Key result
Zebrafish express ace2 and RAAS genes in vascular cells, validating their use in COVID-19 research.
Why the study?
The relationship between the Renin-Angiotensin-Aldosterone System and COVID-19, including how Ace2 and related genes are regulated, is not yet understood.
Establishes zebrafish as a viable preclinical model for studying the intersection of the RAAS system and COVID-19 pathogenesis.
People with underlying conditions, including hypertension, obesity, and diabetes, are especially susceptible to negative outcomes after infection with coronavirus SARS-CoV-2, which causes COVID-19. Hypertension and respiratory inflammation are exacerbated by the Renin-Angiotensin-Aldosterone System (RAAS), which normally protects from rapidly dropping blood pressure via Angiotensin II (Ang II) produced by the enzyme Ace. The Ace paralog Ace2 degrades Ang II, counteracting its chronic effects, and serves as the SARS-CoV-2 receptor. Ace, the coronavirus, and COVID-19 comorbidities all regulate Ace2, but we do not yet understand how. To exploit zebrafish (Danio rerio) to help understand the relationship of the RAAS to COVID-19, we must identify zebrafish orthologs and co-orthologs of human RAAS genes and understand their expression patterns. To achieve these goals, we conducted genomic and phylogenetic analyses and investigated single cell transcriptomes. Results showed that most human RAAS genes have one or more zebrafish orthologs or co-orthologs. Results identified a specific type of enterocyte as the specific site of expression of zebrafish orthologs of key RAAS components, including Ace, Ace2, Slc6a19 (SARS-CoV-2 co-receptor), and the Angiotensin-related peptide cleaving enzymes Anpep (receptor for the common cold coronavirus HCoV-229E), and Dpp4 (receptor for the Middle East Respiratory Syndrome virus, MERS-CoV). Results identified specific vascular cell subtypes expressing Ang II receptors, apelin, and apelin receptor genes. These results identify genes and cell types to exploit zebrafish as a disease model for understanding mechanisms of COVID-19.
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Postlethwait et al. (2021) studied COVID-19 modeling (Renin-Angiotensin-Aldosterone System). Genomic, phylogenetic, and single-cell transcriptome analyses was evaluated on Cellular expression patterns of zebrafish orthologs and co-orthologs of human RAAS genes. Zebrafish express key RAAS components and the SARS-CoV-2 receptor ortholog ace2 specifically in enterocytes and vascular cells, validating its use as a disease model for COVID-19.
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