Aging increases the susceptibility of cisplatin-induced nephrotoxicity

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• 作者：Jiagen Wen ; Meizi Zeng ; Yan Shu ; Dong Guo ; Yi Sun ; Zhen Guo ; Youhong Wang…
• 关键词：Cisplatin ; eGFR ; Inflammatory response ; Nephrotoxicity ; Nrf2 ; Transporters
• 刊名：AGE
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：37
• 期：6
• 全文大小：6,990 KB
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• 作者单位：Jiagen Wen (1) (2)
  Meizi Zeng (1)
  Yan Shu (3)
  Dong Guo (1) (2)
  Yi Sun (4)
  Zhen Guo (1)
  Youhong Wang (1)
  Zhaoqian Liu (1) (2)
  Honghao Zhou (1) (2)
  Wei Zhang (1) (2)
  
  1. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
  2. Hunan Key Laboratory of Pharmacogenetics, Changsha, China
  3. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA
  4. Department of Pathology, The Second Xiangya Hospital of Central South University, Changsha, China
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Life Sciences
  Cell Biology
  Geriatrics and Gerontology
  Molecular Medicine
  
• 出版者：Springer Netherlands
• ISSN：1574-4647

文摘

Cisplatin (CDDP) nephrotoxicity is one of the most common side effects in cancer treatment, causing the disruption of chemotherapy. In this study, we analyzed the influence of nongenetic factors on CDDP-induced nephrotoxiciy using the data from 182 CDDP-treated and 52 carboplatin (CBP)-treated patients. The mean change of eGFR (100 % to baseline) in CDDP-treated patients was ?.2 %, which was significantly lower than that in the population with CBP therapy. By using the chi-squared test and multivariate logistic regression analysis, age (?0 years) is found associated with CDDP-induced nephrotoxicity, with odds ratio (OR) of 9.167 and 11.771, respectively. Three- and 18-month-old mice were employed to study the age-dependent susceptibility of CDDP-induced nephrotoxicity. Biochemical parameters, histopathogical examination, and mRNA biomarkers indicated that old mice were subjected to more severe kidney injury. In addition, old mice accumulated more CDDP in kidney than young mice, and the protein level of CDDP efflux transporter, MATE1, in aged mice kidney was 35 % of that in young mice. Moreover, inflammatory receptor TLR4 was higher in the kidney of old mice, indicating the alteration of inflammatory signaling in old mice. After CDDP administration, the induced alterations of TNF-α, ICAM-1, and TLR4 were more extensive in old mice. To summarize, aging increased the susceptibility of CDDP-induced renal function decline or nephrotoxicity. Keywords Cisplatin eGFR Inflammatory response Nephrotoxicity Nrf2 Transporters