Identification of key metabolites during cisplatin-induced acute kidney injury using an HPLC-TOF/MS-based non-targeted urine and kidney metabolomics approach in rats. (15th February 2020)

• Record Type: Journal Article
• Authors: Qu, Xiaoyu; Gao, Huan; Sun, Jingmeng; Tao, Lina; Zhang, Yueming; Zhai, Jinghui; Song, Yanqing; Hu, Tingting; Li, Zhiyuan
• Is Part Of: Toxicology. Volume 431(2020)
• Publication Date: 2020-02-15
• Subjects: Cisplatin -- Acute kidney injury -- Metabolomics -- Biomarkers -- HPLC-TOF/MS; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2020.152366
• Languages: English
• ISSNs: 0300-483X

Abstract

Highlights: 37 and 35 metabolite levels changed in rat urine and kidneys by CDDP-induced AKI. 7 key metabolic pathways were significantly disrupted by CDDP-induced AKI. 11 sensitive metabolites in urine were screened as potential biomarkers of AKI. 4 off these biomarkers were quantified and confirmed as sensitive biomarkers. Abstract: Kidney injury is a major adverse effect of cisplatin use. Metabolomics has been used to characterize physiological or pathological conditions through identification of metabolites and characterization of the metabolic pathway. Metabolomics profiling could allow for identification of nephrotoxic mechanisms of cisplatin and identification of biomarkers of cisplatin-induced injury. In this study, we performed metabolomics analysis to characterize key changes in metabolite levels during cisplatin-induced acute kidney injury (AKI) in rats, and screened for sensitive biomarkers for early diagnosis using HPLC-TOF/MS. Rats were intraperitoneally injected with 7.5 mg/kg or 15 mg/kg of cisplatin, or normal saline, and 12 h urine and kidney samples were collected after 72 h. Serum biochemical parameters and kidney histological evaluations showed dose-dependent AKI in response to cisplatin. Metabolomics analysis showed that 37 and 35 endogenous metabolite levels changed in rat urine and kidneys, respectively. Seven key metabolic pathways were disrupted, including the tricarboxylic acid cycle (TCA cycle), phenylalanine, tyrosine, and tryptophan biosynthesis, phenylalanine metabolism, glycerophospholipid metabolism, taurine and hypotaurine metabolism, d -glutamine and d -glutamate metabolism, and nicotinate and nicotinamide metabolism. These pathways are involved in energy generation, and amino acid and lipid metabolism, and disruption of these pathways could contribute to oxidative stress injury, inflammation, and cell membrane damage. Furthermore, 11 sensitive metabolites in urine were screened as potential biomarkers of AKI. To validate these biomarkers, we quantified 4 off these biomarkers, and confirmed that levels of these metabolites were altered in urine of rats treated with CDDP.