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 transferasemediated 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.Cisplatin [cis-diamminedichloroplatinum(II)] is an effective antineoplastic agent that was widely applied in the treatment of various types of solid tumors in the past several decades 1-3 . However, due to poor selectivity, cisplatin could cause neurotoxicity, nephrotoxicity, nausea and vomiting, and ototoxicity et al. in clinical [4][5][6][7][8][9][10] . As the principal excretory organ for cisplatin, kidney accumulates and retains platinum to a greater degree than other organs 11,12 . Therefore, nephrotoxicity has long been the most severe and life-threatening toxicity among these side-effects 13,14 . Statistics showed there were about 25-35% patients experienced a significant decline in renal function after receiving a single dose of cisplatin 13,15 . The declines manifested clinically as lower glomerular filtration rate, reduced serum magnesium and potassium levels et al. 13,16 . Research over the past few years has gained significant insights into the mechanisms regarding cisplatin nephrotoxicity, which mainly involved apoptosis, inflammation and oxidative stress et al. [17][18][19][20][21][22] . However, how the toxicity occurs and develops, and how various types of mechanisms are integrated to induce distinct kidney pathology, remain largely unknown.Metabolomics is an emerging -omics approach that could provide information of holistic and time-dependent metabolic variation in response to xenobiotic interventions 23,24 . At present, metabolomics analysis encompasses different strategies depending on the objective of study, namely target analysis of a group of c...

Proximal tubule ATR regulates DNA repair to prevent maladaptive renal injury responses

“…KIM-1 expression was higher in the outer medulla than in the cortex in both ATR Ctrl and ATR RPTC-/mice; however, ATR RPTC-/mice had higher expression of KIM-1 in both regions than did ATR Ctrl mice ( Figure 2, I and J). This observation is consistent with previous reports that the S3 segment of the PT is most sensitive to cisplatin injury (43). Thus, RPTEC Atr gene depletion results in enhanced cisplatin-induced RPTEC injury 96 hours after treatment.…”

Chemotherapy‐induced cachexia dysregulates hypothalamic and systemic lipoamines and is attenuated by cannabigerol

“…The canonical endocannabinoids, N ‐arachidonoyl ethanolamine (AEA / anandamide) and 2‐arachidonoyl glycerol (2‐AG), and an increasing number of the structurally analogous lipoamine and 2‐acyl‐ sn ‐glycerol signalling lipids, have established modulatory roles in many metabolic processes dysregulated in cachectic pathophysiology . Furthermore, recent metabonomic studies of cisplatin toxicity have reported alterations to pathways involved in amino acid and lipid metabolism, involving the substrates for endocannabinoid and lipoamine synthesis . We thus conducted targeted HPLC–MS/MS lipidomic analyses of hypothalamus and plasma samples from animals administered cisplatin and CBG, to test the hypotheses that cisplatin‐induced cachexia is associated with alterations to signalling lipids and that the anti‐cachectic effects of CBG involve normalization of such signalling.…”

“…HPLC and 1 H-NMR spectroscopy-based metabonomic approaches have recently been used to investigate markers of metabolic abnormalities in urine and kidney associated with cisplatin-induced nephrotoxicity. 45,46 Here, we report the use of untargeted 1 H-NMR spectroscopy-based metabonomics to characterize the systemic metabolic disruptions induced by a cachectic dose of cisplatin and to identify metabolic processes involved in the anti-cachectic effects of Chemotherapy-induced cachexia isattenuated by cannabigerol CBG. Biochemical profiles were acquired from the postmortem plasma samples of animals in CON, CIS, and CIS + CBG120 groups.…”

“…49,50 Furthermore, recent metabonomic studies of cisplatin toxicity have reported alterations to pathways involved in amino acid and lipid metabolism, involving the substrates for endocannabinoid and lipoamine synthesis. 46 We thus conducted targeted HPLC-MS/MS lipidomic analyses of hypothalamus and plasma samples from animals administered cisplatin and CBG, to test the hypotheses that cisplatin-induced cachexia is associated with alterations to signalling lipids and that the anti-cachectic effects of CBG involve normalization of such signalling.…”

Toxicology of paraquat and pharmacology of the protective effect of 5-hydroxy-1-methylhydantoin on lung injury caused by paraquat based on metabolomics

“…The potential constituents were screened by PLS-DA as shown in Fig. 3, which revealed the differences in lung tissue in the two groups 16,17 . The PLS-DA scores plot showed very good discrimination between the PQ poisoning group and the control group.…”