title: Identification of microRNA biomarker candidates in urine and plasma from rats with kidney or liver damage.
abstract: MicroRNAs (miRNA) are short single-stranded RNA sequences that have a role in the post-transcriptional regulation of genes. The identification of tissue specific or enriched miRNAs has great potential as novel safety biomarkers. One longstanding goal is to associate the increase of miRNA in biofluids (e.g., plasma and urine) with tissue-specific damage. Next-generation sequencing (miR-seq) was used to analyze changes in miRNA profiles of tissue, plasma and urine samples of rats treated with either a nephrotoxicant (cisplatin) or one of two hepatotoxicants (acetaminophen [APAP] or carbon tetrachloride [CCL4]). Analyses with traditional serum chemistry and histopathology confirmed that toxicant-induced organ damage was specific. In animals treated with cisplatin, levels of five miRNAs were significantly altered in the kidney, 14 in plasma and six in urine. In APAP-treated animals, five miRNAs were altered in the liver, 74 in plasma and six in urine; for CCL4the changes were five, 20 and 6, respectively. Cisplatin treatment caused an elevation of miR-378a in the urine, confirming the findings of other similar studies. There were 17 in common miRNAs elevated in the plasma after treatment with either APAP or CCL4. Four of these (miR-122, -802, -31a and -365) are known to be enriched in the livers of rats. Interestingly, the increase of serum miR-802 in both hepatotoxicant treatments was comparable to that of the well-known liver damage marker miR-122. Taken together, comparative analysis of urine and plasma miRNAs demonstrated their utility as biomarkers of organ injury. Copyright © 2016 The Authors. Journal of Applied Toxicology published by John Wiley & Sons Ltd.
authors.affiliation: Drug Safety Research & Evaluation, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, 02139, USA.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Wolenski
authors.affiliation: Molecular Pathology, Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, 02139, USA.
authors.forename: Pooja
authors.initials: P
authors.lastname: Shah
authors.affiliation: Drug Safety Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, 251-8555, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Sano
authors.affiliation: Drug Safety Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, 251-8555, Japan.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Shinozawa
authors.affiliation: Molecular Pathology, Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, 02139, USA.
authors.forename: Hugues
authors.initials: H
authors.lastname: Bernard
authors.affiliation: Drug Safety Research & Evaluation, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, 02139, USA.
authors.forename: Matt J
authors.initials: MJ
authors.lastname: Gallacher
authors.affiliation: Drug Safety Research & Evaluation, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, 02139, USA.
authors.forename: Shylah D
authors.initials: SD
authors.lastname: Wyllie
authors.affiliation: Drug Safety Research & Evaluation, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, 02139, USA.
authors.forename: Georgianna
authors.initials: G
authors.lastname: Varrone
authors.affiliation: Drug Safety Research & Evaluation, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, 02139, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cicia
authors.affiliation: Drug Safety Research & Evaluation, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, 02139, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Carsillo
authors.affiliation: Drug Safety Research & Evaluation, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, 02139, USA.
authors.forename: Craig D
authors.initials: CD
authors.lastname: Fisher
authors.affiliation: Drug Safety Research & Evaluation, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, 02139, USA.
authors.forename: Sean E
authors.initials: SE
authors.lastname: Ottinger
authors.affiliation: Molecular Pathology, Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, 02139, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Koenig
authors.affiliation: Drug Safety Research & Evaluation, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, 02139, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Kirby
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000652:urine; D002945:Cisplatin / Q000494:pharmacology; D004195:Disease Models, Animal; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007674:Kidney Diseases / Q000097:blood / Q000652:urine; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000097:blood / Q000652:urine; D017207:Rats, Sprague-Dawley
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; D000082:Acetaminophen; D002945:Cisplatin
keywords: bioinformatics; biomarker; hepatotoxicity; miR-seq; microRNA; nephrotoxicity