Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
Toxicol Sci. 2018 Jul 1;164(1):363-374. doi: 10.1093/toxsci/kfy094.
Plasticizer di-(2-ethylhexyl)phthalate (DEHP) is known as an endocrine disruptor and a peroxisome proliferator. A currently epidemiological study has suggested that daily high DEHP intake from phthalate-tainted foods in children may be a risk factor for renal dysfunction. DEHP can leach from medical devices such as blood storage bags and the tubing. Long-term exposure to DEHP is associated with nephropathy and exacerbates chronic kidney diseases (CKDs) progression. However, the detailed effects and molecular mechanisms remain unclear. Here, we hypothesized that DEHP and its major metabolite mono-(2-ethylhexyl)phthalate (MEHP) incited epithelial-to-mesenchymal transition (EMT) and lead to aggravate renal fibrosis progression. Treatment with low-cytotoxic concentration DEHP, but not MEHP, for 72 h obviously induced the morphological and phenotypic changes and EMT markers induction in normal rat renal tubular epithelial cells (NRK-52E). AKT inhibitor MK-2206 inhibited DEHP-induced EMT features and signals of AKT phosphorylation and downstream NF-κB and GSK3β. DEHP did not affect the expression of transforming growth factor-β1 mRNA. DEHP down-regulated the peroxisome proliferator-activated receptor (PPAR)α and PPARγ protein expressions. PPARγ agonist pioglitazone partially and significantly inhibited DEHP-induced EMT induction. In vivo DEHP exposure for 6 weeks enhanced the renal dysfunction and renal fibrosis and mortality rate, but decreased the PPARα and PPARγ protein expressions, in a folic acid-induced kidney fibrosis mouse model. Taken together, these results demonstrate for the first time that DEHP arouses EMT induction and renal fibrosis progression in renal tubular cells and is associated with PPARs downregulation. DEHP exposure potentially exacerbated renal fibrosis/nephropathy in a kidney disease condition.
增塑剂邻苯二甲酸二（2-乙基己基）酯（DEHP）被认为是一种内分泌干扰物和过氧化物酶体增殖物。目前的一项流行病学研究表明，儿童从受邻苯二甲酸酯污染的食物中每天摄入高剂量的 DEHP，可能是肾功能障碍的一个风险因素。DEHP 可以从血袋和管道等医疗器械中浸出。长期接触 DEHP 与肾病有关，并加重慢性肾脏病（CKD）的进展。然而，其详细的作用机制仍不清楚。在这里，我们假设 DEHP 及其主要代谢物单（2-乙基己基）邻苯二甲酸酯（MEHP）引发上皮间质转化（EMT），并导致肾脏纤维化进展加重。用低细胞毒性浓度的 DEHP 处理 72 小时，而不是 MEHP，可明显诱导正常大鼠肾小管上皮细胞（NRK-52E）的形态和表型变化以及 EMT 标志物的诱导。AKT 抑制剂 MK-2206 抑制了 DEHP 诱导的 EMT 特征以及 AKT 磷酸化和下游 NF-κB 和 GSK3β 的信号。DEHP 不影响转化生长因子-β1mRNA 的表达。DEHP 下调过氧化物酶体增殖物激活受体（PPAR）α和 PPARγ 蛋白表达。PPARγ 激动剂吡格列酮部分且显著抑制 DEHP 诱导的 EMT 诱导。在体内，DEHP 暴露 6 周可增强叶酸诱导的肾脏纤维化小鼠模型中的肾功能障碍、肾脏纤维化和死亡率，但降低了 PPARα 和 PPARγ 蛋白的表达。综上所述，这些结果首次表明 DEHP 可引起肾小管细胞 EMT 诱导和肾脏纤维化进展，并与 PPARs 下调有关。DEHP 暴露可能在肾脏疾病状态下加重肾脏纤维化/肾病。
