Nrf2 deficiency impairs the barrier function of mouse oesophageal epithelium.
Nrf2 deficiency impairs the barrier function of mouse oesophageal epithelium.
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DOI：
10.1136/gutjnl-2012-303731
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发表时间：
2014-05
期刊：
影响因子：
24.5
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Chen H;Hu Y;Fang Y;Djukic Z;Yamamoto M;Shaheen NJ;Orlando RC;Chen X
作为一种主要的细胞防御机制，Nrf 2/Keap 1途径调节参与解毒和应激反应的基因的表达。我们先前的研究揭示了Nrf 2/Keap 1通路在小鼠食管发育成熟阶段的激活，表明在上皮防御中具有潜在的功能。在此，我们假设Nrf 2参与食管上皮的屏障功能，并对胃食管反流病（GERD）起保护作用。使用人食管活检样品、小鼠手术模型和Nrf 2-/-小鼠来评估Nrf 2/Keap 1通路在食管粘膜屏障功能中的作用。跨上皮电阻（TEER）测量与微型Ussing室。HE染色和透射电镜观察细胞形态，基因芯片、免疫组化、Western blotting和ChIP分析检测信号通路基因的表达。Nrf 2在正常食管上皮中表达，并在人和小鼠的GERD中被激活。Nrf 2缺乏和胃食管反流在小鼠中，无论是单独或组合，减少TEER和增加食管上皮细胞间隙直径。Nrf 2靶基因和与氧化还原酶活性、线粒体生物合成和能量产生相关的基因组在Nrf 2-/-小鼠的食管上皮中下调。与Nrf 2的抗氧化功能一致，与野生型小鼠相比，Nrf 2-/-小鼠食管上皮细胞中的DNA氧化损伤标志物（8 OHdG）显著增加。有趣的是，ATP生物合成，考克斯IV（线粒体蛋白）和Claudin-4（Cldn 4）的表达下调Nrf 2-/-小鼠的食管上皮，表明能量依赖性紧密连接的完整性受到Nrf 2的调节。ChIP分析证实了Nrf 2与Cldn 4启动子的结合。nrf 2缺陷通过破坏能量依赖性紧密连接损害食管屏障功能。阐明该通路在GERD中的作用对疾病的发病机制和治疗具有潜在的意义。
As a major cellular defense mechanism, the Nrf2/Keap1 pathway regulates expression of genes involved in detoxification and stress response. Our previous study revealed activation of the Nrf2/Keap1 pathway at the maturation phase during mouse esophageal development, suggesting a potential function in epithelial defense. Here we hypothesize that Nrf2 is involved in the barrier function of esophageal epithelium, and plays a protective role against gastroesophageal reflux disease (GERD). Human esophageal biopsy samples, mouse surgical models and Nrf2-/- mice were used to assess the role of the Nrf2/Keap1 pathway in esophageal mucosal barrier function. Trans-epithelial electrical resistance (TEER) was measured with mini-Ussing chambers. Hematoxylin and eosin (HE) staining and transmission electron microscopy were used to examine cell morphology, while gene microarray, immunohistochemistry, Western blotting and ChIP analysis were used to assess the expression of pathway genes. Nrf2 was expressed in normal esophageal epithelium and activated in GERD of both humans and mice. Nrf2 deficiency and gastroesophageal reflux in mice, either alone or in combination, reduced TEER and increased intercellular space diameter in esophageal epithelium. Nrf2 target genes and gene sets associated with oxidoreductase activity, mitochondrial biogenesis and energy production were down-regulated in the esophageal epithelium of Nrf2-/- mice. Consistent with the antioxidative function of Nrf2, a DNA oxidative damage marker (8OHdG) dramatically increased in esophageal epithelial cells of Nrf2-/- mice compared with those of wild-type mice. Interestingly, ATP biogenesis, Cox IV (a mitochondrial protein) and Claudin-4 (Cldn4) expression were down-regulated in the esophageal epithelium of Nrf2-/- mice, suggesting that energy-dependent tight junction integrity was subject to Nrf2 regulation. ChIP analysis confirmed the binding of Nrf2 to Cldn4 promoter. Nrf2 deficiency impairs esophageal barrier function through disrupting energy-dependent tight junction. Elucidating the role of this pathway in GERD has potential implications for the pathogenesis and therapy of the disease.
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影响因子：
14.9
作者：
Malhotra D;Portales-Casamar E;Singh A;Srivastava S;Arenillas D;Happel C;Shyr C;Wakabayashi N;Kensler TW;Wasserman WW;Biswal S
通讯作者：
Biswal S
DOI：
10.1158/1940-6207.capr-10-0296
发表时间：
2011-03
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Egner PA;Chen JG;Wang JB;Wu Y;Sun Y;Lu JH;Zhu J;Zhang YH;Chen YS;Friesen MD;Jacobson LP;Muñoz A;Ng D;Qian GS;Zhu YR;Chen TY;Botting NP;Zhang Q;Fahey JW;Talalay P;Groopman JD;Kensler TW
通讯作者：
Kensler TW
影响因子：
14.9
作者：
Chorley BN;Campbell MR;Wang X;Karaca M;Sambandan D;Bangura F;Xue P;Pi J;Kleeberger SR;Bell DA
通讯作者：
Bell DA
DOI：
10.1152/ajpgi.00158.2007
发表时间：
2007-12-01
影响因子：
4.5
作者：
Jovov, Biljana;Van Itallie, Christina M.;Orlando, Roy C.
通讯作者：
Orlando, Roy C.
影响因子：
4.2
作者：
Amasheh, Maren;Schlichter, Susanne;Schulzke, Joerg D.
通讯作者：
Schulzke, Joerg D.