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Hypothesis for renin-angiotensin inhibitor mitigation of COVID-19
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NSTL
Elsevier
Preexisting hypertension is a known risk factor for severe COVID-19。 Abnormal activation of RAS upregulates angiotensin II (Ang-II) and contributes to severe manifestations of COVID-19。 Although RAS inhibitors (RASi) are a mainstay of antihypertensive therapy， they have been associated (in some animal studies) with an increase in angiotensin converting enzyme 2 (ACE2) receptors that facilitate cellular entry of the SARS-CoV-2 virus。 Nonetheless， current medical practice does not recommend curtailing RASi to protect hypertensive patients from COVID。 On the contrary， there is clinical evidence to support a beneficial effect of RASi for hypertensive patients in the midst of a COVID-19 pandemic， although the precise mechanism for this is unclear。 In this paper， we hypothesize that RASi reduces the severity of COVID-19 by promoting ACE2-AT1R complex formation at the cell surface， where AT1R mediates the major vasopressor effects of Ang-II。 Furthermore， we propose that the interaction between ACE2 and AT1R impedes binding of SARS-CoV-2 to ACE2， thereby allowing ACE2 to convert Ang-II to the more beneficial Ang(1-7)， that has vasodilator and anti-inflammatory activity。 Evidence for ACE2AT1R complex formation during reduced Ang-II comes from receptor colocalization studies in isolated HEK293 cells， but this has not been confirmed in cells having endogenous expression of ACE2 and AT1R。 Since the SARSCoV-2 virus attacks the kidney， as well as the heart and lung， our hypothesis for the effect of RASi on COVID-19 could be tested in vitro using human proximal tubule cells (HK-2)， having ACE2 and AT1 receptors。 Specifically， colocalization of fluorescent labelled: SARS-CoV-2 spike protein， ACE2， and AT1R in HK-2 cells can be used to clarify the mechanism of RASi action in renal and lung epithelia， which could lead to protocols for reducing the severity of COVID-19 in both hypertensive and normotensive patients。
NSTL
Elsevier
