Effects and regulation of ACE2 and TMPRSS2 abundance in healthy humans and in patients with SARS-CoV-2.

Publication date: Jul 08, 2025

The present narrative review focuses on organ distribution, co-localization, age-, and sex-dependent changes in angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) and how such changes associate with SARS-CoV-2 virus entry and disease severity in humans. ACE2 is a membrane-bound enzyme with lower abundance in children/young adults compared with elderly, with no protein abundance difference between ages 35-50 and >80 but higher in females at reproductive age. ACE2 locates predominantly in gastrointestinal (GI)-tract epithelia, kidney proximal tubules, male and female reproductive organs with very low levels in the lungs. Estrogen upregulates ACE2, which can be shed from cells into plasma by, for example ADAM17, while remaining active. TMPRSS2 is a membrane-associated serine protease with androgen dependence. The highest levels in humans are found in male reproductive organs, kidney, and GI-tract. Co-localization with ACE2 in alveolar type 2 cells is based mostly on in vitro studies. Documentation of clustering of ACE2 and TMPRSS2 in human tissues is scarce and best in oral-pharyngeal mucosa. In patients with mild-to-serious COVID-19 disease, there is no consistent change in circulating renin, aldosterone, ACE and ACE2 activities, angiotensin II (ANGII), and Ang1-7. Increased ANGII levels are reported in critically ill patients, while ACE2 is massively present in urine. Use of RAAS inhibitors is not associated with negative outcomes in patients with COVID-19. In conclusion, co-localization of ACE2 and TMPRSS2 in oral and airway epithelia may explain the primary route of infection for SARS-CoV-2 virus. Higher risk for serious disease in elderly males may not be accounted for by quantitative changes in the proteins.

Semantics

Original Article