The Impact of Angiotensin Converting Enzyme Inhibition and/or Angiotensin Receptor Blockade on Tissue Expression of the SARS-CoV-2 Receptor ACE2 in Mice

The angiotensin-converting enzyme 2 (ACE2) is an established receptor and entry point for the novel SARS-CoV-2 coronavirus, as the spike protein on the viral envelope binds the ACE2 receptor Published histological profiling revealed ACE2 to be highly expressed on human lung alveolar epithelial cells and on enterocytes of the small intestine, as well as on arterial and venous endothelial cells Given the widespread abundance of ACE2 across tissues, there has been much speculation regarding whether ACE inhibitors (ACEi) and/or Angiotensin Receptor Blockers (ARB) might alter tissue ACE2 expression and thereby change the risk of transmission or development of severe complications Therefore, the aim of this ongoing study is to measure the impact of ACEi and ARB singly and in combination versus placebo control on tissue distribution of ACE2 in male and female mice A factorial design was employed with the following exposures: ACEi (lisinopril, 10 mg/kg/day), ARB (losartan, 10 mg/kg/day), both drugs, or water control Drugs were delivered via drinking water C57BL/6J Mice were 8 weeks of age at the start of the experiment After 21 days of treatment, four mice (two males and two females) from each treatment group were euthanized, followed by perfusion and tissue collection 12 more untreated mice were combined with the placebo group to increase the sample size of this reference group to 16 (8 males, 8 females) ACE2 protein abundance in brain, kidney, liver, lung, and small intestine was measured by ELISA (Abcam) and normalized to BCA-measured total protein Two-way ANOVA was performed to test for differences in ACE2 levels by organ or sex among untreated mice;Mann-Whitney tests were performed to compare each drug treatment group to the control group Among untreated mice, ACE2 levels differed by organ (p < 0 01), but there were no differences between males and females for a given organ (p = 0 20) Males and females were combined for subsequent analyses After 21 days of treatment, ACEi, ARB, and the combination therapy lowered ACE2 tissue abundance compared to untreated mice in the brain (ACEi p = 0 04;ARB p = 0 04;ACEi+ARB p = 0 01), kidney (ACEi p = 0 03;ARB p = 0 02;ACEi+ARB p = 0 02), and lung (ACEi p = 0 01;ARB p = 0 01;ACEi+ARB p = 0 01) ACEi, but not ARB or combination therapy, lowered ACE2 tissue abundance in the liver (p = 0 02) None of the treatments changed ACE2 tissue abundance in the small intestine These results indicate that ACEi, ARB, or combination therapy reduces levels of ACE2, the SARS-CoV-2 receptor, in key tissues affected by the virus, including lung, kidney, and brain An ongoing validation study will evaluate ACE2 protein and gene expression at earlier time points, as well as after discontinuation of treatment These results will provide valuable insight into the risk or potential benefit of starting or stopping ACEi, ARB, or combination therapy during the COVID-19 pandemic