Figure 7.

Dysregulated RAS in lung and gut epithelium of individuals with diabetes with COVID-19. ACE2, a pleiotropic regulator of the RAS, is hijacked as a receptor for SARS-CoV-2 to promote viral infection. Loss of ACE2 indirectly via proteolytic processing, autophagy, and ADAM17-mediated shedding (not shown) partly drives not only lung but also gut disease in individuals with diabetes with COVID-19. SARS-CoV-2 S1 binding to ACE2 initiates internalization of ACE2:B⁰AT1 complex (gut) or ACE2 (outside of gut). Thus, SARS-CoV-2 by downregulating intestinal ACE2-B⁰AT1 would promote leaky gut syndrome with elevated plasma bacterial lipopolysaccharides and/or peptidoglycans enhancing systemic inflammation. In the lung, virus internalization also promotes a reduction in ACE2 that results in pulmonary pathology. Careful targeting of the RAS axis will likely optimize clinical outcomes in subjects with diabetes infected with SARS-CoV-2. WBC, white blood cell.