Liu Xin, Zhang Linghan, Tang Wenchao, Zhang Tingting, Xiang Ping, Shen Qin, Ye Taotao, Xiao Yuanyuan
Guizhou University of Traditional Chinese Medicine, Guiyang, China.
Guizhou University of Traditional Chinese Medicine, Guiyang, China; Key Laboratory of Forensic Toxicology of Herbal Medicines, Guizhou Education Department, Guiyang, China.
Toxicol Appl Pharmacol. 2023 Apr 15;465:116450. doi: 10.1016/j.taap.2023.116450. Epub 2023 Mar 11.
Cantharidin (CTD), extracted from the traditional Chinese medicine mylabris, has shown significant curative effects against a variety of tumors, but its clinical application is limited by its high toxicity. Studies have revealed that CTD can cause toxicity in the kidneys; however, the underlying molecular mechanisms remain unclear. In this study, we investigated the toxic effects in mouse kidneys following CTD treatment by pathological and ultrastructure observations, biochemical index detection, and transcriptomics, and explored the underlying molecular mechanisms by RNA sequencing (RNA-seq). The results showed that after CTD exposure, the kidneys had different degrees of pathological damage, altered uric acid and creatinine levels in serum, and the antioxidant indexes in tissues were significantly increased. These changes were more pronounced at medium and high doses of CTD. RNA-seq analysis revealed 674 differentially expressed genes compared with the control group, of which 131 were upregulated and 543 were downregulated. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that many differentially expressed genes were closely related to the stress response, the CIDE protein family, and the transporter superfamily, as well as the MAPK, AMPK, and HIF-1 pathways. The reliability of the RNA-seq results was verified by qRT-PCR of the six target genes. These findings offer insight into the molecular mechanisms of renal toxicity caused by CTD and provide an important theoretical basis for the clinical treatment of CTD-induced nephrotoxicity.
斑蝥素（CTD）是从中药斑蝥中提取的，已显示出对多种肿瘤有显著疗效，但其临床应用因高毒性而受到限制。研究表明，CTD可导致肾脏毒性；然而，其潜在的分子机制仍不清楚。在本研究中，我们通过病理和超微结构观察、生化指标检测以及转录组学研究了CTD处理后对小鼠肾脏的毒性作用，并通过RNA测序（RNA-seq）探索了潜在的分子机制。结果表明，CTD暴露后，肾脏出现不同程度的病理损伤，血清尿酸和肌酐水平改变，组织中的抗氧化指标显著升高。这些变化在中高剂量CTD时更为明显。RNA-seq分析显示，与对照组相比有674个差异表达基因，其中131个上调，543个下调。基因本体（GO）和京都基因与基因组百科全书（KEGG）通路富集分析表明，许多差异表达基因与应激反应、CIDE蛋白家族、转运蛋白超家族以及MAPK、AMPK和HIF-1通路密切相关。通过对六个靶基因的qRT-PCR验证了RNA-seq结果的可靠性。这些发现为CTD所致肾毒性的分子机制提供了见解，并为CTD诱导的肾毒性的临床治疗提供了重要的理论依据。
