Liver Fibrosis Can Be Induced by High Salt Intake through Excess Reactive Oxygen Species (ROS) Production
Liver Fibrosis Can Be Induced by High Salt Intake through Excess Reactive Oxygen Species (ROS) Production
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DOI：
10.1021/acs.jafc.5b05897
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发表时间：
2016-02-24
影响因子：
6.1
通讯作者：
Yang, Xuesong
中科院分区：
文献类型：
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作者：
Wang, Guang;Yeung, Cheung-kwan;Yang, Xuesong
众所周知，高盐摄入会导致高血压和其他副作用。然而，目前尚不清楚它是否也会影响成熟或发育中肝脏的纤维化。这项研究通过 H&E、PAS、Masson 和 Sirius 红染色证明，小鼠（饮用水中 4% NaCl）和鸡胚（计算出的鸡蛋最终渗透压为 300 mosm/L）的高盐暴露可能导致肝索紊乱和肝纤维化。同时，小鼠和鸡胚肝脏的结蛋白免疫荧光染色表明，高盐暴露后肝星状细胞被激活。小鼠和鸡胚肝脏的pHIS3和BrdU免疫组织学染色表明细胞增殖减少；此外，TUNEL 分析表明，在高盐暴露下细胞凋亡增加。接下来，培养的鸡肝细胞上的二氢乙锭染色表明，高盐暴露后产生了过量的 ROS。此外，AAPH（一种已知的 ROS 产生诱导剂）处理也诱导鸡胚肝纤维化。小鼠肝脏的 Nrf2 和 Keapl 免疫组织学染色呈阳性表明 Nrf2/Keap1 信号传导参与高盐诱导的 ROS 产生。最后采用CCK8法测定抗氧化剂维生素C是否可以挽救高盐诱导的生长抑制作用。同时RT-PCR结果表明Nrf2/Keapl下游基因HO-1、NQO-1和SOD2参与了这一过程。总之，这些实验表明，高盐摄入量会导致成人和发育中的胚胎出现肝损伤和纤维化的高风险。其病理机制可能是氧化应激与抗氧化系统失衡所致。
High salt intake has been known to cause hypertension and other side effects. However, it is still unclear whether it also affects fibrosis in the mature or developing liver. This study demonstrates that high salt exposure in mice (4% NaCl in drinking water) and chick embryo (calculated final osmolality of the egg was 300 mosm/L) could lead to derangement of the hepatic cords and liver fibrosis using H&E, PAS, Masson, and Sirius red staining. Meanwhile, Desmin immunofluorescent staining of mouse and chick embryo livers indicated that hepatic stellate cells were activated after the high salt exposure. pHIS3 and BrdU immunohistological staining of mouse and chick embryo livers indicated that cell proliferation decreased; as well, TUNEL analyses indicated that cell apoptosis increased in the presence of high salt exposure. Next, dihydroethidium staining on the cultured chick hepatocytes indicated the excess ROS was generated following high salt exposure. Furthermore, AAPH (a known inducer of ROS production) treatment also induced the liver fibrosis in chick embryo. Positive Nrf2 and Keapl immunohistological staining on mouse liver suggested that Nrf2/Keap1 signaling was involved in high salt induced ROS production. Finally, the CCK8 assay was used to determine whether or not the growth inhibitory effect induced by high salt exposure can be rescued by antioxidant-vitamin C. Meanwhile, the RT-PCR result indicated that the Nrf2/Keapl downsteam genes including HO-1, NQO-1, and SOD2 were involved in this process. In sum, these experiments suggest that high salt intake would lead to high risk of liver damage and fibrosis in both adults and developing embryos. The pathological mechanism may be the result from an imbalance between oxidative stress and the antioxidant system.