The effect of renin–angiotensin–aldosterone system inhibitors on organ-specific ace2 expression in zebrafish and its implications for COVID-19

Abstract

Among cases of SARS-CoV-2 infections that result in serious conditions or death, many have pre-existing conditions such as hypertension and are on renin–angiotensin–aldosterone system (RAAS) inhibitors. The angiotensin-converting-enzyme-2 (ACE2), a key protein of the RAAS pathway, also mediates cellular entry of SARS-CoV-2. RAAS inhibitors might affect the expression levels of ace2, which could impact patient susceptibility to SARS-CoV-2. However, multi-organ-specific information is currently lacking and no species other than rodents have been examined. To address this knowledge gap, we treated adult zebrafish with the RAAS inhibitors aliskiren, olmesartan, and captopril for 7 consecutive days and performed qRT-PCR analysis of major RAAS pathway genes in the brain, gill, heart, intestine, kidney, and liver. Both olmesartan and captopril significantly increased ace2 expression in the heart, gill, and kidney. Olmesartan also increased ace2 expression in the intestine. Conversely, aliskiren significantly decreased ace2 expression in the heart. Discontinuation of compound treatments for 7 days did not return ace2 expression to baseline levels. While potential risks or benefits of antihypertensive RAAS inhibitors to SARS-CoV-2 infections in humans remain uncertain, this study provides new insights regarding the impact of RAAS inhibitors on organ-specific ace2 expression in another vertebrate model, thereby providing comparative data and laying scientific groundwork for future clinical decisions of RAAS inhibitor use in the context of COVID-19.

Angiotensin Converting Enzyme Inhibitors May Increase While Active Vitamin D May Decrease the Risk of Severe Pneumonia in SARS-CoV-2 Infected Patients with Chronic Kidney Disease on Maintenance Hemodialysis

“…The relationship between the use of ACEI and the incidence and severity of COVID-19 should be investigated in further studies, especially in vaccinated HD patients. Determination of ACE2 expression could help confirm such a relationship and our hypothesis [46].…”

A randomized controlled trial of renin-angiotensin-aldosterone system inhibitor management in patients admitted in hospital with COVID-19

“…Vertebrate models of zebrafish indicate that RAASi exposure increases expression of ACE2, highlighting the possible interrelationship between RAASi, ACE2 and COVID-19. 29 While reassuring that the use of guideline directed cardiovascular therapies did not decrease during the COVID-19 pandemic, 30 the specific role of RAASi in the context of COVID-19 infections have been explored observational studies 31 , 32 and randomized control trials. 12 , 13 These studies have collectively shown no increase in the risk for COVID-19 severity in patients who continued compared to those who discontinued RAASi therapy.…”

Neuromasts and Olfactory Organs of Zebrafish Larvae Represent Possible Sites of SARS-CoV-2 Pseudovirus Host Cell Entry

“…Our decision to concentrate on the anterior regions of developing embryos/larvae was due to the early appearance of the anterior peripheral sense organs ( 41 , 62 ) and their associated brain regions at these early stages ( 84 ), thus limiting the possible sites of viral entry. Our approach was to identify tissues/organs that express the ACE2 receptor ( 2 , 3 , 74 ) and then link this with the expression of TPC2, reported to be required for vesicle trafficking during SARS-CoV-2 infection ( 17 – 19 ), and associated endocytic activity, a proposed mechanism and pathway of host cell entry ( 4 , 5 ).…”

“…However, considering the nascent status of the olfactory organs at ~5 dpf, we propose that due to a similar combination of factors (i.e., expression of ACE2 and TPC2 and endocytic activity), the sensory cells of the early olfactory epithelium might (like the anterior neuromasts) also be a site of SARS-CoV-2 pseudovirus host cell entry. Other ACE2-expressing tissues and organs have been reported in zebrafish, including the vascular system and the lining of the digestive tract, kidney, liver, gills, and heart ( 3 , 111 , 112 ). However, as the open mouth connects with the pharyngoesophageal region only at 3 dpf ( 64 ), and these link with the rest of digestive tract (and associated organs) to form a continuous structure only at 5 dpf ( 69 ), we suggest that initially, the anterior sensory organs represent the major sites of ACE2-mediated host cell entry.…”

“…Identifying the sites and components of the infection mechanisms and pathways has the potential to facilitate the development of new therapeutic intervention strategies to limit future waves of infection, illness, and death, as well as the resulting socioeconomic disruption. SARS-CoV-2 entry into host cells is initiated when the spike glycoprotein (S protein) of the virus binds to the angiotensin-converting enzyme 2 (ACE2) receptor on the surface of a host cell ( 2 , 3 ). To mediate entry of SARS-CoV-2 into a cell, the S protein needs to be cleaved in two places; it is cleaved by furin (or a furin-like proprotein convertase) into S1 and S2 subunits, and then it is cleaved at the S2′ site, which is internal to S2 ( 4 ).…”