Oral Lisinopril Raises Tissue Levels of ACE2, the SARS-CoV-2 Receptor, in Healthy Male and Female Mice
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Abstract
Angiotensin-converting enzyme 2 (ACE2) is the established cellular receptor for SARS-CoV-2. However, it is unclear whether ACE1 inhibitors (e.g., lisinopril) or angiotensin receptor blockers (e.g., losartan) alter tissue ACE2 expression. This study sought to determine whether lisinopril or losartan, as monotherapies or in combination, changes tissue levels of ACE2 in healthy male and female mice. Mice received lisinopril (10 mg/kg/day), losartan (10 mg/kg/day), or both for 21 days via drinking water. A control group received water without drug. The ACE2 protein index (ACE2 protein/total protein) was determined on the small intestine, lung, kidney, and brain. Oral lisinopril increased the ACE2 protein index across all tissues ( p < 0.0001 vs. control). In contrast, the combination of lisinopril plus losartan did not increase ACE2 levels in any tissue ( p = 0.89 vs. control) and even decreased tissue expression of the Ace2 gene ( p < 0.001 vs. control). Tissue ACE2 remained elevated in the mice 21 days after cessation of lisinopril ( p = 0.02). Plasma ACE2 did not correlate with the ACE2 protein index in any tissue. A sex difference was observed: kidney ACE2 levels were higher in male than in female mice ( p < 0.0001). Oral lisinopril increases ACE2, the cellular receptor for SARS-CoV-2, in tissues that are relevant to the transmission and pathogenesis of COVID-19. Remarkably, the addition of losartan prevented lisinopril-induced increases in ACE2 across tissues. These results suggest that ACE inhibitors and angiotensin receptor blockers interact to determine tissue levels of ACE2.
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SciScore for 10.1101/2021.10.19.465025: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: All experiments and protocols using laboratory mice were reviewed and approved by the NIAID Division of Intramural Research Animal Care and Use Committee (DIR ACUC).
Euthanasia Agents: 25 mL of cold phosphate-buffered saline was administered via transcardial perfusion to remove blood from tissues prior to collection.Sex as a biological variable 2.2 Experimental design: The experiment utilized a factorial design: five male and five female mice comprised each drug treatment group (lisinopril, losartan, lisinopril and losartan combined, or vehicle control) at each time point (Day 21 or Day 42). Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication …SciScore for 10.1101/2021.10.19.465025: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: All experiments and protocols using laboratory mice were reviewed and approved by the NIAID Division of Intramural Research Animal Care and Use Committee (DIR ACUC).
Euthanasia Agents: 25 mL of cold phosphate-buffered saline was administered via transcardial perfusion to remove blood from tissues prior to collection.Sex as a biological variable 2.2 Experimental design: The experiment utilized a factorial design: five male and five female mice comprised each drug treatment group (lisinopril, losartan, lisinopril and losartan combined, or vehicle control) at each time point (Day 21 or Day 42). Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication Authentication: A post hoc multivariate model, prompted by visual inspection of the data, was used to test the effect of sex on kidney ACE2 protein index across both cohorts and all treatment groups. Table 2: Resources
Antibodies Sentences Resources 2.6 Histological profiling of small intestine: Small intestine tissue segments were fixed in 10% Formalin, embedded into paraffin, sliced into 6-8 μm sections by microtome, and stained with immunohistochemical antibodies for ACE2 (Abcam) to determine tissue prevalence and distribution. ACE2suggested: NoneExperimental Models: Organisms/Strains Sentences Resources These forty male and forty female eight-week old C57Bl/6J mice (Jackson Laboratory) were fed standard chow and treated for twenty-one days with either drinking water containing lisinopril (10 mg/kg/day; Sigma Aldrich, L6292), drinking water containing losartan (10 mg/kg/day; Sigma Aldrich, C57Bl/6Jsuggested: NoneResults 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:It is important to note the limitations of this study. All mice used in this study were healthy young adult mice. Hypertension and cardiovascular disease can impact tissue ACE2, and the findings could be different in the setting of cardiovascular disease. While lisinopril and losartan are representative of their drug classes, other ACE inhibitors or ARBs may have different effects on ACE2 abundance. Lastly, while our findings in mice are consistent with the available results in rats, the effects of ACE inhibition and angiotensin receptor blockade on tissue ACE2 levels in humans may be different. A controlled study of tissue ACE2 in humans after initiating an ACE inhibitor, ARB, or combination therapy would be warranted to extend these findings into humans. ACE2 expression is increased in the lungs of patients with COVID-19 comorbidities38, as well as in diabetes 39 and heart failure.40 It is possible that these co-morbidities increase susceptibility to and severity of COVID-19 in part through increased tissue ACE2. In this context, our finding that ACE inhibitor and ARB combination therapy interact to decrease ACE2 gene expression and prevent increases in ACE2 protein levels may offer an avenue to reduce tissue ACE2 in people on ACE inhibitor or ARB monotherapy while still providing protection against cardiovascular or renal disease. While combination therapy of ACE inhibitor with ARB is not widely used, there is precedent for combination therapy for heart failure41, renal di...
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.
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Results from scite Reference Check: We found no unreliable references.
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