title: miR-127 protects proximal tubule cells against ischemia/reperfusion: identification of kinesin family member 3B as miR-127 target.
abstract: Ischemia/reperfusion (I/R) is at the basis of renal transplantation and acute kidney injury. Molecular mechanisms underlying proximal tubule response to I/R will allow the identification of new therapeutic targets for both clinical settings. microRNAs have emerged as crucial and tight regulators of the cellular response to insults including hypoxia. Here, we have identified several miRNAs involved in the response of the proximal tubule cell to I/R. Microarrays and RT-PCR analysis of proximal tubule cells submitted to I/R mimicking conditions in vitro demonstrated that miR-127 is induced during ischemia and also during reperfusion. miR-127 is also modulated in a rat model of renal I/R. Interference approaches demonstrated that ischemic induction of miR-127 is mediated by Hypoxia Inducible Factor-1alpha (HIF-1α) stabilization. Moreover, miR-127 is involved in cell-matrix and cell-cell adhesion maintenance, since overexpression of miR-127 maintains focal adhesion complex assembly and the integrity of tight junctions. miR-127 also regulates intracellular trafficking since miR-127 interference promotes dextran-FITC uptake. In fact, we have identified the Kinesin Family Member 3B (KIF3B), involved in cell trafficking, as a target of miR-127 in rat proximal tubule cells. In summary, we have described a novel role of miR-127 in cell adhesion and its regulation by HIF-1α. We also identified for the first time KIF3B as a miR-127 target. Both, miR-127 and KIF3B appear as key mediators of proximal epithelial tubule cell response to I/R with potential al application in renal ischemic damage management.
authors.affiliation: Department of Pathology, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
authors.forename: Elia
authors.initials: E
authors.lastname: Aguado-Fraile
authors.forename: Edurne
authors.initials: E
authors.lastname: Ramos
authors.forename: David
authors.initials: D
authors.lastname: Sáenz-Morales
authors.forename: Elisa
authors.initials: E
authors.lastname: Conde
authors.forename: Ignacio
authors.initials: I
authors.lastname: Blanco-Sánchez
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Stamatakis
authors.forename: Luis
authors.initials: L
authors.lastname: del Peso
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
authors.forename: María Laura García
authors.initials: ML
authors.lastname: Bermejo
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001692:Biological Transport; D002448:Cell Adhesion; D019295:Computational Biology; D003911:Dextrans; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D015870:Gene Expression; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D003911:Dextrans; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C095899:KIF3B protein, human; D035683:MicroRNAs; C544526:Mirn127 microRNA, rat; D020033:Protein Isoforms; C015219:fluorescein isothiocyanate dextran; C577559:Kif3B protein, rat; D016547:Kinesins; D016650:Fluorescein-5-isothiocyanate