State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China; HKBU Institute for Research and Continuing Education, Shenzhen, China.
State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China.
Sci Total Environ. 2019 Aug 1;676:72-86. doi: 10.1016/j.scitotenv.2019.04.208. Epub 2019 Apr 16.
Environmental pollutants, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), are common surfactants in various consumer products. Epidemiological studies have demonstrated the association of diabetic kidney diseases with PFOA and PFOS. However, mechanisms of metabolic alterations involved are still unclear.
Considering their involvement of glomerular hemodynamics, rat mesangial cells (MCs) are used as an in vitro model of diabetic kidney diseases for exposure to PFOS/PFOA under diabetic condition. Non-targeted metabolomics studies based on liquid chromatography-high resolution mass spectrometry were conducted to determine how PFOA/PFOS promoted fibrotic and proinflammatory responses in the MCs under diabetic condition.
Exposure of PFOA/PFOS (10 μM) increased oxidative stress and the levels of fibrotic and proinflammatory markers in MCs under diabetic condition. We demonstrated for the first time that PFOA and PFOS altered amino acid biosynthesis, citrate cycle, and purine metabolism in MCs under diabetic condition. Compared with diabetic condition, the exposure of PFOA and PFOS under diabetic condition more significantly altered the levels of 13 intracellular metabolites, including L-tyrosine, L-phenylalanine, L-arginine, L-tryptophan, AMP, ADP, UMP, inosine, and hypoxanthine, which have been reported to be related to kidney injury. In addition, PFOA/PFOS treatment significantly altered the expression levels of key enzymes involved in these metabolisms. Treatment with L-tyrosine, L-phenylalanine, L-arginine, and L-tryptophan reduced the levels of fibrotic and inflammatory markers induced by PFOA/PFOS.
Our results suggest that under diabetic condition, exposure of PFOA or PFOS aggravated diabetic kidney injury in vitro by impairing metabolisms of amino acids and purines to induce more fibrosis and inflammation in MCs.
全氟辛酸（PFOA）和全氟辛烷磺酸（PFOS）是各种消费品中常见的表面活性剂，属于环境污染物。流行病学研究表明，糖尿病肾病与 PFOA 和 PFOS 有关。然而，涉及的代谢改变机制尚不清楚。
考虑到它们与肾小球血液动力学的关系，我们使用大鼠肾小球系膜细胞（MCs）作为糖尿病肾病的体外模型，在糖尿病条件下暴露于 PFOS/PFOA。我们进行了基于液相色谱-高分辨质谱的非靶向代谢组学研究，以确定 PFOA/PFOS 如何在糖尿病条件下促进 MCs 的纤维化和促炎反应。
在糖尿病条件下，PFOA/PFOS（10μM）的暴露增加了 MCs 中的氧化应激以及纤维化和促炎标志物的水平。我们首次证明，在糖尿病条件下，PFOA 和 PFOS 改变了 MCs 中的氨基酸生物合成、柠檬酸循环和嘌呤代谢。与糖尿病条件相比，在糖尿病条件下暴露于 PFOA 和 PFOS 更显著地改变了 13 种细胞内代谢物的水平，包括 L-酪氨酸、L-苯丙氨酸、L-精氨酸、L-色氨酸、AMP、ADP、UMP、肌苷和次黄嘌呤，这些代谢物已被报道与肾脏损伤有关。此外，PFOA/PFOS 处理显著改变了这些代谢物相关的关键酶的表达水平。用 L-酪氨酸、L-苯丙氨酸、L-精氨酸和 L-色氨酸处理可降低 PFOA/PFOS 诱导的纤维化和炎症标志物的水平。
我们的结果表明，在糖尿病条件下，PFOA 或 PFOS 的暴露通过损害氨基酸和嘌呤代谢加重了体外糖尿病肾病损伤，从而在 MCs 中诱导更多的纤维化和炎症。
