Fig. 1.

Schematic representation of possible molecular mechanism involved in Covid-19. ACE2 deficiency is occurred in SARS-CoV-2 infection, due to binding of S protein to this receptor as well as shedding of it by ADAM17. ACE2 converts Ang II, a peptide hormone involved in pro-inflammatory activities to Ang 1–7. Binding of Ang 1–7 to Mas receptor indicates various beneficial effects in the human body including vasodilation, anti-thrombotic, anti-fibrotic, and anti-inflammatory. Depletion of ACE2 leads to over-production of Ang II and its binding to AT1R causes activation of ADAM17 protease. ADAM17 can cleave membrane-anchored proteins and immunological cytokines such as IL-6, TNF-α and EGFR ligands, which modulation of them triggers pro-inflammatory pathways. Also, ADAM17 cleavages Notch-ligand complex then the Notch intracellular domain is cleaved by the γ-secretase complex, resulting its release and transfer to the nucleus and the transcriptional activation of Notch target genes such as inflammatory cytokines and furin. Des-arg⁹ bradykinin (DABK) is a biological substrate of ACE2 in the lungs and deficiency of ACE2 led to stimulation of bradykinin receptor (B1R) by DABK and releasing of the pro-inflammatory chemokines. Besides, activation of B1R can cause AT1R upregulation and ADAM17 stimulation lead to transactivation of EGFR. On the other hand, Ang II stimulation can significantly increase the expression of B1R suggesting possible cross-talk between AT1R and B1R in SARS-CoV-2 infection. Created with BioRender.