摘要
The tight junction disorder plays an important role in the pathological process of many chronic diseases, and is becoming a major concern for the clinical application of metal drugs, i.e. anti-diabetic vanadium compounds. The development of novel tight junction protecting agents has thus been a major research focus. Since oxidative stress is the primary cause for vanadium toxicity, the present work tested the protective effects of zinc gluconate （Zn2＋） alone and when combined with vitamin C （VC） on the vanadium compound （VO（acac）z.）-mediated paracellular leakage of MDCK cells. The experimental results showed that VO（acac）2_ treatment significantly increased the paracellular permeability of MDCK monolayer. Zn2＋ alone showed no protective effects and VC ameliorated tight junction leakage of MDCK cells when given in the basal chamber. Interestingly, unilateral treatment with the combination of Zn2＋ and VC effectively prevented the increase of paracellular permeability. In addition, the combination of zinc and VC down-regulated the levels of reactive oxygen species in both the control and VO（acac）2-treated MDCK cells and caused the elevation of intracellular Ca2＋; both effects were beneficial for the maintenance of integrity of intercellular tight junction. Our results provided a simple but very effective method of preventing the metal toxicity for clinical aoNication of anti-diabetic vanadium compounds.
紧密连接紊乱在多种慢性病病理过程中发挥重要作用,也是金属药物(如抗糖尿病钒化合物)临床应用的一个主要问题。寻找紧密连接保护性药物是目前一个努力的工作方向。因钒化合物主要通过氧化应激损伤而产生肾毒性,我们在MDCK细胞单层模型上研究了葡萄糖酸锌,维生素C以及两者联合用药对钒化合物引起的细胞旁通路通透性增加的作用。结果表明,VO(acac)2导致细胞旁通路通透性明显增加。单独使用葡萄糖酸锌没有保护作用;当在底侧给予维生素C时,能够抑制MDCK细胞紧密连接的打开。而在任意单侧同时加入锌和维生素C则能够有效阻止紧密连接通透性的增加。研究发现,维生素C与锌联用在对照组与VO(acac)2作用组中,都能够下调细胞氧化应激水平,并引起细胞内钙的升高。这两种效果都有利于细胞单层紧密连接的完整性维持。实验结果为预防抗糖尿病钒化合物的金属毒性提供了一种简单而且有效的方法。
基金
National Natural Science Foundation of China(Grant No.21271012)
Research Fund for the Doctoral Program of Higher Education of China(Grant No.20090001110068)
