基于TLR4-TBK1-IKKε信号通路探讨栀子苷对果糖代谢综合征大鼠肾保护作用机制

Renal Protection Mechanism of Jasminoidin in Metabolic Syndrome Rat Reduced by Fructose Based on the TLR4-TBK1-IKKε Signal Pathway

目的探讨栀子苷对果糖诱导的代谢综合征大鼠肾保护作用及其可能机制。方法 50只雄性SD大鼠随机分为正常组、模型组、栀子苷组(30、60mg/kg)和别嘌呤醇组(10mg/kg),每组10只,采用10%果糖水建立大鼠代谢综合征肾损伤模型,8周后处死动物,测定胰岛素糖耐量,血清尿酸、肌酐、甘油三酯(TG)、总胆固醇(TC)、白介素-1β(IL-1β)、IL-6和肿瘤坏死因子-α(TNF-α)水平,尿液尿酸、肌酐水平以及肾脏TG、TC、IL-1β、IL-6和TNF-α水平,同时测定肾脏组织核转录因子-κB(NF-κB)和Toll样受体4(TLR4)-TANK结合激酶1(TBK1)-κB抑制因子激酶ε(IKKε)信号通路的表达变化。结果栀子苷显著改善胰岛素抵抗,降低血清尿酸、肌酐、TG、TC、IL-1β、IL-6和TNF-α和肾脏TG、TC、IL-1β、IL-6及TNF-α水平,并显著升高尿液尿酸和肌酐水平,且NF-κB和TLR4-TBK1-IKKε信号通路的激活均得到显著抑制,同时在细胞实验中进一步证实了果糖刺激诱导人肾近端小管上皮细胞系HK-2细胞炎症因子的表达和TLR4-TBK1-IKKε信号通路的激活,而栀子苷和TLR4抑制剂TAK-242可以显著改善上述指标的异常表达。结论栀子苷改善果糖喂养大鼠高尿酸血症、脂质堆积和肾脏炎症,并与抑制TLR4-TBK1-IKKε信号通路激活有关。

OBJECTIVE To investigate the renal protective effects of jasminoidin on the rats with metabolic syndrome induced by fructose.METHODS 50 male SD rats were randomly divided into normal group,model group,jasminoidin group(30,60 mg/kg)and allopurinol group(10 mg/kg),each of 10.The renal injury model in rats with metabolic syndrome was built by 10%fructose.After 8 weeks,the animals were killed.Insulin tolerance tests(ITT),serum uric acid,creatinine,triglyceride(TG)and total cholesterol(TC),interleukin 1β(IL 1β),IL 6 and tumor necrosis factorα(TNFα),urine uric acid,creatinine levels,and renal TG,TC,IL 1β,IL 6 and TNFαlevels were measured.In addition,the changes of nuclear transcription factorκB(NFκB)and Toll like receptor 4(TLR4)TANK binding kinase 1(TBK1)IκB kinaseε(IKKε)signaling pathway in the renal tissue were examined.RESULTS Jasminoidin significantly improved insulin resistance,decreased serum uric acid,creatinine,creatinine,TG,TC,IL 1β,IL 6 and TNFαlevels,and significantly increased urine uric acid and creatinine levels,with reduction of TG,TC,IL 1β,IL 6 and TNFαin the kidney.Jasminoidin also significantly inhibited NFκB and TLR4 TBK1 IKKεsignal pathway.At the same time,it was further confirmed that fructose stimulation induced the increased expression of inflammatory factors and the activation of TLR4 TBK1 IKKεsignaling pathway in human renal proximal tubule epithelial cell line HK 2,and jasminoidin and TLR4 inhibitor TAK 242 significantly improved the abnormal expression of the above index.CONCLUSION The renal protective effects of jasminoidin on the rats with hyperuricemia,lipid accumulation and renal inflammation induced by fructose may be related to its inhibition of TLR4 TBK1 IKKεsignal pathway.