4辛基-衣康酸通过Nrf2/ARE通路抑制氧化应激减轻高脂饮食诱导的早期肾损伤  

Effect of 4-octyl itaconate in attenuating early renal injury induced by high-fat diet through inhibiting oxidative stress via the nuclear factor erythroid 2-related factor 2/antioxidant response element pathway

作　　者：王泸宁 万进东 陈佳瑶 林晓倩 杨剑 Wang Luning;Wan Jindong;Chen Jiayao;Lin Xiaoqian;Yang Jian(Department of Clinical Nutrition,The Third Affiliated Hospital of Chongqing Medical University)

机构地区：[1]重庆医科大学附属第三医院临床营养科,重庆401120

出　　处：《重庆医科大学学报》2025年第2期254-259,共6页Journal of Chongqing Medical University

基　　金：重庆医科大学未来医学青年创新团队资助项目(编号:W0085)。

摘　　要：目的:研究4辛基-衣康酸(4-octyl itaconate,4-OI)通过核因子E2相关因子2(nuclear factor-erythroid 2-related factor2,Nrf2)/抗氧化反应元件(antioxidant response element,ARE)通路减轻高脂饮食(high fat diet,HFD)诱导的早期肾脏损伤的效应及机制。方法:将小鼠随机分为对照组、HFD组、4-OI组3组;HFD组和4-OI组接受HFD喂养12周,4-OI组自HFD喂养第9周起接受4-OI干预。检测糖耐量及尿白蛋白肌酐比值(urinary albumin/creatinine ratio,UACR);苏木精伊红(hematoxylineosin,HE)染色和高碘酸-希夫(periodic acid-Schiff,PAS)染色观察肾皮质病理变化;酶联免疫吸附测定法(enzyme-linked immune sorbent assay,ELISA)检测血脂和肾皮质氧化应激相关指标;检测肾小管损伤标志物及肾皮质Nrf2/ARE通路相关分子的表达水平。结果:4-OI干预可减轻高脂饮食导致的肾近曲小管刷状缘断裂和上皮细胞脱落,降低肾皮质肾小管损伤标志物肾损伤分子1(kidney injury molecule 1,KIM-1)、中性粒细胞明胶酶相关脂质运载蛋白(neutrophil gelatinase-associated lipocalin protein,NGAL)表达和尿液上清液中的UACR含量(P=0.001、P=0.002、P=0.000),减轻肾皮质氧化应激,如还原型谷胱甘肽(glutathione,GSH)、超氧化物歧化酶(superoxide dismutase,SOD)的回升和丙二醛(malondialdehyde,MDA)的回降(P=0.040、P=0.000、P=0.001),增加Nrf2以及Nrf2/ARE通路相关分子血红素加氧酶-1(heme oxygenase 1,HO-1)、NAD(P)H脱氢酶(醌)1(NAD(P)H dehydrogenase[quinone]1,NQO1)、超氧化物歧化酶1(superoxide dismutase 1,SOD1)蛋白表达水平(P=0.003、P=0.000、P=0.001、P=0.000)和mRNA表达水平(P=0.000、P=0.009、P=0.000、P=0.000)。结论:4-OI可能通过激活Nrf2/ARE通路降低肾脏氧化应激水平,从而改善HFD导致的早期肾损伤。Objective:To investigate the effect and mechanism of 4-octyl itaconate(4-OI)in alleviating early renal injury induced by high-fat diet(HFD)via the nuclear factor erythroid 2-related factor 2(Nrf2)/antioxidant response element(ARE)pathway.Methods:Mice were randomly divided into control group,HFD group,and 4-OI group.The mice in the HFD group and the 4-OI group were given HFD feeding for 12 weeks,and those in the 4-OI group were given 4-OI intervention since week 9 of HFD feeding.Glucose tolerance and urinary albumin-to-creatinine ratio(UACR)were measured;HE staining and periodic acid-Schiff staining were used to observe the pathological changes of renal cortex;ELISA was used to measure blood lipids and renal cortical oxidative stress-related indicators;the expression levels of renal tubular injury markers and the molecules involved in the Nrf2/ARE pathway in renal cortex were measured.Results:This study showed that 4-OI intervention significantly alleviated the brush border fracture and epithelial cell shedding of renal proximal convoluted tubules and reduced the expression levels of the renal tubular injury markers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in renal cortex and the content of UACR in urine supernatant(P=0.001,0.002,and 0.000),and it also reduced renal cortical oxidative stress,including the increases in glutathione and superoxide dismutase(SOD)and the reduction in malondialdehyde(P=0.040,0.000,and 0.001).4-OI intervention increased the protein and mRNA expression levels of Nrf2 and the Nrf2/ARE pathway-related molecules heme oxygenase-1,NAD(P)H dehydrogenase[quinone]1,and superoxide dismutase 1(protein expression:P=0.003,0.000,0.001,and 0.000;mRNA expression:P=0.000,0.009,0.000,and 0.000).Conclusion:4-OI may reduce the level of renal oxidative stress by activating the Nrf2/ARE pathway,thereby improving early renal injury caused by HFD.

关 键 词：肾损伤 肾小管 高脂饮食 4辛基-衣康酸 氧化应激 

分 类 号：R151.1[医药卫生—营养与食品卫生学]