title: Toxicogenomic multigene biomarker for predicting the future onset of proximal tubular injury in rats.
abstract: Drug-induced renal tubular injury is a major concern in the preclinical safety evaluation of drug candidates. Toxicogenomics is now a generally accepted tool for identifying chemicals with potential safety problems. The specific aim of the present study was to develop a model for use in predicting the future onset of drug-induced proximal tubular injury following repeated dosing with various nephrotoxicants. In total, 41 nephrotoxic and nonnephrotoxic compounds were used for the present analysis. Male Sprague-Dawley rats were dosed orally or intravenously once daily. Animals were exposed to three different doses (low, middle, and high) of each compound, and kidney tissue was collected at 3, 6, 9, and 24 h after single dosing, and on days 4, 8, 15, and 29 after repeated dosing. Gene expression profiles were generated from kidney total RNA using Affymetrix DNA microarrays. Filter-type gene selection and linear classification algorithms were employed to discriminate future onset of proximal tubular injury. We identified genomic biomarkers for use in future onset prediction using the gene expression profiles determined on day 1, when most of the nephrotoxicants had yet to produce detectable histopathological changes. The model was evaluated using a five-fold cross validation, and achieved a sensitivity of 93% and selectivity of 90% with 19 probes. We also found that the prediction accuracy of the optimized model was substantially higher than that produced by any of the single genomic biomarkers or histopathology. The genes included in our model were primarily involved in DNA replication, cell cycle control, apoptosis, and responses to oxidative stress and chemical stimuli. In summary, our toxicogenomic model is particularly useful for predicting the future onset of proximal tubular injury.
authors.affiliation: Toxicogenomics-Informatics Project, National Institute of Biomedical Innovation, 7-6-8 Asagi Saito, Ibaraki, Osaka 567-0085, Japan. yminowa@nibio.go.jp
authors.forename: Yohsuke
authors.initials: Y
authors.lastname: Minowa
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kondo
authors.forename: Takeki
authors.initials: T
authors.lastname: Uehara
authors.forename: Yuji
authors.initials: Y
authors.lastname: Morikawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okuno
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Nakatsu
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ono
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Maruyama
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kato
authors.forename: Jyoji
authors.initials: J
authors.lastname: Yamate
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamada
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ohno
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Urushidani
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D000818:Animals; D015415:Biomarkers; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics* / Q000473:pathology; D005544:Forecasting; D005819:Genetic Markers / Q000235:genetics*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000293:injuries*; D008297:Male; D005810:Multigene Family / Q000235:genetics*; D046912:Multiprotein Complexes / Q000235:genetics; D011237:Predictive Value of Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D043922:Toxicogenetics
chemical_list: D015415:Biomarkers; D005819:Genetic Markers; D046912:Multiprotein Complexes