ABSTRACT
BACKGROUND AND AIMS: Angiotensin converting enzyme 2 (ACE2) is one of the components of the renin-angiotensin system (RAS) that mainly degrades angiotensin II to angiotensin-(1-7). ACE2 is predominantly expressed in the kidney and the heart, but it has been evidenced in type 2 alveolar lung cells, where it acts as a receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this context, a controversy arose as to whether the use of RAS blockers could increase ACE2 lung expression and the risk infection by COVID-19. This study aimed to investigate the effect of an ACE inhibitor (Ramipril) on ACE2 expression in experimental diabetes. METHOD: 12 weeks old diabetic db/db mice (n=7) were given ramipril (8 mg/Kg/day) during 8 weeks or the respective vehicle. db/m (n=7) vehicle-treated non-diabetic mice were included as controls. ACE2 mRNA expression and enzymatic activity were studied in kidney, heart and lung samples of these animals to identify if the diabetic condition or treatment with ramipril modulated ACE2 expression. RESULTS: In vehicle-treated diabetic db/db animals, ACE2 mRNA expression was significantly increased in the kidney (p<0.001) and ramipril treatment reversed this effect (p=0.026). In the heart, ACE2 expression decreased in db/db when compared to db/m littermates (p=0.035) and ramipril had no effect. We found no differences in ACE2 gene expression in the lung. Besides, ACE2 enzymatic activity was increased in the kidney (29%) and also in the lung (16%) of db/db mice when compared to controls. Ramipril treatment decreased ACE2 activity a 19% in the lung and had no effect in the kidney when compared to untreated db/db (see figure). In the heart, ACE2 activity tended to decrease in db/db mice (29%) when compared to db/m and ramipril increased ACE2 activity (18%) but did not exceed the cardiac ACE2 activity of the db/ m. CONCLUSION: ACE2 is increased in the kidney and the lung, and decreased in the heart of diabetic mice. Ramipril treatment restores ACE2 levels. The results suggest that ACE inhibitors do not increase ACE2 expression and the activity decrease exerted in the lung may be protective against 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.