| 赵 圣,李 登,朱依萍,贝晓宇,蒋君涛,韩邦旻.孕期邻苯二甲酸二正丁酯暴露促进大鼠子代肾小管上皮细胞发生Snail1介导的上皮-间充质转化[J].,2019,19(12):2207-2213 |
| 孕期邻苯二甲酸二正丁酯暴露促进大鼠子代肾小管上皮细胞发生Snail1介导的上皮-间充质转化 |
| Maternal Exposure to Di-n-butyl phthalate Induces Snail1-mediated Epithelial-mesenchymal Transition in Rat Renal Tubular Cell |
| 投稿时间：2019-01-08 修订日期：2019-01-30 |
| DOI：10.13241/j.cnki.pmb.2019.12.002 |
| 中文关键词: 邻苯二甲酸二正丁酯 上皮-间充质转化 Snail1 肾纤维化 |
| 英文关键词: Di-n-butyl phthalate Epithelial-mesenchymal transition Snail1 Renal fibrosis |
| 基金项目:国家自然科学基金项目（81771564） |
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| 中文摘要: |
| 摘要 目的：本实验以DBP暴露的大鼠为模型，研究DBP相关纤维化肾脏细胞上皮-间充质转化（EMT）水平改变以及该过程的调节机制。方法：动物模型中实验组妊娠大鼠在妊娠14-18天期间以800 mg/kg/天的剂量胃饲DBP，使用免疫组织化学（IHC）检测EMT相关指标；使用IHC、Western blot和PCR技术检测转录因子Snail1表达；以肾小管上皮细胞NRK52E作为体外模型，使用同样方法检测DBP暴露对中TGF-β1表达影响，检测H2O2对TGF-β1表达影响、TGF-β1信号通路拮抗剂对DBP诱导的Snail1表达的影响。结果：与对照组相比较，孕期DBP暴露导致子代肾脏E-cadherin指标显著升高，IHC染色强度超过对照组的3倍，N-cadherin指标显著下降，IHC染色强度约为对照组20%（P＜0.05）。 DBP能够显著促进肾小管上皮细胞Snail1表达，IHC染色强度相比对照组升高约2.5倍（P＜0.05），干扰Snail1能够抑制DBP诱导EMT指标的改变；DBP暴露与肾脏TGF-β1高表达相关，TGF-β1信号通路抑制剂能够引起DBP相关的Snail1表达显著降低（约25%）；此外，DBP造成的活性氧(ROS)产物累积促进了肾小管上皮细胞TGF-β1的表达（P＜0.05）。结论：孕期暴露于DBP会导致肾脏ROS产物累积和TGF-β1高表达，进而促进肾小管上皮细胞发生Snail1介导的EMT。 |
| 英文摘要: |
| ABSTRACT Objective: In this study, DBP-exposed rats were used as models to study the changes in the level of fibrotic kidney epithelial-mesenchymal transition (EMT) and the regulatory mechanisms of this process. Methods: Pregnant rats in experimental group were fed with DBP at a dose of 800 mg/kg/day during the 14-18 days of gestation. Immunohistochemistry (IHC) was used to detect relevant indicators of EMT; IHC, Western blot and PCR were used to detect expression of transcription factor Snail1; Renal tubular cells NRK52E was used in vitro. With the same method, expression of TGF-β1 in vivo and in vitro, effect of H2O2 on TGF-β1 expression and effect of TGF-β1 receptor inhibitor on DBP Inducted Snail-mediated EMT was detected. Results: Maternal exposure to DBP promoted the development of EMT in the offspring; Compared with the control group, DBP exposure during pregnancy led to a significant increase in the E-cadherin index of the offspring, IHC staining intensity was 3 times higher than the control group. Also, N-cadherin index decreased significantly, IHC staining intensity was about 20% of the control group (P<0.05). DBP promoted Snail1 expression and interference on Snail1 function leaded to inhibition on DBP-induced EMT (about 20% of the control group). DBP exposure was associated with high expression of TGF-β1 in the kidney, and TGF-β1 receptor inhibitor was able to inhibit the activation of Snail1 by DBP（P＜0.05）. Accumulation of reactive oxygen species (ROS) induced by DBP promoted the expression of TGF-β1 in renal tubular cells. Conclusion: Exposure to DBP during pregnancy leads to accumulation of ROS in the kidney and high expression of TGF-β1, which in turn promotes Snail1-mediated EMT in renal tubular epithelial cells. |
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