Hypothesis for renin-angiotensin inhibitor mitigation of COVID-19

Abstract

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 ACE2-AT1R 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 SARS-CoV-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.

Keywords: ACE2; Angiotensin; Hypertension; Kidney; RAS; Renin; SARS-CoV-2.

Fig. 1

Ultrastructural features of kidneys from postmortems of patients with severe coronavirus disease 2019. Virus particles (red arrowheads) with distinctive spikes (green arrowheads) were present in the cytoplasm of the proximal tubular epithelium. EM preparation: osmium tetroxide post fixation and gradient dehydration, Epon-embedded, toluidine blue-stained “semi-thin” sections cut and stained with uranyl acetate and lead citrate. Viewed with a transmission electron microscope (HT-7800; Hitachi, Tokyo, Japan). Bar = 200 nm. From Ref .

Fig. 2

At high levels of Ang-II (left), increased binding of Ang-II to AT1R enhances availability of ACE2 to the invading virus. Conversely, low levels of Ang-II (right) frees AT1R to form complexes with ACE2 (dashed green lines) that increase conversion of Ang-II to Ang(1–7) and decrease interaction of the virus with ACE2.

Fig. 3

Colocalization of ACE2 and AT1R in HEK293T cells in control conditions (top), or after 2 hrs (middle) and 4 hrs (bottom) treatment with Ang-II (100 nmol/L). HEK293T cells were serum-starved for 24 hrs and treated with Ang-II (100 nmol/L) for the indicated time periods . In the merged panel, yellow indicates colocalization of ACE2 and AT1R. There is much less colocalization after 4 h of Ang-II treatment. Figure is from Ref .

Fig. 4

ARBs enhance AT1-ACE2 complex formation, increase conversion of Ang-II to Ang(1–7), and decrease availability of ACE2 receptors to invading virus. Dashed green lines indicate a putative linkage between AT1R and ACE2.