Unresolved issues
There are also few unresolved issues regarding RAS–COVID-19 interactions. Studies documenting upregulation of ACE2 genetic activity or plasma levels with ACEI/ARB have been predominantly done in animal models. Campbell et al failed to document any increase in Ang (1-9) levels after intravenous ACEI therapy in heart failure patients thus questioning the concept of increased ACE2 activity. A protective role of Ang (1-7) and ACE2 in maintenance of hypertension with prolonged therapy with Captopril is reported. Initially based on such paradoxical reports it was speculated that as hypertensive patients treated with ARBs have elevated expression of ACE2, thus may be more susceptible to COVID-19 infection (Fang et al., 2020). As a preventive measure, a suggestion for withdrawal of ARBs were also made (Fang et al., 2020). But, measurement of plasma and urinary ACE2 levels showed mixed result with most of the studies showed no difference among the patient groups taking ACEI/ARB in various clinical subsets like atrial fibrillation, heart failure and hypertension (Sriram et al., 2020). It has also been suggested that ACE2 can have regulated ectodomain shedding (Jia et al., 2009), thus questioning the very concept of measurement of plasma ACE2 level as the marker of membrane bound SARS-CoV2 ACE2 receptor. Similarly the concept of ACE2 depletion by SARS-CoV2 leading to increased pro-inflammatory Ang II causing lung injury has been shown to reverse with recombinant ACE2 in mouse models (Essig et al., 2020).