title: Renal Medulla is More Sensitive to Cisplatin than Cortex Revealed by Untargeted Mass Spectrometry-Based Metabolomics in Rats.
abstract: 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.
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University, Nanjing 210009, P. R. China.|Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, P. R. China.|State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Pei
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University, Nanjing 210009, P. R. China.|Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, P. R. China.|State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Jia-Qing
authors.initials: JQ
authors.lastname: Chen
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University, Nanjing 210009, P. R. China.|Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, P. R. China.|State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Wan-Qiu
authors.initials: WQ
authors.lastname: Huang
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University, Nanjing 210009, P. R. China.|Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, P. R. China.|State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University, Nanjing 210009, P. R. China.|Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, P. R. China.|State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University, Nanjing 210009, P. R. China.|Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, P. R. China.|State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Zun-Jian
authors.initials: ZJ
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University, Nanjing 210009, P. R. China.|Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, P. R. China.|State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors.forename: Feng-Guo
authors.initials: FG
authors.lastname: Xu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D002853:Chromatography, Liquid; D002945:Cisplatin / Q000009:adverse effects / Q000494:pharmacology*; D019295:Computational Biology / Q000379:methods; D008401:Gas Chromatography-Mass Spectrometry; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D007679:Kidney Medulla / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D013058:Mass Spectrometry; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin