TY - JOUR
T1 - Toxicogenomic biomarkers for renal papillary injury in rats
AU - Uehara, Takeki
AU - Kondo, Chiaki
AU - Morikawa, Yuji
AU - Hanafusa, Hiroyuki
AU - Ueda, Seiko
AU - Minowa, Yohsuke
AU - Nakatsu, Noriyuki
AU - Ono, Atsushi
AU - Maruyama, Toshiyuki
AU - Kato, Ikuo
AU - Yamate, Jyoji
AU - Yamada, Hiroshi
AU - Ohno, Yasuo
AU - Urushidani, Tetsuro
N1 - Funding Information:
This work was supported in part by grants from the Ministry of Health, Labor and Welfare of Japan , H14-001 -Toxico and H19-001 -Toxico.
PY - 2013/1/7
Y1 - 2013/1/7
N2 - 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.
AB - 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.
KW - Igf1
KW - Lamc2
KW - Papillary injury
KW - Rat
KW - Timp1
KW - Toxicogenomics
UR - http://www.scopus.com/inward/record.url?scp=84870575569&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84870575569&partnerID=8YFLogxK
U2 - 10.1016/j.tox.2012.09.012
DO - 10.1016/j.tox.2012.09.012
M3 - Article
C2 - 23142791
AN - SCOPUS:84870575569
SN - 0300-483X
VL - 303
SP - 1
EP - 8
JO - Toxicology
JF - Toxicology
ER -