MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β
Recommended Citation
Hao, J., Lou, Q., Wei, Q., Mei, S., Li, L., Wu, G., … Dong, Z. (2017). MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β. The Journal of biological chemistry, 292(11), 4571–4582. doi:10.1074/jbc.M116.754929
Document Type
Article
Publication Date
3-17-2017
Publication Title
The Journal of biological chemistry
Abstract
Nephrotoxicity is a major adverse effect of cisplatin-mediated chemotherapy in cancer patients. The pathogenesis of cisplatin-induced nephrotoxicity remains largely unclear, making it difficult to design effective renoprotective approaches. Here, we have examined the role of microRNAs (miRNAs) in cisplatin-induced nephrotoxicity. We show that cisplatin nephrotoxicity was not affected by overall depletion of both beneficial and detrimental miRNAs from kidney proximal tubular cells in mice in which the miRNA-generating enzyme Dicer had been conditionally knocked out. To identify miRNAs involved in cisplatin nephrotoxicity, we used microarray analysis to profile miRNA expression and identified 47 up-regulated microRNAs and 20 down-regulated microRNAs in kidney cortical tissues. One up-regulated miRNA was miR-375, whose expression was also induced in cisplatin-treated renal tubular cells. Interestingly, inhibition of miR-375 decreased cisplatin-induced apoptosis, suggesting that miR-375 is a cell-damaging or pro-apoptotic agent. Blockade of P53 or NF-κB attenuated cisplatin-induced miR-375 expression, supporting a role of P53 and NF-κB in miR-375 induction. We also identified hepatocyte nuclear factor 1 homeobox B (HNF-1β) as a key downstream target of miR-375. Of note, we further demonstrated that HNF-1β protected renal cells against cisplatin-induced apoptosis. Together, these results suggest that upon cisplatin exposure, P53 and NF-κB collaboratively induce miR-375 expression, which, in turn, represses HNF-1β activity, resulting in renal tubular cell apoptosis and nephrotoxicity.
Medical Subject Headings
Animals; Antineoplastic Agents; Apoptosis; Cisplatin; Gene Expression Regulation; Hepatocyte Nuclear Factor 1-beta; Kidney; Mice; Mice, Knockout; MicroRNAs; Ribonuclease III
PubMed ID
28119452
Volume
292
Issue
11
First Page
4571
Last Page
4582
Comments
This research was originally published in the Journal of Biological Chemistry. Author(s). Title. J. Biol. Chem. Year; Vol:pp-pp. © the American Society for Biochemistry and Molecular Biology or © the Author(s).