Identification and verification of novel biomarkers for drug-induced renal papillary necrosis in rats using toxicoproteomic and toxicogenomic approaches

• SASAKI Daisuke

  Drug Safety Research Labs., Astellas Pharma Inc., Japan Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan

• KANKI Masayuki

  Drug Safety Research Labs., Astellas Pharma Inc., Japan

• NISHIHARA Kumiko

  Drug Safety Research Labs., Astellas Pharma Inc., Japan

• HIRAMOTO Masashi

  Analysis & Pharmacokinetics Research Labs., Astellas Pharma Inc., Japan

• YURI Masatoshi

  Analysis & Pharmacokinetics Research Labs., Astellas Pharma Inc., Japan

• UMENO Hitomi

  Drug Safety Research Labs., Astellas Pharma Inc., Japan

• MORIGUCHI Akira

  Drug Safety Research Labs., Astellas Pharma Inc., Japan

• MITORI Hikaru

  Drug Safety Research Labs., Astellas Pharma Inc., Japan

• HIROTA Rika

  Drug Safety Research Labs., Astellas Pharma Inc., Japan

• SEKI Jiro

  Drug Safety Research Labs., Astellas Pharma Inc., Japan

• MIYAMAE Yoichi

  Drug Safety Research Labs., Astellas Pharma Inc., Japan

• HWANG Gi-Wook

  Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan

• NAGANUMA Akira

  Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan

抄録

Renal papillary necrosis (RPN) is a type of kidney injury induced by diabetes or nonsteroidal anti-inflammatory drugs or anticancer drugs. However, no biomarkers (BMs) capable of detecting prognostic or early stages of RPN in humans have been identified at present. We therefore explored novel BMs suitable for the early detection of RPN using toxicoproteomic (TPx) and toxicogenomic (TGx) techniques. Urine and kidney papilla from rat models of RPN induced by 2-bromoethylamine hydrobromide were used for TPx and TGx, respectively, and we also conducted histopathological examinations for comparisons with BM candidates. In addition, our present results were compared with those obtained using model rats with glomerular or proximal tubular injury induced by puromycin, cisplatin, or gentamicin. As a result of the TPx analysis of urine from RPN model rats, 94 proteins were identified as BM candidates, which included a number of acute phase proteins. From the TGx analysis, changes in the expression of mRNAs involved in the enhancement of IL-1 signaling, apoptosis, and oxidative stress were observed. In particular, elevation of fibrinogen and C3 were detected by both TPx and TGx analyses and were considered to be BMs associated with RPN. However, the levels of fibrinogen and C3 were also increased in urine by proximal tubular injury. Thus, fibrinogen and C3 do not only detect RPN, but also serve as BMs of proximal tubular injury. The increase in acute phase proteins is thought to be due to the enhancement of inflammation-related signaling. We are presently screening for other RPN-specific BMs among the remaining 92 BM candidates.

収録刊行物

• 日本毒性学会学術年会

  日本毒性学会学術年会 39.2 (0), AP-75-, 2012

  日本毒性学会

詳細情報

• CRID: 1390282680523242624
• NII論文ID: 130005009238
• DOI: 10.14869/toxpt.39.2.0.ap-75.0
• 本文言語コード: ja
• データソース種別:
  • JaLC
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可