*1.2. Imbalance of Renin Angiotensin System*

The renin angiotensin system (RAS) is a well-known physiological system responsible for controlling cardiovascular dynamics through the modulation of blood pressure. In particular, angiotensinogen is converted into angiotensin I by renin, produced in the kidneys. Angiotensin I is transformed into angiotensin II by an extracellular angiotensin converting enzyme (ACE). Angiotensin II binds to the G protein-coupled receptor (GPCR), angiotensin II type 1 receptor (AT1R) in order to initiate its physiological functions. In general, the activation of AT1R by angiotensin II causes several physiologically important events including vasoconstriction, inflammation, thrombosis and production of reactive oxygen species (ROS). Angiotensin II is further degraded into angiotensin 1–7 by the action of the ACE2 enzyme. Angiotensin 1–7 binds to another GPCR and induces physiological events essentially opposite to those induced by AT1R activation, which include vasodilation, anti-inflammatory, antifibrosis, antithrombosis and ROS neutralization. ACE2 plays a key role as a negative regulator in the overall RAS pathway, exerting protective functions in various RAS-based models of pathogenesis. ACE2 also limits the expression by macrophages of several proinflammatory cytokines.

In the pulmonary phase of COVID-19, SARS-CoV-2 enters the type 2 pneumocyte by inducing the internalization of ACE2 and resulting in down-regulation and deficiency of ACE2. SARS-CoV-2-induced ACE2 deficiency reduces the conversion of angiotensin II to angiotensinogen 1–7 and increases the availability of angiotensin II. Excessive angiotensin II causes AT1R to over-activate, resulting in an imbalance of RAS. However, it should be remembered that SARS-CoV-2 invades host cells via two receptors: ACE2 and through cluster of differentiation 147 (CD147) transmembrane protein mediated endocytosis [7].

Although it has a lower affinity for the COVID-19 virus than ACE2, CD127 specifically accounts for the increase in blood glucose in infected patients, the risk of delayed COVID-19 in women, the increased susceptibility in geriatrics, and the increased susceptibility to T lymphocyte infections [8].
