title: miR-125b transcriptionally increased by Nrf2 inhibits AhR repressor, which protects kidney from cisplatin-induced injury.
abstract: MicroRNAs (miRNAs) have a role in the cellular defense mechanism. Nuclear factor erythroid-2-related factor 2 (Nrf2) increases antioxidant enzyme capacity. However, miRNA transcriptionally controlled by Nrf2 had been uncharacterized. Here we report that miR-125b is transactivated by Nrf2 and inhibits aryl hydrocarbon receptor (AhR) repressor (AhRR). Bioinformatic approaches enabled us to extract six candidate miRNAs. Of them, only miR-125b was increased in the kidney of mice treated with oltipraz. Nrf2 overexpression enhanced primary, precursor and mature miR-125b levels. Functional assays revealed MIR125B1 is a bona fide target gene of Nrf2. Oltipraz treatment protected the kidney from cisplatin toxicity with increase of miR-125b. Consistently, Nrf2 knockout abrogated an adaptive increase of miR-125b elicited by cisplatin, augmenting kidney injury. An integrative network of miRNA and messenger RNA changes enabled us to predict miR-125b as an inhibitor of AhRR for the control of AhR activity and cell survival. In our molecular study, miR-125b inhibited AhRR and thereby activated AhR, leading to the induction of mdm2. Consistently, p53 activation by cisplatin was diminished by either miR-125b or oltipraz treatment. The results of experiments using miR-125b mimic or small interfering RNA of AhRR verified the role of miR-125b in AhRR regulation for kidney protection. In conclusion, miR-125b is transcriptionally activated by Nrf2 and serves as an inhibitor of AhRR, which contributes to protecting kidney from acute injury.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors.forename: M S
authors.initials: MS
authors.lastname: Joo
authors.forename: C G
authors.initials: CG
authors.lastname: Lee
authors.forename: J H
authors.initials: JH
authors.lastname: Koo
authors.forename: S G
authors.initials: SG
authors.lastname: Kim
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D002945:Cisplatin / Q000009:adverse effects*; D019295:Computational Biology; D056945:Hep G2 Cells; D006801:Humans; D015151:Immunoblotting; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D018336:Receptors, Aryl Hydrocarbon; D002945:Cisplatin