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

Brooks, Steven D.; Smith, Rachel L.; Moreira, Aline da Silva; Ackerman, Hans C.

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, change tissue levels of ACE2 in healthy male and female mice. Mice were treated for 21 days with drinking water containing lisinopril (10 mg/kg/day), losartan (10 mg/kg/day), or both. A control group was given water without drug. ACE2 protein index, the ratio of ACE2 protein to total protein, was determined on tissues from the small intestine, lung, kidney, and brain. Oral lisinopril increased ACE2 protein index across all tissues (p < 0.0001 vs vehicle control). In contrast, the combination of lisinopril plus losartan did not increase ACE2 levels in any tissue (p = 0.89 vs vehicle control), and even decreased tissue expression of the Ace2 gene compared to controls (p = 0.0004). In a second cohort evaluated twenty-one days after cessation of drug treatment, the group previously treated with lisinopril had higher ACE2 than the group previously treated with vehicle control (p = 0.02). ACE2 protein index differed across tissues (p < 0.0001). Across both cohorts, plasma ACE2 did not correlate with ACE2 protein index in any tissue; however, a sex difference was observed: kidney ACE2 levels were higher in males than females (p < 0.0001). These results demonstrate that 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.