COVID-19 and the Renin-Angiotensin System.
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ABSTRACT:
SUBMITTER: Malha L
PROVIDER: S-EPMC7118533 | biostudies-literature | 2020 May
REPOSITORIES: biostudies-literature
Publications
COVID-19 and the Renin-Angiotensin System.
Malha Line L Mueller Franco B FB Pecker Mark S MS Mann Samuel J SJ August Phyllis P Feig Peter U PU
Kidney international reports 20200327 5
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Project description:The renin-angiotensin system (RAS) plays a pivotal role in a wide series of physiological processes, among which inflammation and blood pressure regulation. One of its key components, the angiotensin-converting enzyme 2, has been identified as the entry point of the SARS-CoV-2 virus into the host cells, and therefore a lot of research has been devoted to study RAS dysregulation in COVID-19. Here we discuss the alterations of the regulatory RAS axes due to SARS-CoV-2 infection on the basis of a series of recent clinical investigations and experimental analyzes quantifying, e.g., the levels and activity of RAS components. We performed a comprehensive meta-analysis of these data in view of disentangling the links between the impaired RAS functioning and the pathophysiological characteristics of COVID-19. We also review the effects of several RAS-targeting drugs and how they could potentially help restore the normal RAS functionality and minimize the COVID-19 severity. Finally, we discuss the conflicting evidence found in the literature and the open questions on RAS dysregulation in SARS-CoV-2 infection whose resolution would improve our understanding of COVID-19.
| S-EPMC8535134 | biostudies-literature
Project description:The emergency of SARS-CoV-2 in China started a novel challenge to the scientific community. As the virus turns pandemic, scientists try to map the cellular mechanisms and pathways of SARS-CoV-2 related to the pathogenesis of Coronavirus Disease 2019 (Covid-19). After transmembrane angiotensin-converting enzyme 2 (ACE2) has been found to be SARS-CoV-2 receptor, we hypothesized an immune-hematological mechanism for Covid-19 based on renin-angiotensin system (RAS) imbalance to explain clinical, laboratory and imaging findings on disease course. We believe that exaggerated activation of ACE/Angiotensin II (Ang II)/Angiotensin Type 1 (AT1) receptor RAS axis in line with reduction of ACE2/Angiotensin-(1-7)/Mas receptor may exert a pivotal role in the pathogenesis of Covid-19. In this perspective, we discuss potential mechanisms and evidence on this hypothesis.
| S-EPMC7276636 | biostudies-literature
Project description:SARS-CoV-2 gains cell entry via angiotensin-converting enzyme (ACE) 2, a membrane-bound enzyme of the "alternative" (alt) renin-angiotensin system (RAS). ACE2 counteracts angiotensin II by converting it to potentially protective angiotensin 1-7. Using mass spectrometry, we assessed key metabolites of the classical RAS (angiotensins I-II) and alt-RAS (angiotensins 1-7 and 1-5) pathways as well as ACE and ACE2 concentrations in 159 patients hospitalized with COVID-19, stratified by disease severity (severe, n = 76; non-severe: n = 83). Plasma renin activity (PRA-S) was calculated as the sum of RAS metabolites. We estimated ACE activity using the angiotensin II:I ratio (ACE-S) and estimated systemic alt-RAS activation using the ratio of alt-RAS axis metabolites to PRA-S (ALT-S). We applied mixed linear models to assess how PRA-S and ACE/ACE2 concentrations affected ALT-S, ACE-S, and angiotensins II and 1-7. Median angiotensin I and II levels were higher with severe versus non-severe COVID-19 (angiotensin I: 86 versus 30 pmol/L, p < 0.01; angiotensin II: 114 versus 58 pmol/L, p < 0.05), demonstrating activation of classical RAS. The difference disappeared with analysis limited to patients not taking a RAS inhibitor (angiotensin I: 40 versus 31 pmol/L, p = 0.251; angiotensin II: 76 versus 99 pmol/L, p = 0.833). ALT-S in severe COVID-19 increased with time (days 1-6: 0.12; days 11-16: 0.22) and correlated with ACE2 concentration (r = 0.831). ACE-S was lower in severe versus non-severe COVID-19 (1.6 versus 2.6; p < 0.001), but ACE concentrations were similar between groups and correlated weakly with ACE-S (r = 0.232). ACE2 and ACE-S trajectories in severe COVID-19, however, did not differ between survivors and non-survivors. Overall RAS alteration in severe COVID-19 resembled severity of disease-matched patients with influenza. In mixed linear models, renin activity most strongly predicted angiotensin II and 1-7 levels. ACE2 also predicted angiotensin 1-7 levels and ALT-S. No single factor or the combined model, however, could fully explain ACE-S. ACE2 and ACE-S trajectories in severe COVID-19 did not differ between survivors and non-survivors. In conclusion, angiotensin II was elevated in severe COVID-19 but was markedly influenced by RAS inhibitors and driven by overall RAS activation. ACE-S was significantly lower with severe COVID-19 and did not correlate with ACE concentrations. A shift to the alt-RAS axis because of increased ACE2 could partially explain the relative reduction in angiotensin II levels.
| S-EPMC9684482 | biostudies-literature
Project description:The newly emergent novel coronavirus disease 2019 (COVID-19) outbreak, which is caused by SARS-CoV-2 virus, has posed a serious threat to global public health and caused worldwide social and economic breakdown. Angiotensin-converting enzyme 2 (ACE2) is expressed in human vascular endothelium, respiratory epithelium, and other cell types, and is thought to be a primary mechanism of SARS-CoV-2 entry and infection. In physiological condition, ACE2 via its carboxypeptidase activity generates angiotensin fragments (Ang 1-9 and Ang 1-7), and plays an essential role in the renin-angiotensin system (RAS), which is a critical regulator of cardiovascular homeostasis. SARS-CoV-2 via its surface spike glycoprotein interacts with ACE2 and invades the host cells. Once inside the host cells, SARS-CoV-2 induces acute respiratory distress syndrome (ARDS), stimulates immune response (i.e., cytokine storm) and vascular damage. SARS-CoV-2 induced endothelial cell injury could exacerbate endothelial dysfunction, which is a hallmark of aging, hypertension, and obesity, leading to further complications. The pathophysiology of endothelial dysfunction and injury offers insights into COVID-19 associated mortality. Here we reviewed the molecular basis of SARS-CoV-2 infection, the roles of ACE2, RAS signaling, and a possible link between the pre-existing endothelial dysfunction and SARS-CoV-2 induced endothelial injury in COVID-19 associated mortality. We also surveyed the roles of cell adhesion molecules (CAMs), including CD209L/L-SIGN and CD209/DC-SIGN in SARS-CoV-2 infection and other related viruses. Understanding the molecular mechanisms of infection, the vascular damage caused by SARS-CoV-2 and pathways involved in the regulation of endothelial dysfunction could lead to new therapeutic strategies against COVID-19.
| S-EPMC7407648 | biostudies-literature
Project description:With the multiplication of COVID-19 severe acute respiratory syndrome cases due to SARS-COV2, some concerns about angiotensin-converting enzyme 1 (ACE1) inhibitors (ACEi) and angiotensin II type 1 receptor blockers (ARB) have emerged. Since the ACE2 (angiotensin-converting enzyme 2) enzyme is the receptor that allows SARS COV2 entry into cells, the fear was that pre-existing treatment with ACEi or ARB might increase the risk of developing severe or fatal severe acute respiratory syndrome in case of COVID-19 infection. The present article discusses these concerns. ACE2 is a membrane-bound enzyme (carboxypeptidase) that contributes to the inactivation of angiotensin II and therefore physiologically counters angiotensin II effects. ACEis do not inhibit ACE2. Although ARBs have been shown to up-regulate ACE2 tissue expression in experimental animals, evidence was not always consistent in human studies. Moreover, to date there is no evidence that ACEi or ARB administration facilitates SARS-COV2 cell entry by increasing ACE2 tissue expression in either animal or human studies. Finally, some studies support the hypothesis that elevated ACE2 membrane expression and tissue activity by administration of ARB and/or infusion of soluble ACE2 could confer protective properties against inflammatory tissue damage in COVID-19 infection. In summary, based on the currently available evidence and as advocated by many medical societies, ACEi or ARB should not be discontinued because of concerns with COVID-19 infection, except when the hemodynamic situation is precarious and case-by-case adjustment is required.
| S-EPMC7172808 | biostudies-literature
Project description:The functional receptor to SARS-CoV-2, the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic, is angiotensin-converting enzyme-2 (ACE-2), the same enzyme that physiologically counters the renin-angiotensin system (RAS) activation. Some researchers have questioned RAS inhibitors' safety in COVID-19 patients since these drugs have demonstrated an increase in ACE-2 expression in preclinical studies; therefore, they may facilitate viral invasion. On the contrary, others have hypothesized a protective role of RAS inhibitors against COVID-19-associated lung injury. Overall, the data are grossly inadequate to reach any conclusion since no human trials have yet evaluated the effects of RAS inhibitors in COVID-19. We review the current data and pathophysiological mechanisms behind this intriguing interplay between the RAS inhibitors and the COVID-19.
| S-EPMC7596458 | biostudies-literature
Project description:A massive worldwide vaccination campaign constitutes the main tool against the COVID-19 pandemic. However, drug treatments are also necessary. Antivirals are the most frequently considered treatments. However, strategies targeting mechanisms involved in disease aggravation may also be effective. A major role of the tissue renin-angiotensin system (RAS) in the pathophysiology and severity of COVID-19 has been suggested. The main link between RAS and COVID-19 is angiotensin-converting enzyme 2 (ACE2), a central RAS component and the primary binding site for SARS-CoV-2 that facilitates the virus entry into host cells. An initial suggestion that the susceptibility to infection and disease severity may be enhanced by angiotensin type-1 receptor blockers (ARBs) and ACE inhibitors (ACEIs) because they increase ACE2 levels, led to the consideration of discontinuing treatments in thousands of patients. More recent experimental and clinical data indicate that ACEIs and, particularly, ARBs can be beneficial for COVID-19 outcome, both by reducing inflammatory responses and by triggering mechanisms (such as ADAM17 inhibition) counteracting viral entry. Strategies directly activating RAS anti-inflammatory components such as soluble ACE2, Angiotensin 1-7 analogues, and Mas or AT2 receptor agonists may also be beneficial. However, while ACEIs and ARBs are cheap and widely used, the second type of strategies are currently under study.
| S-EPMC8962306 | biostudies-literature
Project description:In the early months of the coronavirus disease 2019 (COVID-19) pandemic, a hypothesis emerged suggesting that pharmacologic inhibitors of the renin-angiotensin system (RAS) may increase COVID-19 severity. This hypothesis was based on the role of angiotensin-converting enzyme 2 (ACE2), a counterregulatory component of the RAS, as the binding site for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), allowing viral entry into host cells. Extrapolations from prior evidence led to speculation that upregulation of ACE2 by RAS blockade may increase the risk of adverse outcomes from COVID-19. However, counterarguments pointed to evidence of potential protective effects of ACE2 and RAS blockade with regard to acute lung injury, as well as substantial risks from discontinuing these commonly used and important medications. Here we provide an overview of classic RAS physiology and the crucial role of ACE2 in systemic pathways affected by COVID-19. Additionally, we critically review the physiologic and epidemiologic evidence surrounding the interactions between RAS blockade and COVID-19. We review recently published trial evidence and propose important future directions to improve upon our understanding of these relationships.
| S-EPMC7929063 | biostudies-literature
Project description:AimsTo describe the characteristics of patients hospitalized with COVID-19 (including their long-term at-home medication use), and compare them with regard to the course of the disease. To assess the association between renin-angiotensin system inhibitors (RASIs) and disease progression and critical outcomes.Methods and resultsAll consecutive hospitalized patients with laboratory-confirmed COVID-19 in a university hospital in Amiens (France) were included in this study. The primary composite endpoint was admission to an intensive care unit (ICU) or death before ICU admission. Univariable and multivariable logistic regression models were used to identify factors associated with the composite endpoint. Between 28 February 2020 and 30 March 2020, a total of 499 local patients tested positive for SARS-CoV-2. Of these, 231 were not hospitalized {males 33%; median [interquartile range (IQR)] age: 44 (32-54)}, and 268 were hospitalized [males 58%; median (IQR) age: 73 (61-84)]. A total of 116 patients met the primary endpoint: 47 died before ICU admission, and 69 were admitted to the ICU. Patients meeting the primary endpoint were more likely than patients not meeting the primary endpoint to have coronary heart disease and to have been taking RASIs; however, the two subsets of patients did not differ with regard to median age. After adjustment for other associated variables, the risk of meeting the composite endpoint was 1.73 times higher (odds ratio 1.73, 95% confidence interval 1.02-2.93) in patients treated at baseline with a RASI than in patients not treated with this drug class. This association was confirmed when the analysis was restricted to patients treated with antihypertensive agents.ConclusionsWe highlighted a potential safety signal for RASIs, the long-term use of which was independently associated with a higher risk of severe COVID-19 and a poor outcome. Due to the widespread use of this important drug class, formal proof based on clinical trials is needed to better understand the association between RASIs and complications of COVID-19.
| S-EPMC7314068 | biostudies-literature
Project description:AimsThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the ACE2 component of the renin-angiotensin aldosterone system (RAAS) and infects the human cells. The aims of the present review were to look at the role and alteration of the RAAS components in SARS-CoV-2 infection, therapeutic approaches, and clinical trials in this field.MethodsWe surveyed the literature (PubMed, Web of Science, and Scopus) till August 18, 2021, and 59 published papers regarding the components of the RAAS and their role and alterations in SARS-CoV-2 infection along with various COVID-19 therapies based on the RASS components were included in the study.ResultsACE inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor inhibitors are agents that significantly enhance the ACE2 and Ang-(1-7) levels, which can be suggestive for their role as therapeutics against SARS-CoV-2 infection. Beta-adrenergic blockers, which negatively regulate renin release from juxtaglomerular cells, and vitamin D, as a regulator of the RAAS and renin expression, are proposed therapeutics in the treatment of COVID-19. Some antihyperglycemic agents could be potentially protective against COVID-19-induced lung injury. Also, the inhibition of the Janus kinase/signal transducer and activator of the transcription pathway as a potential treatment for COVID-19 has been suggested. Finally, resveratrol, an antioxidant that can suppress Ang II, has been suggested as an adjunct to other therapies.ConclusionRegarding the suggested potential therapies for COVID-19, there are many clinical trials whose results might change the treatment strategies of SARS-CoV-2 infection. So, the results of well-organized clinical trials on the efficacy and safety of the mentioned agents in the treatment of COVID-19 will be useful in the management and therapy of the disease.
| S-EPMC8596942 | biostudies-literature