The renin–angiotensin system: An integrated view of lung disease and coagulopathy in COVID-19 and therapeutic implications

Diamond, Betty

doi:10.1084/jem.20201000

Cited by 26 publications

(28 citation statements)

References 37 publications

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“…Although possible ISG-type ACE2 induction was considered as a risk for increasing SARS-CoV-2 infection, ACE2 deficiency rather than overexpression is discussed as a greater problem potentially contributing to COVID-19 morbidity [11][12][13]34 . Functional ACE2 deficiency occurs due to internalization of the SARS-CoV-2-ACE2 complex 2,35 , which restricts ACE2 from performing its physiological functions, including its role as a carboxypeptidase for angiotensin II and des-Arg9-bradykinin and other peptide hormones.…”

Section: Discussionmentioning

confidence: 99%

Interferons and viruses induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor

et al. 2020

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ells expressing ACE2 are potential targets of SARS-CoV-2 infection 1,2. Studies based on single-cell RNA sequencing (scRNA-seq) of lung cells have identified type II pneumocytes, ciliated cells and transient secretory cells as the main types of ACE2-expressing cell 3,4. Furthermore, ACE2 was proposed to be an ISG, on the basis of its inducible expression in cells treated with interferons (IFNs) or infected by viruses that induce IFN responses, such as influenza 4,5. These findings implied that the induction of ACE2 expression in IFN-high conditions could result in an amplified risk of SARS-CoV-2 infection 4,5. Concerns could also be raised about possible ACE2-inducing side effects of IFN-based treatments proposed for COVID-19 (refs. 6-9). ACE2 plays multiple roles in normal physiological conditions and as part of the host tissue-protective machinery in damaging conditions, including viral infections. As a terminal carboxypeptidase, ACE2 cleaves a single carboxy-terminal residue from peptide hormones such as angiotensin II and des-Arg9-bradykinin. ACE and ACE2 belong to the renin-angiotensin-aldosterone system, which regulates blood pressure and fluid-electrolyte balance; dysfunction of this system contributes to comorbidities in COVID-19 (refs. 10,11). des-Arg9-bradykinin is generated from bradykinin and belongs to the kallikrein-kinin system, which is critical in regulating vascular leakage and pulmonary edema, early signs of severe COVID-19 (refs. 12,13). High plasma angiotensin II levels were found to be responsible for coronavirus-associated acute respiratory distress syndrome (ARDS), lung damage and high mortality in mouse models 14,15 and as a predictor of lethality in avian influenza in humans 16,17. In the same conditions, ACE2, which decreases the levels of angiotensin II, was identified as a protective factor. The hijacking of the normal host tissue-protective machinery guarded by ACE2 was suggested as a mechanism through which SARS-CoV-2 could infect more cells 4,5. Thus, it is critically important to identify factors affecting ACE2 expression in normal physiological processes and during viral infections and associated pathologies, such as in COVID-19. Herein, aiming to explore the IFN-inducible expression of ACE2 and its role in SARS-CoV-2 infection, we identified a novel, truncated isoform of ACE2, which we designate as dACE2. We then showed that dACE2, but not ACE2, is induced in various human cell types by IFNs and viruses; this information is important to consider for future therapeutic strategies and understanding COVID-19 susceptibility and outcomes. Results dACE2 is a novel inducible isoform of ACE2. To address the extent to which IFNs induce the expression of ACE2 in human cells, we used our existing RNA-seq dataset (NCBI Sequence Read Archive (SRA): PRJNA512015) of a breast cancer cell line T47D infected with Sendai virus (SeV), known to be a strong inducer of IFNs and ISGs 18-20. IFNs were not expressed in T47D cells at baseline, but SeV strongly induced expression of IFNB1, a type I IFN, an...

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Section: Discussionmentioning

confidence: 99%

Interferons and viruses induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor

et al. 2020

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“…Angiotensin II is generated from its precursor angiotensin I by ACE, and is proteolytically converted into another biologically active peptide, angiotensin-(1-7) by ACE2 10,11 . ACE and ACE2 belong to the renin-angiotensin-aldosterone system, which regulates blood pressure and fluid-electrolyte balance; dysfunction of this system contributes to comorbidities in COVID-19 10,12 . des-Arg9-bradykinin is generated from bradykinin and belongs to the kallikrein-kinin system, which is critical in regulating vascular leakage and pulmonary edema, early signs of severe COVID-19 13,14 .…”

Section: Introductionmentioning

confidence: 99%

Interferons and viruses induce a novel primate-specific isoform dACE2 and not the SARS-CoV-2 receptor ACE2

Onabajo

Banday

Yan

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes COVID-19, utilizes angiotensin-converting enzyme 2 (ACE2) for entry into target cells. ACE2 has been proposed as an interferon-stimulated gene (ISG). Thus, interferon-induced variability in ACE2 expression levels could be important for susceptibility to COVID-19 or its outcomes. Here, we report the discovery of a novel, primate-specific isoform of ACE2, which we designate as deltaACE2 (dACE2). We demonstrate that dACE2, but not ACE2, is an ISG. In vitro, dACE2, which lacks 356 N-terminal amino acids, was non-functional in binding the SARS-CoV-2 spike protein and as a carboxypeptidase. Our results reconcile current knowledge on ACE2 expression and suggest that the ISG-type induction of dACE2 in IFN-high conditions created by treatments, inflammatory tumor microenvironment, or viral co-infections is unlikely to affect the cellular entry of SARS-CoV-2 and promote infection.

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“…Likely, this has a role in microcirculatory dysfunction, intense inflammation, hypercoagulability, tissue damage, and fibrosis ( Figure 3 ). Lung inflammation in SARS CoV-19 disease exemplifies the outcome of Ang II/Ang 1-7 imbalance: Ang II enhances vascular permeability along infiltration of neutrophils into alveolae and indirectly via induction of interleukin 8 (IL-8; Diamond, 2020 ). Accumulation of neutrophils and their accompanied prooxidative role lead to loss of alveolar epithelial cells and the development of ARDS.…”

Section: Unbalanced Ras In Sars-cov 19 Diseasementioning

confidence: 99%

“…Since IL-6 plays a key role in the recruitment of lymphoid cells and myeloid cells, including activated T cells and macrophages ( Murakami et al, 2019 ), and likely enhances defensin release (Higazi AAR, unpublished data), its elevated levels during senescence may contribute to the enhanced COVID-19 mortality in aged people and to coagulopathy. Interestingly, AT1R density is increased, while AT2R abundance declines under inflammatory conditions ( Diamond, 2020 ). Collectively, these results may explain proinflammatory cytokine release and hypercoagulopathy during SARS-CoV-2 infection via the associated Ang II pathway and a possible therapeutic target via the IL-6-STAT3 axis ( Diamond, 2020 ).…”

Section: Knowledge Gaps: the Missing Pieces In The Puzzlementioning

confidence: 99%

“…Interestingly, AT1R density is increased, while AT2R abundance declines under inflammatory conditions ( Diamond, 2020 ). Collectively, these results may explain proinflammatory cytokine release and hypercoagulopathy during SARS-CoV-2 infection via the associated Ang II pathway and a possible therapeutic target via the IL-6-STAT3 axis ( Diamond, 2020 ).…”

Section: Knowledge Gaps: the Missing Pieces In The Puzzlementioning

confidence: 99%

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ACE2, COVID-19 Infection, Inflammation, and Coagulopathy: Missing Pieces in the Puzzle

et al. 2020

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Engulfed by the grave consequences of the coronavirus disease 2019 (COVID-19) pandemic, a better understanding of the unique pattern of viral invasion and virulence is of utmost importance. Angiotensin (Ang)-converting enzyme (ACE) 2 is a key component in COVID-19 infection. Expressed on cell membranes in target pulmonary and intestinal host cells, ACE2 serves as an anchor for initial viral homing, binding to COVID-19 spike-protein domains to enable viral entry into cells and subsequent replication. Viral attachment is facilitated by a multiplicity of membranal and circulating proteases that further uncover attachment loci. Inherent or acquired enhancement of membrane ACE2 expression, likely leads to a higher degree of infection and may explain the predisposition to severe disease among males, diabetics, or patients with respiratory or cardiac diseases. Additionally, once attached, viral intracellular translocation and replication leads to depletion of membranal ACE2 through degradation and shedding. ACE2 generates Ang 1-7, which serves a critical role in counterbalancing the vasoconstrictive, pro-inflammatory, and pro-coagulant effects of ACE-induced Ang II. Therefore, Ang 1-7 may decline in tissues infected by COVID-19, leading to unopposed deleterious outcomes of Ang II. This likely leads to microcirculatory derangement with endothelial damage, profound inflammation, and coagulopathy that characterize the more severe clinical manifestations of COVID-19 infection. Our understanding of COVID-ACE2 associations is incomplete, and some conceptual formulations are currently speculative, leading to controversies over issues such as the usage of ACE inhibitors or Ang-receptor blockers (ARBs). This highlights the importance of focusing on ACE2 physiology in the evaluation and management of COVID-19 disease.

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The renin–angiotensin system: An integrated view of lung disease and coagulopathy in COVID-19 and therapeutic implications

Cited by 26 publications

References 37 publications

Interferons and viruses induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor

Interferons and viruses induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor

Interferons and viruses induce a novel primate-specific isoform dACE2 and not the SARS-CoV-2 receptor ACE2

ACE2, COVID-19 Infection, Inflammation, and Coagulopathy: Missing Pieces in the Puzzle

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