Abstract
Fasudil is a derivative of 5-isoquinoline sulfonamide, which is a Rho kinase inhibitor, a wide range of pharmacological effects. Fasudil has been shown to attenuate kidney injury caused by certain substances. In the present study, metabolomic analysis of mouse kidney tissues ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry was used to determine the metabolomic changes in cisplatin-induced kidney injury and the fasudil-induced attenuation of cisplatin-induced kidney injury. Metabolomic profiling of kidney tissues revealed significant differences in metabolites between the control group and the cisplatin group and between the cisplatin group and the fasudil-intervention group. With metabolomic approach, 68 endogenous differential metabolites were found, and multivariate statistical analysis, accurate molecular weights, isotope tracers, mass-spectrometry secondary-fragment information, and standard-reference comparisons were used to identify these substances. Based on these differential metabolites, a metabolic-pathway network was constructed and revealed that fasudil primarily attenuated cisplatin-induced renal injury by modulating lipid and amino-acid metabolism. These results further demonstrate that kidney injury can be induced by cisplatin and, moreover, suggest that fasudil can be used to reduce kidney injury at early stages in patients treated with cisplatin.
Highlights
Cisplatin (CDDP) is a platinum-based chemotherapy drug that inhibits cellular division and exhibits broad-spectrum anti-tumor activity
Fas was purchased from Chase Sun Co., Ltd. (Tianjin, China), high-performance liquid chromatography (HPLC) grade methanol and acetonitrile were purchased from Merck & Co. (Darmstadt, Germany), formic acid was purchased from Fluka Chemicals Ltd. (Buchs, Switzerland), ultrapure water was prepared from the Milli-Q ultrapure water system (Millipore, Bedford, MA, U.S.A.) in our lab, and other reagents were of analytical grade
We detected the two indicators commonly used in renal function: creatinine and urea nitrogen (BUN), and the level of acute kidney injury (AKI) markers: the serum kidney injury molecule 1 (KIM-1)
Summary
Cisplatin (CDDP) is a platinum-based chemotherapy drug that inhibits cellular division and exhibits broad-spectrum anti-tumor activity. CDDP can be used to treat solid tumors, such as those caused by head and neck cancer, testicular cancer, ovarian cancer, and lung cancer [1]. Its side effects—which include severe ototoxicity, nephrotoxicity, and myelosuppression [3]—limit the use of CDDP [4]. Nephrotoxicity is the primary adverse reaction of CDDP. The increase in risk factors for nephrotoxicity can be related to the dose and frequency of CDDP use, as well as factors such as female sex, old age, and smoking. CDDP-induced kidney injury is a complex process involving multiple pathways that can cause changes at the molecular level [6,7]
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