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Comparative analysis of gene expression between renal cortex and papilla in nedaplatin-induced nephrotoxicity in rats

Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan, takeki.uehara{at}shionogi.co.jp

Takako Miyoshi

Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan

Noriko Tsuchiya

Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan

Koichi Masuno

Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan

Manabu Okada

Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan

Satoshi Inoue

Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan

Mikinori Torii

Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan

Jyoji Yamate

Department of Veterinary Pathology, Graduate School of Agriculture and Biological Science, Osaka Prefecture University, 1-1 Gakuen-cho, Sakai, Osaka 599-8531, Japan

Toshiyuki Maruyama

Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan

To elucidate the mechanism of nephrotoxicity caused by anti-neoplastic platinum complex, nedaplatin (NDP), treatment with a particular focus on the renal papillary toxicity, we analysed the gene expression profiles of two renal regions, the cortex (RC) and the papilla (RP) in rat kidneys. Male Wistar rats received a single administration of 10 mg/kg intravenous NDP or vehicle alone (5% xylitol solution) and were sacrificed six days later. The kidneys were dissected into the RC and RP and used for histopathological and microarray analyses. Histopathologically, NDP caused characteristic renal lesions, such as necrosis, single cell necrosis (with TUNEL TdT-mediated dUTP-biotin nick end labelling-positive) and regeneration/hyperplasia of the epithelial cells in both renal regions. Global gene expression analysis revealed that several genes involved in various functional categories were commonly deregulated in both renal regions, such as apoptosis, cell cycle regulation, DNA metabolism, cell migration/adhesion and cytoskeleton organization or genes induced as a perturbation of oxidative status and calcium homeostasis. Comparative analysis of gene expression between RC and RP revealed that genes encoding several subtypes of cytokeratins were identified as being specifically overexpressed in RP by the NDP treatment. Differential expression patterns of these selected genes observed by microarray analysis were further confirmed by quantitative real time RT-PCR and immunohistochemistry, which demonstrated increased expression of cytokeratins (CKs) 14 and 19 at the epithelium covering RP and/or collecting duct epithelium. Overall, the results contribute to understanding the renal molecular events of NDP-induced nephrotoxicity including novel potential biomarker genes encoding CKs 14 and 19 that may serve as indicators of renal papillary toxicity. Human & Experimental Toxicology (2007) 26, 767—780

Key Words: toxicogenomics • gene expression • renal papillary toxicity • nedaplatin • cytokeratin

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