title: Renin expression in developing zebrafish is associated with angiogenesis and requires the Notch pathway and endothelium.
abstract: Although renin is a critical regulatory enzyme of the cardiovascular system, its roles in organogenesis and the establishment of cardiovascular homeostasis remain unclear. Mammalian renin-expressing cells are widespread in embryonic kidneys but are highly restricted, specialized endocrine cells in adults. With a functional pronephros, embryonic zebrafish are ideal for delineating the developmental functions of renin-expressing cells and the mechanisms governing renin transcription. Larval zebrafish renin expression originates in the mural cells of the juxtaglomerular anterior mesenteric artery and subsequently at extrarenal sites. The role of renin was determined by assessing responses to renin-angiotensin system blockade, salinity variation, and renal perfusion ablation. Renin expression did not respond to renal flow ablation but was modulated by inhibition of angiotensin-converting enzyme and altered salinity. Our data in larval fish are consistent with conservation of renin's physiological functions. Using transgenic renin reporter fish, with mindbomb and cloche mutants, we show that Notch signaling and the endothelium are essential for developmental renin expression. After inhibition of angiogenesis, renin-expressing cells precede angiogenic sprouts. Arising from separate lineages, but relying on mutual interplay with endothelial cells, renin-expressing cells are among the earliest mural cells observed in larval fish, performing both endocrine and paracrine functions.
authors.affiliation: University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, Little France, The University of Edinburgh, Edinburgh, United Kingdom; and srider@staffmail.ed.ac.uk.
authors.forename: Sebastien A
authors.identifier: http://orcid.org/0000-0002-1020-4002
authors.initials: SA
authors.lastname: Rider
authors.affiliation: University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, Little France, The University of Edinburgh, Edinburgh, United Kingdom; and.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Mullins
authors.affiliation: University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, Little France, The University of Edinburgh, Edinburgh, United Kingdom; and.
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Verdon
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Calum A
authors.initials: CA
authors.lastname: MacRae
authors.affiliation: University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, Little France, The University of Edinburgh, Edinburgh, United Kingdom; and.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mullins
mesh_terms: D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism*; D006439:Hemodynamics / Q000502:physiology; D007814:Larva; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D012039:Regional Blood Flow / Q000502:physiology; D012083:Renin / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D015027:Zebrafish / Q000378:metabolism*
chemical_list: D051880:Receptors, Notch; D040262:Receptors, Vascular Endothelial Growth Factor; D012083:Renin
keywords: angiogenesis; endothelium; notch; renin; zebrafish