title: Toxicogenomic biomarkers for renal papillary injury in rats.
abstract: Renal papillary injury is a common side effect observed during nonclinical and clinical investigations in drug development. The present study aimed to identify genomic biomarkers for early and sensitive detection of renal papillary injury in rats. We hypothesized that previously identified genomic biomarkers for tubular injury might be applicable for the sensitive detection of papillary injury in rats. We selected 18 genes as candidate biomarkers for papillary injury based on previously published studies and analyzed their expression profiles by RT-PCR in each kidney region, namely the cortex, cortico-medullary junction, and papilla in various nephrotoxicity models. Comparative analysis of gene expression profiles revealed that some genes were commonly upregulated or downregulated in the renal papilla, reflecting papillary injuries induced by 2-bromoethylamine hydrobromide, phenylbutazone, or n-phenylanthranilic acid. By applying receiver operator characteristics analysis, six candidate biomarkers were identified and their usefulness was confirmed by using an independent data set. The three top-ranked genes, Timp1, Igf1, and Lamc2, exhibited the best prediction performance in an external data set with area under the curve (AUC) values of greater than 0.91. An optimized support vector machine model consisting of three genes achieved the highest AUC value of 0.99. In conclusion, even though definitive validation studies are required for the establishment of their usefulness and reliability, these identified genes may prove to be the most promising candidate genomic biomarkers of renal papillary injury in rats.
authors.affiliation: Drug Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan. takeki.uehara@shionogi.co.jp
authors.forename: Takeki
authors.initials: T
authors.lastname: Uehara
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kondo
authors.forename: Yuji
authors.initials: Y
authors.lastname: Morikawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hanafusa
authors.forename: Seiko
authors.initials: S
authors.lastname: Ueda
authors.forename: Yohsuke
authors.initials: Y
authors.lastname: Minowa
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: D000818:Animals; D019540:Area Under Curve; D015536:Down-Regulation / Q000187:drug effects; D005021:Ethylamines / Q000633:toxicity; D020869:Gene Expression Profiling; D005819:Genetic Markers; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D007679:Kidney Medulla / Q000187:drug effects* / Q000473:pathology; D007797:Laminin / Q000235:genetics*; D008297:Male; D010653:Phenylbutazone / Q000633:toxicity; D012372:ROC Curve; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics*; D043922:Toxicogenetics / Q000379:methods; D015854:Up-Regulation / Q000187:drug effects; D062367:ortho-Aminobenzoates / Q000633:toxicity
chemical_list: D005021:Ethylamines; D005819:Genetic Markers; C578689:LAMC2 protein, rat; D007797:Laminin; C576839:TIMP1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; C548904:insulin-like growth factor-1, rat; D062367:ortho-Aminobenzoates; C004504:2-bromoethylamine; D007334:Insulin-Like Growth Factor I; C001209:fenamic acid; D010653:Phenylbutazone