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.
Highlights
RNA polymerase II-like messenger RNA transcription and are subsequently processed to miRNAs by drosha and dicer.[6]
In view of the lack of an understanding on miRNA controlled by oxidative stress, this study investigated the levels of miRNAs increased by Nrf[2] in the kidney and elucidated the functional role of specific miRNA in the survival of renal cells against cisplatin toxicity
Tel: +822 880 7840; Fax: +822 872 1795; E-mail: sgk@snu.ac.kr Keywords: miR-125b; Nrf[2]; AhRR; acute kidney injury; cisplatin Abbreviations: AhR, aryl hydrocarbon receptor; AhRR, AhR repressor; antioxidant response elements (ARE), antioxidant response element; ASO, antisense oligonucleotide; BUN, blood urea nitrogen; cDNA, complementary DNA; ChIP, chromatin immunoprecipitation; Cis, cisplatin; KIM1, kidney injury molecule-1; KO, knockout; miRNA, microRNA; mRNA, messenger RNA; Mut, mutant; Nrf[2], nuclear factor erythroid-2-related factor 2; pri-miRNA, primary miRNA; qRT-PCR, quantitative real-time PCR; SFN, sulforaphane; siRNA, small interfering RNA; UTR, untranslated region; Veh, vehicle; WT, wild type; XRE, xenobiotic response element Received 22.8.13; revised 25.9.13; accepted 26.9.13; Edited by E Candi miR-125b as an inhibitor of Ahr repressor MS Joo et al network integrating miRNA and mRNA changes to predict a target regulated by the miRNA identified
Summary
RNA polymerase II-like messenger RNA (mRNA) transcription and are subsequently processed to miRNAs by drosha and dicer.[6] Transcriptional induction of pri-miRNA is the crucial step for the control of total miRNA content Transcription factors such as p53, NF-kB, and C/EBPb participate in the transcription of miR-34a, miR-155, and miR-143.7–9 It has been shown that oxidative stress induced by toxicant changed a profiling of miRNA expression levels.[10] the specific miRNA induced by oxidative stress and the responsible transcription factor(s) were uncharacterized. In view of the lack of an understanding on miRNA controlled by oxidative stress, this study investigated the levels of miRNAs increased by Nrf[2] in the kidney and elucidated the functional role of specific miRNA in the survival of renal cells against cisplatin toxicity. Our results indicate that activated Nrf[2] may upregulate miR-125b in the kidney
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
