Expression of ACE2, Soluble ACE2, Angiotensin I, Angiotensin II and Angiotensin-(1-7) Is Modulated in COVID-19 Patients

  1. Ikram Omar Osman
  2. Cléa Melenotte
  3. Philippe Brouqui
  4. Matthieu Million
  5. Jean-Christophe Lagier
  6. Philippe Parola
  7. Andréas Stein
  8. Bernard La Scola
  9. Line Meddeb
  10. Jean-Louis Mege
  11. Didier Raoult
  12. Christian A. Devaux

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Abstract

The etiological agent of COVID-19 SARS-CoV-2, is primarily a pulmonary-tropic coronavirus. Infection of alveolar pneumocytes by SARS-CoV-2 requires virus binding to the angiotensin I converting enzyme 2 (ACE2) monocarboxypeptidase. ACE2, present on the surface of many cell types, is known to be a regulator of blood pressure homeostasis through its ability to catalyze the proteolysis of Angiotensin II (Ang II) into Angiotensin-(1-7) [Ang-(1-7)]. We therefore hypothesized that SARS-CoV-2 could trigger variations of ACE2 expression and Ang II plasma concentration in SARS-CoV-2-infected patients. We report here, that circulating blood cells from COVID-19 patients express less ACE2 mRNA than cells from healthy volunteers. At the level of circulating cells, this ACE2 gene dysregulation mainly affects the monocytes, which also show a lower expression of membrane ACE2 protein. Moreover, soluble ACE2 (sACE2) plasma concentrations are lower in prolonged viral shedders than in healthy controls, while the concentration of sACE2 returns to normal levels in short viral shedders. In the plasma of prolonged viral shedders, we also found higher concentrations of Ang II and angiotensin I (Ang I). On the other hand, the plasma levels of Ang-(1-7) remains almost stable in prolonged viral shedders but seems insufficient to prevent the adverse effects of Ang II accumulation. Altogether, these data evidence that the SARS-CoV-2 may affect the expression of blood pressure regulators with possible harmful consequences on COVID-19 outcome.

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  1. Version published to 10.3389/fimmu.2021.625732
  2. ScreenIT

    SciScore for 10.1101/2021.02.08.21251001: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementConsent: An informed written consent was obtained from each participant to the protocol (both patients and healthy volunteers).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Cells were analyzed according to fluorescence intensity using an anti-ACE2-monoclonal antibody (mAb) labeled with Alexa Fluor 488 (R&D Systems, Minneapolis, USA) and mAb anti-CD3-PC5, anti-CD20-PC7, anti-CD16-PE, and anti-CD14-APC purchased from Beckman (Beckman coulter, Villepinte, France)
    anti-ACE2-monoclonal
    suggested: None
    anti-CD3-PC5
    suggested: None
    anti-CD20-PC7
    suggested: None
    anti-CD16-PE
    suggested: None
    anti-CD14-APC
    suggested: None
    Software and Algorithms
    SentencesResources
    The qPCR experiments were performed using specific oligonucleotide primers (Specific primers were designed using the Primer3 software) and hot-start polymerase (SYBR Green Fast Master Mix; Roche Diagnostics).
    Primer3
    suggested: (Primer3, RRID:SCR_003139)
    Fluorescence intensity was measured using a Canto II cytofluorometer (Becton Dickinson, Biosciences, Le Pont de Claix, France) and the results were analyzed using a BD FACSDiva software v.6. 1.3 (Becton Dickinson, New Jersey, USA).
    BD FACSDiva
    suggested: (BD FACSDiva Software, RRID:SCR_001456)
    The data were submitted to multivariate principal component analysis (PCA) biplot (score plot + loading plot) (RStudio) and hierarchical clustering heatmap analysis (ClustVis).
    ClustVis
    suggested: (ClustVis, RRID:SCR_017133)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    There is not such limitation for the quantification of soluble compounds (sACE2, AngI, AngII and Ang(1-7) in plasma. Regarding the cohort of 44 patients we studied, there is a possible bias due to their sex, age, and treatment. It is generally considered that among patients with symptomatic COVID-19, about two-thirds are men whereas in our studied group of COVID-19, men represented only 16.6% of the group. Another possible bias lies in the recruitment of patients with 83.4% women in the COVID-19 group to be compared to 46.6% in the healthy control group. Regarding the plasma concentration of sACE2, literature reports that males express little higher ACE2 than females (46, 50). This can be linked to the finding that ACE2 is encoded by a gene mapping to chromosomal position Xp22 (32), and is in agreement with the observation that conversion of Ang II to Ang (1-7) by ACE2 was higher in males than females (51). However, in the small number of cases studied, we found no significant difference between males and females for the expression of ACE2 mRNA. At the time of first clinical examination, although blood pressure was verified for all patients, it was only recorded on the admission sheet for 15/44 patients. In the COVID-19 patients group, 4 patients (patient code: IHU_12, IHU_21, IHU_40, and IHU_44) showed hypokalemia while 2 patients showed hyperkalemia (patient code: IHU_15 and IHU_48), and in the group of patients healed from COVID-19, 2 patients showed hyperkalemia (patient ...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  3. Version published to 10.1101/2021.02.08.21251001v1 on medRxiv