title: Microvesicles derived from endothelial progenitor cells protect the kidney from ischemia-reperfusion injury by microRNA-dependent reprogramming of resident renal cells.
abstract: Endothelial progenitor cells are known to reverse acute kidney injury by paracrine mechanisms. We previously found that microvesicles released from these progenitor cells activate an angiogenic program in endothelial cells by horizontal mRNA transfer. Here, we tested whether these microvesicles prevent acute kidney injury in a rat model of ischemia-reperfusion injury. The RNA content of microvesicles was enriched in microRNAs (miRNAs) that modulate proliferation, angiogenesis, and apoptosis. After intravenous injection following ischemia-reperfusion, the microvesicles were localized within peritubular capillaries and tubular cells. This conferred functional and morphologic protection from acute kidney injury by enhanced tubular cell proliferation, reduced apoptosis, and leukocyte infiltration. Microvesicles also protected against progression of chronic kidney damage by inhibiting capillary rarefaction, glomerulosclerosis, and tubulointerstitial fibrosis. The renoprotective effect of microvesicles was lost after treatment with RNase, nonspecific miRNA depletion of microvesicles by Dicer knock-down in the progenitor cells, or depletion of pro-angiogenic miR-126 and miR-296 by transfection with specific miR-antagomirs. Thus, microvesicles derived from endothelial progenitor cells protect the kidney from ischemic acute injury by delivering their RNA content, the miRNA cargo of which contributes to reprogramming hypoxic resident renal cells to a regenerative program.
authors.affiliation: Dialysis and Kidney Transplantation Unit, Department of Internal Medicine, Center for Experimental Medical Research (CeRMS) and Nephrology, University of Torino, Torino, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cantaluppi
authors.forename: Stefano
authors.initials: S
authors.lastname: Gatti
authors.forename: Davide
authors.initials: D
authors.lastname: Medica
authors.forename: Federico
authors.initials: F
authors.lastname: Figliolini
authors.forename: Stefania
authors.initials: S
authors.lastname: Bruno
authors.forename: Maria C
authors.initials: MC
authors.lastname: Deregibus
authors.forename: Andrea
authors.initials: A
authors.lastname: Sordi
authors.forename: Luigi
authors.initials: L
authors.lastname: Biancone
authors.forename: Ciro
authors.initials: C
authors.lastname: Tetta
authors.forename: Giovanni
authors.initials: G
authors.lastname: Camussi
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia; D049109:Cell Proliferation; D055252:Cell-Derived Microparticles / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation; D007668:Kidney / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D009841:Oligonucleotides / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D012038:Regeneration; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014162:Transfection
chemical_list: C571458:MIRN126 microRNA, rat; D035683:MicroRNAs; D009841:Oligonucleotides; D043244:Ribonuclease III