Abstract
Background: Angiotensin-converting enzyme 2 (ACE2) is recognized as the main cellular receptor for the new coronavirus, SARS-CoV-2, that facilitates its entry into the host target cell, leading to the fatal viral infection, coronavirus disease 2019 (COVID-19). Thus, it is considered as a main therapeutic target in the SARS-CoV-2 infection. The dual role of ACE2 as a gate for SARS-CoV-2 virus and as a part of lung and multi-organ protection has built a scientific debate that affects the choice of treatments used against COVID-19 patient. ACE2 inhibitors like anti-ACE2 antibodies were first introduced as therapeutic solutions that, theoretically, would decrease the availability of target molecules for SARS-CoV-2 by downregulating ACE2 expression. However, animal studies showed that ACE2 upregulation acts as a counterbalance to the hypertensive pro-inflammatory angiotensin I-converting enzyme (ACE) in the renin–angiotensin system (RAS) and results in a protective role against acute lung injury – a fatal consequence of the disease. The current study tests the effect of ACE2-activating treatments against the outcome of genetic variations in the population that have ACE2-upregulatory effects.
 Conclusion Despite its role as a receptor for the SARS-CoV-2 virus, experimental studies and the genetic polymorphisms in populations that have ACE2 upregulation revealed a protective role against COVID-19 infection.
 
 Key words: ACE2 ACE COVID-19 treatments genetic variations
Highlights
A retrospective study by Zhang et al found that COVID-19 patients, who were taking angiotensin-converting enzyme inhibitor (ACEI) and angiotensin-receptor blocker (ARB) as a hypertension treatment, have a low mortality rate. This is in line with the animal studies that showed a potential protective effect with high Angiotensin-converting enzyme 2 (ACE2) levels as a result of the increasing production of the vasodilator angiotensin 1–7, which ameliorates the severity of acute lung injury in SARS-CoVinfected mice [12]
Genetic association studies revealed that genetic polymorphisms that result in high ACE2 levels are associated with low infection and low rates [16,17,18]
This can be taken as evidence for the protective shift toward the ACE2 axis
Summary
The mechanism for SARS-CoV-2 infection necessitates the binding of the virus to the membrane-bound form of angiotensin-converting enzyme 2 (ACE2) receptor, followed by the internalization of the complex by the infected host cell [1]. Some researchers believed that the increased expression of the ACE2 receptor may elevate the rate of SARS-CoV-2 infection via increasing viral load, morbidity, and mortality. They assumed that ACE2 inhibitors like anti-ACE-2 antibodies could be used to block SARS-CoV-2 binding to the receptor [6, 7]. Recombinant soluble ACE2 has been introduced to neutralize SARS-CoV-2 by binding to the viral spike protein, and at the same time minimizing injury to multiple organs, including lungs, kidneys, and heart [9, 10]. The current study believes that the shift from ACE to the ACE2 axis has a beneficial effect against COVID19. The effect of ACE2-activating treatment is discussed and compared to the protective effect of ACE2 upregulating genetic polymorphisms in populations
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