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).