1 Department of Biochemistry, University College of Medical Sciences (University of Delhi) and Guru Teg Bahadur Hospital, Dilshad Garden, Delhi, India.
2 Multidisciplinary Research Unit, University College of Medical Sciences (University of Delhi) and Guru Teg Bahadur Hospital, Dilshad Garden, Delhi, India.
Hum Exp Toxicol. 2019 May;38(5):567-577. doi: 10.1177/0960327119828136. Epub 2019 Feb 5.
This study investigated the effect of heptachlor-induced oxidative stress (OS) on transforming growth factor (TGF)-β1-mediated epithelial to mesenchymal transition (EMT) in human renal proximal tubular epithelial (HK-2) cells. Following treatment of HK-2 cells with an increasing concentration of heptachlor (0.01-10 µM) for 24 h, the intracellular reactive oxygen species and malondialdehyde level increased, whereas the glutathione-s-hydroxylase (GSH) level declined significantly in a dose-dependent manner. Pretreatment with N-acetyl cysteine attenuates the heptachlor-induced OS. In this study, we have shown that heptachlor-induced OS regulates the mRNA expression of TGF-β1-mediated Smad signalling genes accompanied by increased nuclear localization of phosphorylated Smad-2 and phosphorylated Smad-3. Furthermore, the m-RNA and protein level of epithelial marker, that is, E-cadherin decreased while the mesenchymal marker, that is, α-smooth muscle actin increased in heptachlor exposed HK-2 cells. In conclusion, heptachlor-induced OS might be responsible for the activation of TGF-β1/Smad signalling which ultimately leads to renal damage by means of EMT.
本研究探讨了七氯诱导的氧化应激（OS）对人肾近端肾小管上皮（HK-2）细胞中转化生长因子（TGF）-β1 介导的上皮间质转化（EMT）的影响。用递增浓度的七氯（0.01-10 μM）处理 HK-2 细胞 24 h 后，细胞内活性氧和丙二醛水平呈剂量依赖性显著增加，而谷胱甘肽-s-羟化酶（GSH）水平则明显下降。N-乙酰半胱氨酸预处理可减轻七氯诱导的 OS。在本研究中，我们已经表明，七氯诱导的 OS 调节 TGF-β1 介导的 Smad 信号基因的 mRNA 表达，伴随着磷酸化 Smad-2 和磷酸化 Smad-3 的核内定位增加。此外，在暴露于七氯的 HK-2 细胞中，上皮标志物 E-钙黏蛋白的 m-RNA 和蛋白水平降低，而间充质标志物 α-平滑肌肌动蛋白增加。总之，七氯诱导的 OS 可能是 TGF-β1/Smad 信号通路激活的原因，最终通过 EMT 导致肾脏损伤。
