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冬凌草甲素调控LXRα信号通路改善肥胖相关性肾病的作用及机制研究
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| 篇名： | 冬凌草甲素调控LXRα信号通路改善肥胖相关性肾病的作用及机制研究 |
| TITLE： | Study on the effect and mechanism of oridonin improving obesity-related glomerulopathy via regulating the LXRα signaling pathway |
| 摘要： | 目的 基于肝X受体α（LXRα）信号通路，探讨冬凌草甲素（ORI）对肥胖相关性肾病（ORG）小鼠的改善作用及机制。方法通过对LXRα野生型纯合子（LXRα+/+）小鼠和LXRα纯合敲除（LXRα－/－）小鼠进行肾脏转录组高通量测序以及京都基因与基因组百科全书通路富集分析，预测LXRα调控的关键通路和作用靶点，并通过Westernblot实验进行验证。采用高脂饮食诱导构建ORG小鼠模型。以LXRα激动剂GW3965（30mg/kg）为阳性对照，检测或观察连续灌胃50、100mg/kgORI4周（每天1次）后小鼠体重、肾脏质量、肾组织病理形态学变化以及血清中肾功能指标、血脂指标水平和肾组织中炎症因子水平，评价ORI改善ORG的药效；同时，检测小鼠肾组织中LXRα及其调控靶点的mRNA和蛋白表达，验证ORI改善ORG的机制。结果与LXRα+/+小鼠相比，LXRα－/－小鼠肾组织中上调差异基因显著富集于花生四烯酸（AA）代谢通路，其中Cyp4a12的表达显著上调（校正P值＜0.05）；Westernblot实验证实，LXRα－/－小鼠肾组织中细胞色素P450家族4亚家族A成员12（CYP4A12）蛋白表达显著上调（P＜0.05）。药效实验结果显示，50、100mg/kgORI均可显著改善ORG小鼠肾组织病理形态学变化，降低体重、肾脏质量以及血清肌酐、尿素氮、血脂水平和肾组织中白细胞介素6（IL-6）、IL-1β水平（P＜0.05）；同时，其可显著上调肾组织中LXRα核蛋白、ABCA1蛋白及其mRNA表达（P＜0.05），下调CYP4A12蛋白及其mRNA表达（P＜0.05）。结论ORI可能通过激活LXRα信号通路，下调CYP4A12表达，抑制AA致炎性代谢，从而发挥对ORG的改善作用。 |
| ABSTRACT： | Abstract OBJECTIVE To explore the therapeutic efficacy and mechanism of oridonin （ORI） against obesity-related glomerulopathy （ORG） based on the liver X receptor α （LXRα） signaling pathway. METHODS Kidney tissues of LXRα wild-type homozygous （LXRα+/+） mice and LXRα homozygous knockout （LXRα－/－） mice were subjected to high-throughput renal transcriptome sequencing and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis to predict key pathways and targets regulated by LXRα， followed by verification via Western blot assay. An ORG mouse model was established by feeding a high-fat diet. The LXRα agonist GW3965 （30 mg/kg） was set as the positive control. After intragastric administration of 50 mg/kg and 100 mg/kg ORI once daily for 4 consecutive weeks， the body weight， renal weight， renal histopathological alterations， serum renal function indicators， blood lipid levels and inflammatory factor levels in renal tissue of mice were detected and observed to evaluate the efficacy of ORI in alleviating ORG. Meanwhile， the mRNA and protein expression levels of LXRα and its downstream targets in mouse renal tissues were detected to validate the mechanism by which ORI relieves ORG. RESULTS Compared with LXRα+/+ mice， the upregulated differentially expressed genes in renal tissues of LXRα－/－ mice were significantly enriched in the arachidonic acid（AA） metabolic pathway， and the expression level of Cyp4a12 was markedly elevated （adjusted P＜0.05）. Western blot results verified that cytochrome P450 family 4 subfamily A member 12（CYP4A12）protein expression was significantly increased in the kidneys of LXRα－/－ mice （P＜0.05）. Pharmacodynamic results showed that both 50 mg/kg and 100 mg/kg ORI notably improved renal pathological lesions in ORG mice； these two doses reduced body weight， renal weight， serum creatinine， blood urea nitrogen， blood lipid levels as well as renal interleukin-6 （IL-6） and IL-1β levels （P＜0.05）. In addition， ORI significantly upregulated the mRNA and protein expression of renal nuclear LXRα and ABCA1， and downregulated the mRNA and protein expression of CYP4A12（P＜0.05）. CONCLUSIONS ORI may exert an ameliorative effect on ORG by activating the LXRα signaling pathway， downregulating CYP4A12 expression， and inhibiting AA-induced inflammatory metabolism. |
| 期刊： | 2026年第37卷第15期 |
| 作者： | 赵墨苑；王炎玉；周本杰；乡世健；陈宇莲 |
| AUTHORS： | ZHAO Moyuan，WANG Yanyu，ZHOU Benjie，XIANG Shijian，CHEN Yulian |
| 关键字： | 冬凌草甲素；肥胖相关性肾病；肝X受体α；CYP4A12；脂毒性 |
| KEYWORDS： | oridonin； obesity-related glomerulopathy； liver X receptor α； CYP4A12； lipotoxicity |
| 阅读数： | 1 次 |
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