Kidney and Lung ACE2 expression after an ACE inhibitor or an Ang II receptor blocker: implications for COVID-19
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Abstract
Background
There have been concerns that ACE inhibitors and Ang II receptor blockers may cause an increase in ACE2, the main receptor for SARs-CoV-2.
Methods
Kidneys from two genetic models of kidney ACE ablation and mice treated with captopril or telmisartan were used to examine ACE2 in isolated kidney and lung membranes.
Results
In a global ACE KO mice, ACE2 protein abundance in kidney membranes was reduced to 42 % of wild type, p < 0.05. In ACE 8/8 mice that over-expresses cardiac ACE protein but also has no kidney ACE expression, ACE2 protein in kidney membranes was also decreased (38 % of the WT, p<0.01). In kidney membranes from mice that received captopril or telmisartan for 2 weeks there was a reduction in ACE2 protein (37% in captopril treated p<0.01) and 76% in telmisartan treated p <0.05). In lung membranes the expression of ACE2 was very low and not detected by western blotting but no significant differences in terms of ACE2 activity could be detected in mice treated with captopril (118% of control) or telmisartan (93% of control).
Conclusions
Genetic kidney ACE protein deficiency, suppressed enzymatic activity by Captopril or blockade of the AT1 receptor with telmisartan are all associated with a decrease in ACE2 in kidney membranes. ACE2 protein in kidney or lungs is decreased or unaffected by RAS blockers indicating that these medications can not pose a risk for SARS-CoV-2 infection related to amplification of ACE2 at these two target sites for viral entry.
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SciScore for 10.1101/2020.05.20.106658: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: Animal Models: All studies were conducted with the review and approval of the Institutional Animal Care and Use Committee of Northwestern University. Randomization Two other experimental groups of 12-14 weeks old C57BLKS/J mice were randomly assigned to drink either tap water (vehicle, n=6) or tap water with an angiotensin II receptor antagonist, telmisartan (Boehringer Ingelheim), at a dose of 2 mg*kg−1*day−1 (n=6) for 14 days. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Antibodies Sentences Resources ACE2 protein was detected using our affinity purified rabbit anti-ACE2 antibody (obtained as … SciScore for 10.1101/2020.05.20.106658: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: Animal Models: All studies were conducted with the review and approval of the Institutional Animal Care and Use Committee of Northwestern University. Randomization Two other experimental groups of 12-14 weeks old C57BLKS/J mice were randomly assigned to drink either tap water (vehicle, n=6) or tap water with an angiotensin II receptor antagonist, telmisartan (Boehringer Ingelheim), at a dose of 2 mg*kg−1*day−1 (n=6) for 14 days. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Antibodies Sentences Resources ACE2 protein was detected using our affinity purified rabbit anti-ACE2 antibody (obtained as described in. anti-ACE2suggested: NoneExperimental Models: Organisms/Strains Sentences Resources ACE.4 mice have the somatic ACE promoter replaced by the kidney androgen-regulated protein promoter which in these mice is essentially non-functional(26); in the absence of exogenous androgens the levels of kidney ACE are less than 1% of normal and no ACE is detected in other organs; this model is overtly hypotensive (26). ACE.4suggested: NoneIn addition, ACE8/8 mice have significant levels of ACE activity in the lung and in the plasma and blood (27). ACE8/8suggested: NoneTo examine the effect of pharmacological ACE inhibition on ACE2, two groups of 12-14 weeks old C57BLKS/J mice were assigned to drink either tap water (n=8) or tap water with an ACE inhibitor, captopril, (n=8) at a dose of 120 mg*kg−1*day−1 for 14 days. C57BLKS/Jsuggested: NoneSoftware and Algorithms Sentences Resources Primers and probes for ACE were designed using Primer Express software (Applied Biosystems). Primer Expresssuggested: (Primer Express, RRID:SCR_014326)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 found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).
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.
- No funding statement was detected.
- No protocol registration statement was detected.
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