Ramipril decreases lung and kidney angiotensin converting enzyme 2 (ACE2) in diabetic mice: Lessons for COVID-19 infection

ABSTRACT

Background: ACE2 is a component of the renin-angiotensin system(RAS) that mainly degrades angiotensin II to angiotensin(1-7). It is expressed in renal tubular cells. Lung type 2 alveolar cells also express ACE2 where it acts as a receptor for SARS-CoV-2, which is responsible for the current coronavirus disease 2019(COVID-19) pandemic. A controversy raised regarding the use of RAS blockers in COVID-19 patients despite its demonstrated efficacy in cardiovascular disease. We studied the effect of ramipril on ACE2 expression in experimental diabetes. Methods: 12 weeks old diabetic db/db mice were given ramipril(8 mg/Kg/day) or vehicle during 8 weeks. db/m mice were used as controls. ACE2 expression and enzymatic activity were studied in kidney, heart and lung. Results: In non-treated db/db, ACE2 mRNA expression was increased in kidney(p<0.0001) and ramipril treatment reversed this effect. In heart, ACE2 expression decreased in db/db when compared to db/m(p=0.028) and ramipril had no effect. We found no differences in lung. ACE2 enzymatic activity was increased 23% in kidney and 22% in lung of db/db mice when compared to db/m. Ramipril treatment decreased ACE2 activity 25% in the lung and 13% in the kidney when compared to untreated db/db. In the heart, ACE2 activity tended to decrease in db/db mice when compared to db/m, and increased with ramipril, but did not exceed the cardiac ACE2 activity of the db/m. Conclusions: ACE2 is increased in the kidney and in the lung, and decreased in the heart of diabetic mice. Ramipril treatment restores ACE2. Our results suggest that diabetes and hypertension may per se be risk factors for COVID-19 and not the treatment with ACE inhibitors, which may exert a protective effect on COVID-19 infection.