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. 2021 Oct 4;9(11):786–798. doi: 10.1016/S2213-8587(21)00244-8

Figure 1.

Figure 1

The RAAS in COVID-19

(A) When the RAAS is activated, angiotensinogen produced in the liver is cleaved to angiotensin I in the kidney. Angiotensin I is further converted to angiotensin II by ACE. Angiotensin II binds to its receptors, AT1R and AT2R, causing the release of aldosterone from the zona glomerulosa in the adrenal cortex. In the second part of the RAAS, angiotensin II is converted by ACE2 to the vasodilatory angiotensin 1–7, which binds to its Mas receptor, thereby possessing opposing actions of angiotensin II and ACE. (B) ACE2 consists of two forms, a membrane-spanning protein and a circulating soluble form, both capable of binding to the spike protein on the surface of SARS-CoV-2. Expression of ACE2 is regulated by HMGB1 and SMARCA4. Following infection with SARS-CoV-2, the viral spike protein is cleaved by TMPRSS2 and the membrane form of ACE2 is internalised with the virus, leading to a decrease in ACE2. This stage might result in overactivation of the ACE or angiotensin II part of the RAAS, thereby augmenting signalling through AT1R and AT2R. Virus entry is facilitated by NRP1, which promotes the interaction between SARS-CoV-2 and ACE2. A suggested alternative receptor for virus entry is DPP-4. RAAS=renin–angiotensin–aldosterone system. ACE=angiotensin-converting enzyme.