensin （Ang） Ⅰ, Ang Ⅱ, and Ang-（1-7） levels using radioimmunoassays. During liver transplantation, hemodynamic parameters were determined and blood was simultaneously obtained from the portal vein and radial artery in order to measure RAS components. RESULTS： PRA and angiotensins were elevated in ALD when compared to MLD and controls （P 〈 0.05）. In contrast, Ang Ⅱ was significantly reduced in MLD. Ang-（1-7）/Ang Ⅱ ratios were increased in MLD when compared to controls and ALD. During transplantation, Ang Ⅱ levels were lower and Ang-（1-7）/Ang Ⅱ ratios were higher in the splanchnic circulation than in the peripheral circulation （0.52 ± 0.08 vs 0.38 ±0.04, P 〈 0.02）, whereas the peripheral circulating Ang Ⅱ/Ang Ⅰ ratio was elevated in comparison to splanchnic levels （0.18 ±0.02 vs 0.13 ±0.02, P 〈 0.04）. Ang-（1-7）/ Ang Ⅱ ratios positively correlated with cardiac output （r = 0.66） and negatively correlated with systemic vascular resistance （r = -0.70）. CONCLUSION： Our findings suggest that the relationship between Ang-（1-7） and Ang Ⅱ may play a role in the hemodynamic changes of human cirrhosis.

The Beneficial Effect of Renin-Angiotensin-Aldosterone System Blockade in Treatment of Hypertension, Resistant to Conventional Antihypertensives, in Patients on Maintenance Hemodialysis

Background: Hypertension (HTN) is present in up to 90% of end stage kidney disease (ESRD) patients irrespective of the etiology of their kidney disease. Moreover, it is an important modifiable risk factor for progression to ESRD and its overall cardiovascular morbidity and mortality. Objective: to evaluate, prospectively, the role of Renin-Angiotensin-Aldosterone System blockade (RAAS) in HTN, resistant to 3 conventional antihypertensives, in patients on maintenance hemodialysis (MHD). Patients and methods: A total of 52 such patients were treated with Ramipril and 5 with Losartan after intolerable cough/shortness of breath following Ramipril-use. None of the patients had fluid depletion, renal artery stenosis and primary endocrinopathy. The study group was compared to a matched control group of MHD patients with normal blood pressure following 3 drugs-combination therapies. Results: All patients, with resistant HTN, had significant activation of RAAS system prior to treatment compared to inactive one in the control group. In those with resistant HTN, control of HTN, was established within 2 weeks of therapy and was associated with suppression of the RAAS. Such therapy was associated with minor side effects. Conclusion: Our study has shown that RAAS blockade is safe and effective in controlling such resistant HTN in MHD patients.

Origin and genomic characteristics of SARS-CoV-2 and its interaction with angiotensin converting enzyme type 2 receptors, focusing on the gastrointestinal tract

The emergence of coronavirus disease-2019 induced by a newly identified bcoronavirus, namely severe acute respiratory syndrome coronavirus 2(SARSCoV-2) has constituted a public health emergency. Even though it was considered a zoonotic disease, the virus has also spread among humans via respiratory secretions. The expression and distribution of angiotensin converting enzyme type 2(ACE2) in various human organs might also show other possible infection routes. High ACE2 ribonucleic acid expression has been identified in the gastrointestinal tract(GI) indicating its importance as a possible infection pathway of SARS-CoV-2. ACE2 induces viral entry into the host and most importantly has been found to be associated with the function of the gut. Its deficiency has been implicated in several pathologies such as colorectal inflammation. The renin-angiotensin system(RAS) is an essential regulatory cascade operating both at a local tissue level and at the systemic or circulatory level. The RAS may be important in the pathogenesis of chronic liver disease and is associated with the up-regulation of ACE2. Thus, the aim of this review is firstly, the analysis of some important general and genome characteristics of SARS-CoV-2 and secondly, and most importantly, to focus on the utility of ACE2 receptors in both SARS-CoV-2 replication and pathogenesis, especially in the GI tract.

Renin Angiotensin System Components and Cancer: Reports of Association

Renin-Angiotensin System (RAS) is involved with hypertension and other cardiovascular diseases. However, the association of RAS components to cancer still causes suspicion. To try to clarify this, here we aimed to show this association for three important components: Angiotensin Converting Enzyme 1 (ACE1), Angiotensin Type 1 Receptor (AGTR1) and Angiotensin Type 2 Receptor (AGTR2). The first articles show that association of RAS components with cancer dates back to the 70’s. ECA1 and AGTR1 have close association with cancer and ACE1 inhibitors or AGTR1 blockers are candidates to treatment of some tumors. Moreover, the action of AGTR2 is still controversial, but most studies show that the increased expression of AGTR2 can attack the cancer cells. In breast cancer, these components have also been widely studied and many works have shown that the correlation exists. Therefore specific target using these RAS components could be a beneficial, novel therapy to various tumors.

Renin-angiotensin system in the central nervous system:focus on Huntington’s disease

The renin-angiotensin system(RAS)was originally conceived as a circulating hormonal system involved in the regulation of cardiovascular and renal homeostasis.With the discovery of local RAS components in diverse organs,including the brain,and related biologically active peptides.

Interferon Regulatory Factor 5 and Renin-Angiotensin-Aldosterone System Polymorphisms in Coronary Artery Disease: An Overview of Experimental and Clinical Studies

Heart diseases are the main cause of mortality in Mexico, being coronary heart disease the most frequent in the country. Its high prevalence makes important the study of the pathophysiology and the search for prognostic factors. Different genes and polymorphisms promote atherogenesis and coronary artery disease, they affect inflammatory and vascular pathological processes. Interferon regulatory factor 5 (IRF5) is associated with coronary heart disease, it promotes chronic inflammation and cytokines release;it could trigger immune reactions and its activating receptors express in the vascular endothelium. Besides, polymorphisms in the renin-angiotensin-aldosterone system (RAAS) are implied with coronary disease, they are found in angiotensinogen (AGT), angiotensin II type 1 receptor (AT1R), angiotensin II type 2 receptor (AT2R), and angiotensin-converting enzyme (ACE) genes. These genetic polymorphisms are associated with a prothrombotic state, endothelial dysfunction, and immune activation. Multiple experimental studies showed that chronic activation of RAAS and chronic expression of IRF5 generates an environment prone to the development of atherosclerosis, and autoimmune and cardiovascular diseases. Studying these specific genes and their relationship with coronary heart disease will allow a better understanding of the pathological process and possibly the quest for new treatments.

Renin angiotensin system in liver diseases: Friend or foe?

In the last three decades,the understanding of the renin angiotensin system(RAS)has been changed by the discoveries of functional local systems,novel biologically active peptides,additional specific receptors,alternative pathways of angiotensin(Ang)?Ⅱ?generation,and new roles for enzymes and precursor components other than those in Ang?Ⅱ?synthesis.In this regard,the discovery that Ang-(1-7)opposes the pressor,proliferative,pro-fibrotic,and pro-inflammatory effects mediated by Ang?Ⅱ?has contributed to the realization that the RAS is composed of two axes.The first axis consists of the angiotensin-converting enzyme(ACE),with Ang?Ⅱ?as the end product,and the angiotensin type 1(AT1)receptor as the main effector mediating the biological actions of Ang?Ⅱ.The second axis results from ACE2-mediated hydrolysis of Ang?Ⅱ,leading to the production of Ang-(1-7),with the Mas receptor as the main effector conveying the vasodilatory,antiproliferative,anti-fibrotic,and anti-inflammatory effects of Ang-(1-7).Experimental and clinical studies have shown that both axes of the RAS may take part in the pathogenesis of liver diseases.In this manuscript,we summarize the current evidence regarding the role of RAS in hepatic cirrhosis and its complications,including hemodynamic changes and hepatorenal syndrome.The therapeutic potential of the modulation of RAS molecules in liver diseases is also discussed.