title: MicroRNA-155 deficient mice experience heightened kidney toxicity when dosed with cisplatin.
abstract: The development of nephrotoxicity limits the maximum achievable dosage and treatment intervals for cisplatin chemotherapy. Therefore, identifying mechanisms that regulate this toxicity could offer novel methods to optimize cisplatin delivery. MicroRNAs are capable of regulating many different genes, and can influence diverse cellular processes, including cell death and apoptosis. We previously observed miR-155 to be highly increased following ischemic or toxic injury to the kidneys and, therefore, sought to determine whether mice deficient in miR-155 would respond differently to kidney injury. We treated C57BL/6 and miR-155(-/-) mice with 20 mg/kg of cisplatin and found a significantly higher level of kidney injury in the miR-155(-/-) mice. Genome-wide expression profiling and bioinformatic analysis indicated the activation of a number of canonical signaling pathways relating to apoptosis and oxidative stress over the course of the injury, and identified potential upstream regulators of these effects. One predicted upstream regulator was c-Fos, which has two confirmed miR-155 binding sites in its 3' UTR and, therefore, can be directly regulated by miR-155. We established that the miR-155(-/-) mice had significantly higher levels of c-Fos mRNA and protein than the C57BL/6 mice at 72 h after cisplatin exposure. These data indicate a role for miR-155 in the cisplatin response and suggest that targeting of c-Fos could be investigated to reduce cisplatin-induced nephrotoxicity.
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Pellegrini
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas.
authors.forename: Tao
authors.initials: T
authors.lastname: Han
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Bijol
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Janani
authors.initials: J
authors.lastname: Saikumar
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Florin L
authors.initials: FL
authors.lastname: Craciun
authors.affiliation: Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, Massachusetts.
authors.forename: William W
authors.initials: WW
authors.lastname: Chen
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas.
authors.forename: James C
authors.initials: JC
authors.lastname: Fuscoe
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, Massachusetts Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts vvaidya@partners.org.
authors.forename: Vishal S
authors.initials: VS
authors.lastname: Vaidya
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002945:Cisplatin; D019295:Computational Biology; D004195:Disease Models, Animal; D005355:Fibrosis; D020869:Gene Expression Profiling / Q000379:methods; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D016760:Proto-Oncogene Proteins c-fos; D002945:Cisplatin
keywords: Kidney toxicity; cisplatin; miRNAs; microRNA-155