Comparative Studies of Renin-Null Zebrafish and Mice Provide New Functional Insights

Scott Hoffmann, Linda Mullins, Sebastien Rider, Cara Brown, Charlotte B Buckley, Adrienne Assmus, Ziwen Li, Mariana Sierra Beltran, Neil Henderson, Jorge Del Pozo, Alexandre De Goes Martini, Maria Luisa S Sequeira-Lopez, R Ariel Gomez, John Mullins

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

BACKGROUND: The renin-angiotensin system is highly conserved across vertebrates, including zebrafish, which possess orthologous genes coding for renin-angiotensin system proteins, and specialized mural cells of the kidney arterioles, capable of synthesising and secreting renin.

METHODS: We generated zebrafish with CRISPR-Cas9-targeted knockout of renin (ren-/-) to investigate renin function in a low blood pressure environment. We used single-cell (10×) RNA sequencing analysis to compare the transcriptome profiles of renin lineage cells from mesonephric kidneys of ren-/- with ren+/+ zebrafish and with the metanephric kidneys of Ren1c-/- and Ren1c+/+ mice.

RESULTS: The ren-/- larvae exhibited delays in larval growth, glomerular fusion and appearance of a swim bladder, but were viable and withstood low salinity during early larval stages. Optogenetic ablation of renin-expressing cells, located at the anterior mesenteric artery of 3-day-old larvae, caused a loss of tone, due to diminished contractility. The ren-/- mesonephric kidney exhibited vacuolated cells in the proximal tubule, which were also observed in Ren1c-/- mouse kidney. Fluorescent reporters for renin and smooth muscle actin (tg(ren:LifeAct-RFP; acta2:EGFP)), revealed a dramatic recruitment of renin lineage cells along the renal vasculature of adult ren-/- fish, suggesting a continued requirement for renin, in the absence of detectable angiotensin metabolites, as seen in the Ren1YFP Ren1c-/- mouse. Both phenotypes were rescued by alleles lacking the potential for glycosylation at exon 2, suggesting that glycosylation is not essential for normal physiological function.

CONCLUSIONS: Phenotypic similarities and transcriptional variations between mouse and zebrafish renin knockouts suggests evolution of renin cell function with terrestrial survival.

Original languageEnglish
Article numberHYPERTENSIONAHA12118600
Pages (from-to)E56-E66
Issue number3
Early online date10 Jan 2022
Publication statusPublished - Mar 2022

Keywords / Materials (for Non-textual outputs)

  • actins
  • glycosylation
  • pericytes
  • renin
  • zebrafish


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