SARS-CoV-2 Spike Protein Regulation of Angiotensin Converting Enzyme 2 and Tissue Renin-Angiotensin Systems: Influence of Biologic Sex
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Abstract
Angiotensin converting enzyme 2 (ACE2) is an enzyme that limits activity of the renin-angiotensin system (RAS) and also serves as a receptor for the SARS-CoV-2 Spike (S) protein. Binding of S protein to ACE2 causes internalization which activates local RAS. ACE2 is on the X chromosome and its expression is regulated by sex hormones. In this study, we defined ACE2 mRNA abundance and examined effects of S protein on ACE2 activity and/or angiotensin II (AngII) levels in pivotal tissues (lung, adipose) from male and female mice. In lung, ACE2 mRNA abundance was reduced following gonadectomy (GDX) of male and female mice and was higher in XX than XY mice of the Four Core Genotypes (FCG). Reductions in lung ACE2 mRNA abundance by GDX occurred in XX, but not XY FCG female mice. Lung mRNA abundance of ADAM17 and TMPRSS2, enzymes that shed cell surface ACE2 and facilitate viral cell entry, was reduced by GDX in male but not female mice. For comparison, adipose ACE2 mRNA abundance was higher in female than male mice and higher in XX than XY FCG mice. Adipose ADAM17 mRNA abundance was increased by GDX of male and female mice. S protein reduced ACE2 activity in alveolar type II epithelial cells and 3T3-L1 adipocytes. Administration of S protein to male and female mice increased lung AngII levels and decreased adipose ACE2 activity in male but not female mice. These results demonstrate that sex differences in ACE2 expression levels may impact local RAS following S protein exposures.
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SciScore for 10.1101/2021.09.14.460275: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: All animal protocols were reviewed and approved by the University of Kentucky Institutional Animal Care and Use Committee and adhere to the guidelines of the National Institutes of Health. Sex as a biological variable Primary isolates of lung ATII cells: Alveolar type II (ATII) cells were isolated from male mice as described previously.(27) Briefly, lungs were removed and digested in dispase, the resulting cell suspension was filtered, and ATII cells were separated by differential adherence to culture plates coated with exclusion antibodies.(28, 29). Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
… SciScore for 10.1101/2021.09.14.460275: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: All animal protocols were reviewed and approved by the University of Kentucky Institutional Animal Care and Use Committee and adhere to the guidelines of the National Institutes of Health. Sex as a biological variable Primary isolates of lung ATII cells: Alveolar type II (ATII) cells were isolated from male mice as described previously.(27) Briefly, lungs were removed and digested in dispase, the resulting cell suspension was filtered, and ATII cells were separated by differential adherence to culture plates coated with exclusion antibodies.(28, 29). Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources 3T3-L1 adipocytes: Murine 3T3-L1 cells were obtained from ATCC (CL-173) and maintained in DMEM containing fetal bovine serum (FBS, 10%). 3T3-L1suggested: NoneExperimental Models: Organisms/Strains Sentences Resources Animals: To define sex differences in mRNA abundance of ACE2 and associated cell machinery, male and female Ldlr-/- mice (2 months of age; n = 4 mice/group/sex) were obtained from the Jackson Laboratory. Ldlr-/-suggested: NoneSoftware and Algorithms Sentences Resources ReliOn), 3-isobutyl-1-methylxanthine (0.5 mM, Catalog I6879, Sigma-Aldrich), dexamethasone (1.0 μM, Catalog# 194561, MP Bio), and rosiglitazone (2 μM; Catolog# 194561, Sigma-Aldrich) for three days. ReliOnsuggested: (RELION, RRID:SCR_016274)Data were analyzed and graphed using GraphPad Prism 9.0.2 software. GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.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.
Results from scite Reference Check: We found no unreliable references.
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