Department of Pharmacy, The First Hospital of Jilin University, Changchun 130021, China.
Department of Technical Center, Changchun Customs District, Changchun 130062, China.
Biochem Pharmacol. 2021 Jan;183:114299. doi: 10.1016/j.bcp.2020.114299. Epub 2020 Oct 24.
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.
顺铂（CDDP）诱导的急性肾损伤（AKI）限制了 CDDP 的治疗用途，这迫切需要解决。我们之前的研究表明，黄芪甲苷（AS IV），一种中药黄芪的活性化合物，可减轻 CDDP 诱导的 AKI。为了探索其机制，我们进行了代谢组学研究，以探索改变的代谢途径并筛选敏感的生物标志物。24 只大鼠被随机分为三组，分别用载剂溶液（对照）、腹腔注射 CDDP 和腹腔注射 CDDP 加口服 AS IV 处理。通过高效液相色谱-飞行时间质谱分析血清、尿液和肾脏样本的代谢谱。由于 AS IV 介导的对 CDDP 诱导的 AKI 的保护作用，尿液样本中有 38 种关键代谢物、血清样本中有 20 种、肾脏样本中有 16 种发生了明显改变。与仅用 CDDP 处理相比，CDDP+AS IV 联合治疗显著改变了血液中的两条途径（不饱和脂肪酸和丙氨酸、天冬氨酸和谷氨酸代谢的生物合成）、尿液中的五条途径（苯丙氨酸代谢；苯丙氨酸、酪氨酸和色氨酸生物合成；精氨酸生物合成；精氨酸和脯氨酸代谢；组氨酸代谢）和肾脏中的五条途径（谷胱甘肽代谢；丙氨酸、天冬氨酸和谷氨酸代谢；乙醛酸和二羧酸代谢；精氨酸和脯氨酸代谢；D-谷氨酰胺和 D-谷氨酸代谢）。代谢途径主要与炎症反应、氧化应激和能量代谢的改善有关。血清中的花生四烯酸和尿液中的 L-组氨酸和 L-蛋氨酸被鉴定为敏感生物标志物。这项研究为理解 AS IV 介导的对 CDDP 诱导的 AKI 的保护机制提供了新的见解，并确定了三个候选生物标志物，用于评估预防性治疗和评估治疗效果。
