title: Vasopressin Regulates Extracellular Vesicle Uptake by Kidney Collecting Duct Cells.
abstract: Extracellular vesicles (ECVs) facilitate intercellular communication along the nephron, with the potential to change the function of the recipient cell. However, it is not known whether this is a regulated process analogous to other signaling systems. We investigated the potential hormonal regulation of ECV transfer and report that desmopressin, a vasopressin analogue, stimulated the uptake of fluorescently loaded ECVs into a kidney collecting duct cell line (mCCDC11) and into primary cells. Exposure of mCCDC11cells to ECVs isolated from cells overexpressing microRNA-503 led to downregulated expression of microRNA-503 target genes, but only in the presence of desmopressin. Mechanistically, ECV entry into mCCDC11cells required cAMP production, was reduced by inhibiting dynamin, and was selective for ECVs from kidney tubular cells. In vivo, we measured the urinary excretion and tissue uptake of fluorescently loaded ECVs delivered systemically to mice before and after administration of the vasopressin V2 receptor antagonist tolvaptan. In control-treated mice, we recovered 2.5% of administered ECVs in the urine; tolvaptan increased recovery five-fold and reduced ECV deposition in kidney tissue. Furthermore, in a patient with central diabetes insipidus, desmopressin reduced the excretion of ECVs derived from glomerular and proximal tubular cells. These data are consistent with vasopressin-regulated uptake of ECVs in vivo We conclude that ECV uptake is a specific and regulated process. Physiologically, ECVs are a new mechanism of intercellular communication; therapeutically, ECVs may be a vehicle by which RNA therapy could be targeted to specific cells for the treatment of kidney disease.
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh and.
authors.forename: Wilna
authors.initials: W
authors.lastname: Oosthuyzen
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh and.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Scullion
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh and.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Ivy
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh and.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Morrison
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh and.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Hunter
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine, Edinburgh, United Kingdom; and.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Starkey Lewis
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine, Edinburgh, United Kingdom; and.
authors.forename: Eoghan
authors.initials: E
authors.lastname: O'Duibhir
authors.affiliation: Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Street
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Caporali
authors.affiliation: Medical Research Council Centre for Inflammation Research, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Gregory
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine, Edinburgh, United Kingdom; and.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Forbes
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh and.
authors.forename: David J
authors.initials: DJ
authors.lastname: Webb
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh and.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Bailey
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh and james.dear@ed.ac.uk.
authors.forename: James W
authors.initials: JW
authors.lastname: Dear
mesh_terms: D000293:Adolescent; D000818:Animals; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D000067128:Extracellular Vesicles / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007685:Kidney Tubules, Collecting / Q000166:cytology* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D051381:Rats; D014667:Vasopressins / Q000502:physiology*
chemical_list: D014667:Vasopressins; D003894:Deamino Arginine Vasopressin
keywords: exosomes; vasopressin; vesicles