Reply to Letter to the Editor: "Don't judge too RAShly: the multifaceted role of the renin-angiotensin system and its therapeutic potential in COVID-19".

to the editor: We would like to congratulate Drs. Thomas Walther and Wolfgang M. Kuebler (2) for their lucid comments and thoughtful viewpoints and agree with most of their arguments.

The purpose of our letter (1) was to initiate a thoughtful discourse among experts in the field, underscoring the unknown and debated potential impact of contradictory mechanisms that operate through angiotensin-converting enzyme 2 (ACE2) on viral invasion and preservation of lung integrity during COVID-19 infection. We are aware of the well-established beneficial contribution of the ACE2-Ang-(1–7)-Mas receptor (Mas-R) axis to the integrity of the pulmonary system, especially during clinical settings of lung injury. Unfortunately, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses ACE2 as a Trojan horse to invade target cells. Therefore, the dilemma is how to prevent SARS-CoV-2 binding to ACE2 without inactivation of this enzyme and blocking its crucial beneficial properties. It is appealing to consider blockade of ACE2 as a clever way to eradicate the disadvantageous contribution of ACE2 as a viral entry route to target pulmonary alveolar cells. However, such blockade of ACE2 should not come at the expense of forgoing the advantageous effects of this enzyme in generating Ang-(1–7). Therefore, the first recommendation in our letter in this context, namely COVID-19 pulmonary complications, was using Mas-R agonists (AVE0991 or Ang-(1–7) to overcome the viral elimination of ACE2. Indeed, we mentioned using MLN-4760, an ACE2 antagonist, as a potential measure to change the enzyme configuration and possibly to attenuate its binding site affinity to the SARS-CoV-2 and eventually viral internalization into ACE2-expressing cells. However, it is obvious, as emphasized by Drs. Walther and Kuebler, that such an approach should be combined with Ang-(1–7) replacement therapy along with any ACE2 blocking therapy. In line with such a therapeutic strategy, we alternatively suggest (although this suggestion was mistakenly dropped from our Letter) using an ACE2 activator (Diminazene) in COVID-19 disease to maintain the positive effects of this enzyme, still hoping to change its configuration and possibly its affinity to SARS-CoV-2. We are aware that the catalytic active site of ACE2 is distant from the SARS binding site, but the effects of MLN-4760 and Diminazene on the affinity of ACE2 to SARS-CoV-2 merit evaluation in our view.

In addition, our letter did not argue for withdrawal of anti-RAAS (renin-angiotensin-aldosterone system) medications for the entire infected population. We referred to the relevant literature concerning the upregulation of ACE2 in certain diseases including heart failure and diabetes, especially under RAAS inhibitors. Theoretically, this trend may provide a rational explanation for the susceptibility of this subgroup of infected patients to exaggerated COVID-19-related clinical manifestations and to mortality, as reported in some published studies, though admittedly not fully validated in multiple studies. Such preliminary reports need to be balanced against the proven beneficial effects of this class of medication in preventing cardiovascular and kidney morbidity and mortality under non-COVID-19 conditions. Therefore, while it may be premature to propose cessation of RAAS blockers as currently occasionally suggested by some, emerging different views are worthy of debate for the benefit of patient care. For instance, in the case of noninfected patients given RAAS blockers for uncomplicated hypertension, conversion for a while to calcium channel blockers or other antihypertensive medications during the current pandemic deserves consideration, unless a clear benefit of RAAS blockade or given agents in the pathway is proven.

Collectively, the ideal therapeutic intervention might be to selectively block the viral attachment site on the ACE2 molecule while preserving its catalytic region. Until this goal is achieved, manipulation of ACE2 by pharmacological or immunological compounds that affect its configuration along reduced affinity to SARS-CoV-2 seems attractive, as long as the reduction of ACE2 catalytic activity is replenished with Ang-(1–7) or Mas-R agonist.

GRANTS

This work was supported in part by the Israel Science Foundation (Grants 544/18 and 182115) and the Kaylie Family Foundation.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

Z.A.A., K.S., S.N.H., S.K., and Z.A. drafted manuscript; edited and revised manuscript; and approved final version of manuscript.