miR-127 protects proximal tubule cells against ischemia/reperfusion: identification of kinesin family member 3B as miR-127 target

• Published in: PloS one 2012-09, Vol.7 (9), p.e44305-e44305
• Main Authors: Aguado-Fraile, Elia, Ramos, Edurne, Sáenz-Morales, David, Conde, Elisa, Blanco-Sánchez, Ignacio, Stamatakis, Konstantinos, del Peso, Luis, Cuppen, Edwin, Brüne, Bernhard, Bermejo, María Laura García
• Format: Article
• Language: English
• Subjects: Adhesion; Animals; Base Sequence; Binding Sites; Biological Transport; Biology; Cell Adhesion; Computational Biology; Cytoskeleton; Dextran; Dextrans; Fluorescein-5-isothiocyanate - analogs & derivatives; Gene Expression; Genomes; Health aspects; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Interference; Ischemia; Kidney transplantation; Kidney Tubules, Proximal - metabolism; Kidney Tubules, Proximal - pathology; Kinesin; Kinesin - genetics; Kinesin - metabolism; Male; MicroRNA; MicroRNAs; MicroRNAs - metabolism; Mimicry; miRNA; Molecular modelling; Molecular Sequence Data; Oligonucleotide Array Sequence Analysis; Pathology; Physiology; Polymerase chain reaction; Protein Binding; Protein Isoforms - genetics; Protein Isoforms - metabolism; Rats; Rats, Sprague-Dawley; Regulators; Reperfusion; Reperfusion Injury - genetics; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Rodents; Signal Transduction; Target recognition; Therapeutic applications; Tight junctions; Transplantation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0044305

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.