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

Diabetes. 2021 Mar;70(3):759-771. doi: 10.2337/db20-0765. Epub 2020 Dec 11.

Abstract

The causes of the increased risk of severe coronavirus disease 2019 (COVID-19) in people with diabetes are unclear. It has been speculated that renin-angiotensin system (RAS) blockers may promote COVID-19 by increasing ACE2, which severe acute respiratory syndrome coronavirus 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, quantitative RT-PCR, and liquid chromatography-tandem mass spectrometry, 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 with aged controls, whereas TMPRSS2 (primarily distal nephron) was highest in telmisartan-treated animals. Upregulation of lung ACE2 activity in comorbid diabetes may contribute to an increased risk of severe COVID-19. This upregulation is driven by comorbidity and not by RAS blockade.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Angiotensin-Converting Enzyme 2 / drug effects
  • Angiotensin-Converting Enzyme 2 / genetics*
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Animals
  • COVID-19
  • Diabetes Mellitus, Experimental / metabolism*
  • Diet, High-Fat*
  • Immunoblotting
  • In Situ Hybridization
  • Kidney / drug effects
  • Kidney / metabolism*
  • Lung / drug effects
  • Lung / metabolism*
  • Male
  • Mice
  • Ramipril / pharmacology
  • Receptors, Coronavirus / drug effects
  • Receptors, Coronavirus / genetics
  • Receptors, Coronavirus / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • SARS-CoV-2
  • Serine Endopeptidases / drug effects
  • Serine Endopeptidases / genetics*
  • Serine Endopeptidases / metabolism
  • Telmisartan / pharmacology

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Angiotensin-Converting Enzyme Inhibitors
  • Receptors, Coronavirus
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2
  • Serine Endopeptidases
  • TMPRSS2 protein, mouse
  • Ramipril
  • Telmisartan

Grant support