title: Transfer of microRNA-486-5p from human endothelial colony forming cell-derived exosomes reduces ischemic kidney injury.
abstract: Administration of human cord blood endothelial colony-forming cells (ECFCs) or their exosomes protects mice against kidney ischemia/reperfusion injury. Here we studied the microRNA (miRNA) content of ECFC exosomes and the role of miRNA transfer in kidney and endothelial cell protection. ECFC exosomes were enriched in miR-486-5p, which targets the phosphatase and tensin homolog (PTEN) and the Akt pathway. In cultured endothelial cells exposed to hypoxia, incubation with ECFC exosomes increased miR-486-5p, decreased PTEN, and stimulated Akt phosphorylation. Exposure of hypoxic endothelial cells to conditioned medium from ECFCs pretreated with anti-miR-486-5p blocked increases in miR-486-5p and phosphorylated Akt, restored expression of PTEN, and enhanced apoptosis. Coculture of endothelial cells with ECFCs enhanced endothelial miR-486-5p levels. Targeting of PTEN by miR-486-5p was observed in endothelial cells, and PTEN knockdown blocked apoptosis. In mice with ischemic kidney injury, infusion of ECFC exosomes induced potent functional and histologic protection, associated with increased kidney miR-486-5p levels, decreased PTEN, and activation of Akt. Infusion of exosomes from ECFCs transfected with anti-miR-486-5p had no protective effect. Thus, delivery of ECFC exosomes reduces ischemic kidney injury via transfer of miR-486-5p targeting PTEN. Exosomes enriched in miR-486-5p could represent a therapeutic tool in acute kidney injury.
authors.affiliation: Division of Nephrology, Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Viñas
authors.affiliation: Division of Nephrology, Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Dylan
authors.initials: D
authors.lastname: Burger
authors.affiliation: Division of Nephrology, Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Zimpelmann
authors.affiliation: Division of Nephrology, Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Randa
authors.initials: R
authors.lastname: Haneef
authors.affiliation: Division of Nephrology, Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: William
authors.initials: W
authors.lastname: Knoll
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Pearl
authors.initials: P
authors.lastname: Campbell
authors.affiliation: Division of Nephrology, Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Alex
authors.initials: A
authors.lastname: Gutsol
authors.affiliation: Division of Nephrology, Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Carter
authors.affiliation: Division of Hematology, Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: David S
authors.initials: DS
authors.lastname: Allan
authors.affiliation: Division of Nephrology, Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada. Electronic address: kburns@ottawahospital.on.ca.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Burns
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology; D055354:Exosomes / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism*
chemical_list: C560945:MIRN486 microRNA, human; D035683:MicroRNAs; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: ECFC; acute kidney injury; exosome apoptosis; miR-486-5p