Altered metabolic profiles and biomarkers associated with astragaloside IV-mediated protection against cisplatin-induced acute kidney injury in rats: An HPLC-TOF/MS-based untargeted metabolomics study.

Cisplatin (CDDP)-induced acute kidney injury (AKI) limits the therapeutic use of CDDP, which urgently needs to be addressed. Our previous study demonstrated that astragaloside IV (AS IV), an active compound of the traditional Chinese herb Astragalus membranaceus, alleviated CDDP-induced AKI. To explore the mechanism, we performed a metabolomics study to explore the altered metabolic pathways and screen for sensitive biomarkers. Twenty-four rats were randomly divided into three groups, which were treated with vehicle solutions (Control), intraperitoneally injected CDDP, and intraperitoneally injected CDDP plus oral AS IV, respectively. Metabolic profiles of serum, urine, and kidney samples were analyzed by high-performance liquid chromatography-time of flight mass spectrometry. There were 38 key metabolites in the urine samples, 20 in the serum samples, and 16 in the kidney samples that were significantly altered due to AS IV-mediated protection against CDDP-induced AKI relative to CDDP-only treatment. CDDP + AS IV co-treatment significantly altered two pathways in the blood (biosynthesis of unsaturated fatty acids and alanine, aspartate, and glutamate metabolism), five pathways in the urine (phenylalanine metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis; arginine biosynthesis; arginine and proline metabolism; and histidine metabolism), and five pathways in the kidneys (glutathione metabolism; alanine, aspartate, and glutamate metabolism; glyoxylate and dicarboxylate metabolism; arginine and proline metabolism; and D-glutamine and D-glutamate metabolism). The metabolic pathways were mainly associated with improvements in inflammatory responses, oxidative stress, and energy metabolism. Adrenic acid in serum and L-histidine and L-methionine in urine were identified as sensitive biomarkers. This study provides new insights to understand the mechanism of AS IV-mediated protection against CDDP-induced AKI and has identified three candidate biomarkers to evaluate preventative treatment and assess therapeutic effectiveness.