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.
Highlights
Metabolomics is an emerging -omics approach that could provide information of holistic and time-dependent metabolic variation in response to xenobiotic interventions[23,24]
Cisplatin is taken into the cells primarily by organic cation transporter 2 (OCT2) of the proximal tubules and transported to the apical site where it is bio-activated into a more potent metabolite by gamma-glutamyl transpeptidases that are present in the proximal tubules
Previous mechanism studies of cisplatin nephrotoxicity showed that the most damaged region is renal proximal tubule[12,43], which is generally thought to be located in cortex
Summary
Metabolomics is an emerging -omics approach that could provide information of holistic and time-dependent metabolic variation in response to xenobiotic interventions[23,24]. We have investigated the time- and dose-dependent effect of cisplatin nephrotoxicity using untargeted metabolomics approach, and biomarkers with characteristic of time- and dose-dependence were screened out[38]. In these metabolomic studies related to cisplatin nephrotoxicity, serum, plasma and urine were most frequently studied biological matrixes[33,34,35,37,38]. When kidney was targeted to conduct metabolomics study of cisplatin nephrotoxicity, the spatial difference was always neglected. In order to depict the underlying metabolic mechanism of spatial difference of kidney in response to cisplatin, mass spectrometry-based untargeted metabolomics approach was performed in the present study. Medulla showed higher sensitivity to cisplatin than cortex as its metabolic profiling was affected more dose-dependently. Together our study provides novel insights into the mechanism underlying cisplatin nephrotoxicity from the perspective of metabolomics
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