Oral Lisinopril Raises Tissue Levels of ACE2, the SARS-CoV-2 Receptor, in Healthy Male and Female Mice

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.

ACEI or not to ACEI: Review on using ACEI and ARBs on COVID-19 patients: Systemic review

“…In contrast, the combination of lisinopril with losartan prevented the lisinopril-induced increase in tissue ACE2 levels. And so, the expression of ACE2 is different in different tissue [31].…”

Determinants of Post-COVID-19 Conditions among SARS-CoV-2-Infected Patients in Saudi Arabia: A Web-Based Cross-Sectional Study

“…Moreover, ACE2 expression in patients with hypertension and diabetes is high due to the long-term medication of ACE inhibitors. A previous study on mice showed that ACE blockers increase the expression of ACE2 in the small intestine, lung, kidney, and brain; consequently, this may increase the risk of infection or reinfection, resulting in high virus titters [ 32 ]. In our study population, participants with one or more comorbidity diseases may be at increased risk of developing post-COVID-19 conditions.…”

Advances in Modelling COVID-19 in Animals

“…A recent preprint article reported that the ACE inhibitor Lisinopril can raise the ACE2 expression landscape in the lungs, small intestine, kidney and brain of healthy mice, an effect that persists to at least 21 days post-termination of treatment (Brooks et al, 2022). Captopril, which also acts as an ACE inhibitor, appears to improve lung pathology and reduce inflammation during SARS-CoV2 infection in an angiotensin II-induced hypertensive and hACE2-expressing mouse model, without any detectable effect on viral load (Gao et al, 2021).…”