EFFECTS OF RAS INHIBITORS ON TISSUE ACE2 EXPRESSION IN ANIMAL MODELS

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) protects against organ damages by overactivated renin-angiotensin system (RAS). Also, ACE2 exerts a role as the receptors for SARS-CoV-2 to enter host target cells. Based on limited number of articles reporting that RAS inhibitors induced upregulation of cardiac or renal ACE2 in animal models, concern have arisen that RAS inhibitors may aggravate SARS-CoV-2 infection and COVID-19 severity. Therefore, we performed a comprehensive review by applying the standard searching strategy for systematic reviews to investigate the effects of RAS inhibitors on cardiac, vascular, renal and pulmonary mRNA/protein ACE2 expression in healthy animals and disease animal models. We identified 88 eligible articles including 167 experiments. In RAS inhibitors-treated healthy animals, only 3 (heart 2, kidneys 1) of 37 experiments showed ACE2 expression greater than twice of the control (overexpression) whereas others showed no/marginal change in the heart, arteries, kidneys, lungs, and other organs. Among 102 disease models (130 experiments), baseline ACE2 was overexpressed in 16 models (18 experiments), less than half the control level (repression) in 28 models (40 experiments) and remained no/marginal change in 51 models (74 experiments). RAS inhibitors induced ACE2 overexpression from no/marginal change levels in only 7 experiments, 4 (myocardial infarction 2, heart failure 1, diabetic nephropathy 1) of which were not supported by other experiments under similar conditions. In 36 experiments, RAS inhibitors reversed or prevented disease-induced repression, yielding no/marginal change. Thus, ACE2 overexpression is a rare consequence of RAS inhibitors treatment in healthy animals and disease models. Future studies should clarify the pathophysiological significance of reversal or prevention of ACE2 repression induced by RAS inhibitors in disease models.