FIGURE 2.

The imbalance in the renin-angiotensin system (RAS) system caused by SARS-CoV-2 and the role of sACE2 in prevention of progression into the cytokine storm. (1) Following the entry of the virus into the host cell via the ACE2 receptor-mediated endocytosis, decreasing of the plasma membrane ACE2 levels and conversion of Ang II to Ang 1-7 occurs. (2a, 2b) Reduced ACE2 level in the cell membrane results in Ang II accumulation due to ACE enzymatic activity and in turn detrimental consequences of ACE2 depletion. Accumulation of Ang II may cause a shift in RAS axis toward the harmful arm of RAS system through AT1R over-activation. (3a, 3b) AngII/AT1R axis activation enhances ROS production which stimulates the nuclear translocation of the transcription factor NF-κB. (4) NF-κB is a key regulator of macrophage-driven inflammatory reaction and plays a critical role in polarization toward the pro-inflammatory M1 phenotype. (5a, 5b) Following activation of NF-κB, excessive release of pro-inflammatory cytokines, including IL-6, IL-1, and TNF-α, leads to cytokine storm. (6) The deleterious inflammation can cause endothelial dysfunction, endothelial leakage, hyper-coagulation, thrombosis, atherosclerosis, and eventually leads to tissue damage and sever multi-organ destruction. (7) In parallel with increased expression of inflammatory genes, sACE2 expression can make balance in RAS system as sACE2 can perform its enzymatic activity in the extracellular space. (8) Production of Ang 1-7 via enzymatic cleavage possesses counteracting effects against negative consequences of Ang II. Ang 1-7 has protective functions mainly in heart, kidney, brain, and lungs. Ang 1-7 promotes anti-inflammatory M2 phenotype and reduces pro-inflammatory M1 phenotype and reduces expression of pro-inflammatory cytokines. (9) Ang-(1-7) by acting via the Mas receptor inhibits NF-κB signaling pathways and interferes with inflammation. (10) sACE2 can also block viruses as a decoy receptor and this viral trapping reduces viral load.