5.2. Angiotensin 2 (Ang II)
The renin-angiotensin system (RAS) plays an important role in regulating vascular and kidney functions. In this system, angiotensin I (Ang I) is generated by cleavage of angiotensinogen by renin, and then ACE converts Ang I to Ang II. ACE2 functions to converse Ang II to Ang 1-7 (Figure 2). Ang II activates Ang II receptor type 1 (AT1R) and Ang II receptor type 2 (AT2R). Activation of AT1R induces detrimental effects, such as inflammation with release of cytokines, fibrosis, and impaired redox balance, and vasoconstriction (Eguchi, Kawai, Scalia & Rizzo, 2018), while activation of AT2R leads to anti-inflammatory, anti-fibrotic, and vasodilation (D’Ardes et al., 2020). Ang II can also increase the recruitment of immune cells to the injury sites and enhances the release of inflammatory cytokines (Nataraj et al., 1999). Ang II may regulate TLR4 mediated pathway by upregulating the expression of TLR4 and the downstream pathways (Wu et al., 2009).
Ang II induced cell signaling pathway is a potential mechanism underlying the cytokine storm caused by SARS‐CoV‐2. The binding of S-protein of SARS‐CoV‐2 to ACE2 on the cell surface caused downregulation of ACE2 expression. The reduced expression and activity of ACE2 resulted in an increase in Ang II, leading to elevated inflammatory responses (Figure 2). The Ang II regulators to balance the Ang II double edged function might benefit COVID-19.