姜黄素调控TLR4/NF-κB和NRF2/HO-1信号通路改善草酸钙晶体诱导的小鼠肾损伤  

Curcumin attenuates calcium oxalate crystal-induced renal injury via regulation of TLR4/NF-κB and NRF2/HO-1 pathways in mouse model

作　　者：何彦丰[1,2,3] 赖文斌 陈文炜 刘昌毅 卢凯鑫[1,2,3] 张华 江涛 高锐[1,2,3] HE Yan-feng;LAI Wen-bin;CHEN Wen-wei;LIU Chang-yi;LU Kai-xin;ZHANG Hua;JIANG Tao;GAO Rui(Dept of Urology,the First Affiliated Hospital of Fujian Medical University,Fuzhou 350005,China;Dept of Urology,National Region Medical Center,Binhai Campus of the First Affiliated Hospital,Fujian Medical University,Fuzhou 350212,China;Fujian institute of Urology,the First Affiliated Hospital,Fujian Medical University,Fuzhou 350005,China;The Dept of Urology,The Second Nanping Hospital,Nanping Fujian 354200,China)

机构地区：[1]福建医科大学附属第一医院泌尿外科,福建福州350005 [2]福建医科大学附属第一医院滨海院区国家区域医疗中心泌尿外科,福建福州350212 [3]福建医科大学泌尿外科研究所,福建福州350005 [4]南平市第二医院泌尿外科,福建南平354200

出　　处：《中国药理学通报》2024年第9期1701-1708,共8页Chinese Pharmacological Bulletin

基　　金：福建省教育厅中青年教师教育科研项目(No JAT200127);福建医科大学启航基金项目(No 2020QH1021)。

摘　　要：目的探讨姜黄素(curcumin,CUR)对乙醛酸诱导的小鼠肾结石形成模型中肾损伤的保护作用及其机制。方法通过连续腹腔注射乙醛酸,建立小鼠肾结石形成模型。以一水草酸钙(calcium oxalate monohydrate,COM)诱导HK-2细胞作为体外模型。小鼠模型经CUR作用后,测定肾小管损伤、炎症细胞因子水平,研究CUR对小鼠肾结石的保护作用;CUR对COM诱导HK-2作用后,检测细胞活力及炎症因子;Western blot检测小鼠肾组织和HK-2细胞Toll样受体4(TLR4)/核因子κB(NF-κB)和核因子红血球相关因子2(NRF2)/血红素加氧酶1(HO-1)通路相关蛋白;为进一步探讨CUR对TLR4/NF-κB和NRF2/HO-1通路的调控作用,采用NRF2抑制剂ML385和TLR4激动剂CCL-34分别作用于COM诱导的HK-2细胞,以进行功能增益和功能丧失检测。结果CUR改善小鼠肾结石形成模型损伤,抑制炎症和抗氧化作用;促进COM诱导HK-2细胞的活力,抑制炎症因子的表达。CUR抑制TLR4/NF-κB通路中蛋白的表达,促使NRF2从细胞质转移到细胞核,并促进HO-1的表达。ML385和CCL-34分别抵消CUR对COM诱导HK-2细胞抗炎作用的影响。结论CUR通过调控小鼠肾结石形成模型TLR4/NF-κB和NRF2/HO-1通路改善肾损伤。Aim To investigate the protective effects of curcumin(CUR)on crystal-induced renal injury and its underlying mechanism in the mouse model of nephrolithiasis.Methods The mouse model of stone formation was established via successive intraperitoneal injection of glyoxylate.Proximal tubular epithelial cell line HK-2 treated with calcium oxalate monohydrate(COM)was used as an in vitro model.The protective role of CUR on nephrolithiasis was tested by determination of tubular injury,crystal deposition and adhesion,levels of inflammatory cytokines.In vitro,the effects of CUR on the cell viability and inflammatory factors of HK-2 cells were measured.The proteins in the Toll-like receptor 4(TLR4)/nuclear factorκB(NF-κB)and nuclear factor erythroid 2-related factor 2(NRF2)/hemeoxygenase-1(HO-1)signaling pathways were measured by Western blot for confirming the relationship between CUR and these pathways.Finally,NRF2 inhibitor ML385 and TLR4 activator CCL-34 were respectively used on COM-induced HK-2 cells exposed to CUR for the conduction of gain-of-function and loss-of-function assays.Results CUR improves the damage in the mouse model of kidney stone formation,inhibits inflammation and antioxidative effects;promotes the viability of HK-2 cells induced by COM,and inhibits the expression of inflammatory factors.CUR suppresses the expression of proteins in the TLR4/NF-κB pathway,promotes the transfer of NRF2 from the cytoplasm to the nucleus,and enhances the expression of HO-1.ML385 and CCL-34 respectively counteract the anti-inflammatory effects of CUR on COM-induced HK-2 cells.Conclusions Taken together,our study demonstrates the protective effect of CUR on the deposition of kidney stone and consequent tubular injury.CUR through regulation of the TLR4/NF-kB and NRF2/HO-1 pathways improves renal injury.

关 键 词：姜黄素 肾结石 肾小管上皮细胞 TOLL样受体4 NRF2 炎症 

分 类 号：R-332[医药卫生] R282.71R322.61R364.5R692.4