Lung and Kidney ACE2 and TMPRSS2 in Renin Angiotensin System Blocker Treated Comorbid Diabetic Mice Mimicking Host Factors That Have Been Linked to Severe COVID-19

The causes of the increased risk of severe COVID-19 in persons with diabetes are unclear. It has been speculated that renin angiotensin system (RAS) blockers may promote COVID-19 by increasing ACE2, which SARS-CoV-2 uses to enter host cells, along with the host protease TMPRSS2. Taking a reverse translational approach and by combining in situ hybridization, primary cell isolation, immunoblotting, qRT-PCR and LC-MS/MS we studied lung and kidney ACE2 and TMPRSS2 in diabetic mice mimicking host factors linked to severe COVID-19. In healthy young mice, neither the ACE inhibitor ramipril nor the AT1 receptor blocker telmisartan affected lung or kidney ACE2 or TMPRSS2, except for a small increase in kidney ACE2 protein with ramipril. In contrast, mice with comorbid diabetes (aging, high fat diet and streptozotocin-induced diabetes) had heightened lung ACE2 and TMPRSS2 protein levels and increased lung ACE2 activity. None of these parameters were affected by RAS blockade. ACE2 was similarly upregulated in the kidneys of mice with comorbid diabetes compared to aged controls, whereas TMPRSS2 (primarily distal nephron) was highest in telmisartan-treated animals. Upregulation of lung ACE2 activity in comorbid diabetes may contribute to increased risk of severe COVID-19. This upregulation is driven by comorbidity and not by RAS blockade.