Key result
Renin-angiotensin system inhibitors rarely caused ACE2 overexpression in healthy animals (3 of 38 experiments) or disease models (7 of 130 experiments), but frequently reversed or prevented disease-induced ACE2 repression.
Why the study?
Concerns arose that RAS inhibitors might aggravate SARS-CoV-2 infection based on claims from some animal experiments that they cause ACE2 overexpression.
Do renin-angiotensin system inhibitors cause ACE2 overexpression in healthy animals and disease models?
Systematic Review (n=168)
Do renin-angiotensin system inhibitors cause ACE2 overexpression in healthy animals and disease models?
ACE2 overexpression is a rare consequence of RASI treatment in animal models, challenging the theoretical concern that these drugs might aggravate SARS-CoV-2 infection by upregulating its receptor.
Rare RAS inhibitor-induced ACE2 overexpression in animal models supports preclinical safety; leaves open human translation.
Angiotensin-converting enzyme 2 (ACE2) protects against organ damage in hypertension and cardiovascular diseases by counter regulating the renin-angiotensin system (RAS). ACE2 is also the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on the claim that RAS inhibitors (RASIs) cause ACE2 overexpression in some animal experiments, concerns have arisen that RASIs may aggravate SARS-CoV-2 infection and coronavirus disease-2019 severity in RASI-treated patients. To achieve a comprehensive review, a systematic search of MEDLINE/PubMed was conducted regarding the effects of RASIs on tissue ACE2 mRNA/protein expression in healthy animals and animal models of human diseases. We identified 88 eligible articles involving 168 experiments in the heart, kidneys, lungs, and other organs. Three of 38 experiments involving healthy animals showed ACE2 expression greater than twice that of the control (overexpression). Among 102 disease models (130 experiments), baseline ACE2 was overexpressed in 16 models (18 experiments) and less than half the control level (repression) in 28 models (40 experiments). In 72 experiments, RASIs did not change ACE2 levels from the baseline levels of disease models. RASIs caused ACE2 overexpression compared to control levels in seven experiments, some of which were unsupported by other experiments under similar conditions. In 36 experiments, RASIs reversed or prevented disease-induced ACE2 repression, yielding no or marginal changes. Therefore, ACE2 overexpression appears to be a rare rather than common consequence of RASI treatment in healthy animals and disease models. Future studies should clarify the pathophysiological significance of RASI-induced reversal or prevention of ACE2 repression in disease models.
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Kai et al. (2021) conducted a systematic review in Healthy animals and animal models of human diseases (n=168). Renin-angiotensin system inhibitors (RASIs) vs. Control or sham animals was evaluated on Relative changes in tissue expression of ACE2 mRNA or protein compared to control or sham. Renin-angiotensin system inhibitors rarely caused ACE2 overexpression in healthy animals (3 of 38 experiments) or disease models (7 of 130 experiments), but frequently reversed or prevented disease-induced ACE2 repression.
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