Renal Medulla is More Sensitive to Cisplatin than Cortex Revealed by Untargeted Mass Spectrometry-Based Metabolomics in Rats
Renal Medulla is More Sensitive to Cisplatin than Cortex Revealed by Untargeted Mass Spectrometry-Based Metabolomics in Rats
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基于非靶向质谱的大鼠代谢组学显示，肾髓质对顺铂比皮质更敏感
DOI：
10.1038/srep44804
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发表时间：
2017-03
影响因子：
4.6
通讯作者：
Xu Feng Guo
中科院分区：
文献类型：
--
作者：
Zhang Pei;Chen Jia Qing;Huang Wan Qiu;Li Wei;Huang Yin;Zhang Zun Jian;Xu Feng Guo
长期以来，肾毒性一直是顺铂最严重和危及生命的副作用，因此其抗癌作用受到限制。以往的病理学研究表明，顺铂可以损伤肾皮质和肾髓质。我们的TUNEL（末端脱氧核苷酸转移酶介导的dUTP缺口末端标记）检测结果进一步揭示了髓质比皮质受到更严重的损伤。为了揭示顺铂作用空间差异的潜在代谢机制，本研究采用基于质谱的非靶向代谢组学方法，对单剂量顺铂（2.5，5和10 mg/kg）给药后大鼠肾皮质和髓质代谢产物进行了分析。最终筛选出皮质和髓质中的差异代谢产物分别为53和55个。随机森林、正交偏最小二乘判别分析和代谢累积倍数变化分析显示，髓质的代谢变化比皮质的代谢变化具有更明显的剂量依赖性，证实了髓质对顺铂暴露更敏感的结论。此外，29种中间体被认为是灵敏度差异的最主要代谢产物。顺铂阻断的代谢途径主要包括氨基酸、能量、脂质、嘧啶、嘌呤和肌酸代谢。本研究为顺铂肾毒性机制的研究提供了新的思路。
Nephrotoxicity has long been the most severe and life-threatening side-effect of cisplatin, whose anticancer effect is therefore restricted. Previous pathological studies have shown that both renal cortex and medulla could be injured by cisplatin. Our TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling) assay results further uncovered that medulla subjected more severe injury than cortex. In order to depict the underlying metabolic mechanism of spatial difference in response to cisplatin, in the present study, mass spectrometry-based untargeted metabolomics approach was applied to profile renal cortex and medulla metabolites of rat after receiving a single dose of cisplatin (2.5, 5 or 10 mg/kg). Eventually, 53 and 55 differential metabolites in cortex and medulla were screened out, respectively. Random forest, orthogonal partial least squares-discriminant analysis and metabolic cumulative fold change analysis revealed that metabolic changes in medulla were more obviously dose-dependent than those in cortex, which confirmed the conclusion that medulla was more sensitive to cisplatin exposure. Furthermore, 29 intermediates were recognized as the most contributive metabolites for the sensitivity difference. Metabolic pathways interrupted by cisplatin mainly included amino acid, energy, lipid, pyrimidine, purine, and creatine metabolism. Our findings provide new insight into the mechanism study of cisplatin-induced nephrotoxicity.
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DOI：
10.1097/00000441-196107000-00060
发表时间：
1961-07
期刊：
--
影响因子：
--
作者：
A. C. Guyton;J. Hall
通讯作者：
A. C. Guyton;J. Hall
影响因子：
4.3
作者：
Huang, Yin;Tian, Yuan;Zhang, Zunjian
通讯作者：
Zhang, Zunjian
影响因子：
19.6
作者：
Tsuruya, K;Ninomiya, T;Iida, M
通讯作者：
Iida, M
DOI：
10.1097/00000421-199004000-00009
发表时间：
1990-04
期刊：
American Journal of Clinical Oncology
影响因子：
--
作者：
Milton Rabinowits;L. Souhami;R. Gil;C. Andrade;H. Paiva
通讯作者：
Milton Rabinowits;L. Souhami;R. Gil;C. Andrade;H. Paiva
DOI：
--
发表时间：
1980-06
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
D. Dobyan;J. Levi;C. Jacobs;J. Kosek;M. Weiner
通讯作者：
D. Dobyan;J. Levi;C. Jacobs;J. Kosek;M. Weiner