Toxicogenomic biomarkers for renal papillary injury in rats

Takeki Uehara, Chiaki Kondo, Yuji Morikawa, Hiroyuki Hanafusa, Seiko Ueda, Yohsuke Minowa, Noriyuki Nakatsu, Atsushi Ono, Toshiyuki Maruyama, Ikuo Kato, Jyoji Yamate, Hiroshi Yamada, Yasuo Ohno, Tetsuro Urushidani

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalToxicology
Volume303
DOIs
Publication statusPublished - Jan 7 2013
Externally publishedYes

Fingerprint

Toxicogenetics
Biomarkers
Rats
Genes
Kidney
Wounds and Injuries
Area Under Curve
Phenylbutazone
Gene expression
Support vector machines
Validation Studies
Transcriptome
Acids
Down-Regulation
Pharmaceutical Preparations
Polymerase Chain Reaction

Keywords

  • Igf1
  • Lamc2
  • Papillary injury
  • Rat
  • Timp1
  • Toxicogenomics

ASJC Scopus subject areas

  • Toxicology

Cite this

Uehara, T., Kondo, C., Morikawa, Y., Hanafusa, H., Ueda, S., Minowa, Y., ... Urushidani, T. (2013). Toxicogenomic biomarkers for renal papillary injury in rats. Toxicology, 303, 1-8. https://doi.org/10.1016/j.tox.2012.09.012

Toxicogenomic biomarkers for renal papillary injury in rats. / Uehara, Takeki; Kondo, Chiaki; Morikawa, Yuji; Hanafusa, Hiroyuki; Ueda, Seiko; Minowa, Yohsuke; Nakatsu, Noriyuki; Ono, Atsushi; Maruyama, Toshiyuki; Kato, Ikuo; Yamate, Jyoji; Yamada, Hiroshi; Ohno, Yasuo; Urushidani, Tetsuro.

In: Toxicology, Vol. 303, 07.01.2013, p. 1-8.

Research output: Contribution to journalArticle

Uehara, T, Kondo, C, Morikawa, Y, Hanafusa, H, Ueda, S, Minowa, Y, Nakatsu, N, Ono, A, Maruyama, T, Kato, I, Yamate, J, Yamada, H, Ohno, Y & Urushidani, T 2013, 'Toxicogenomic biomarkers for renal papillary injury in rats', Toxicology, vol. 303, pp. 1-8. https://doi.org/10.1016/j.tox.2012.09.012
Uehara T, Kondo C, Morikawa Y, Hanafusa H, Ueda S, Minowa Y et al. Toxicogenomic biomarkers for renal papillary injury in rats. Toxicology. 2013 Jan 7;303:1-8. https://doi.org/10.1016/j.tox.2012.09.012
Uehara, Takeki ; Kondo, Chiaki ; Morikawa, Yuji ; Hanafusa, Hiroyuki ; Ueda, Seiko ; Minowa, Yohsuke ; Nakatsu, Noriyuki ; Ono, Atsushi ; Maruyama, Toshiyuki ; Kato, Ikuo ; Yamate, Jyoji ; Yamada, Hiroshi ; Ohno, Yasuo ; Urushidani, Tetsuro. / Toxicogenomic biomarkers for renal papillary injury in rats. In: Toxicology. 2013 ; Vol. 303. pp. 1-8.
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