Environmental toxicants such as phthalate have been involved in multiple health disorders including renal diseases. Oxidative damage is implicated in many alterations caused by phthalate especially the di(2-ethylhexyl) phthalate (DEHP), which is the most useful phthalate. However, information regarding its mechanism of renal damage is lacking. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates gene expression implicated in free radical scavenging and cytoprotection including the antioxidant glutathione (GSH) pathway. The aim of this study was to assess whether DEHP affects the Nrf2 pathway and the GSH concentration. Mice were divided into four groups: a control group and three groups treated with DEHP at different concentrations (5, 50, and 200 mg/kg body weight) for 30 days. Our results showed that DEHP altered the normal levels of serum biochemical parameters creatinine (CREA), urea, and lactate dehydrogenase (LDH). This phthalate caused oxidative damage through the induction of lipid peroxidation and protein oxidation as marked by increase of protein carbonyl (PC) and loss of protein-bound sulfhydryls (PSH). Simultaneously, DEHP treatment decreased the protein level of Nrf-2, HO-1, and GCLC (responsible of GSH synthesis) and decreased the GSH level. Inhibition of the Nrf2 pathway is related to the activation of the mitochondrial pathway of apoptosis. This apoptotic process is evidenced by an upregulation of p53 and Bax protein levels in addition to a downregulation of Bcl-2. Collectively, our data demonstrated that depletion of Nrf2 and GSH was associated with the elevation of oxidative stress and the activation of intrinsic apoptosis in mouse kidney treated with DEHP.

邻苯二甲酸盐等环境毒物与包括肾脏疾病在内的多种健康疾病有关。氧化损伤与邻苯二甲酸酯引起的许多变化有关，尤其是邻苯二甲酸二（2-乙基己基）酯（DEHP），它是最有用的邻苯二甲酸酯。然而，缺乏有关其肾损伤机制的信息。转录因子核因子红细胞 2 相关因子 2 (Nrf2) 调节与自由基清除和细胞保护有关的基因表达，包括抗氧化剂谷胱甘肽 (GSH) 途径。本研究的目的是评估 DEHP 是否影响 Nrf2 途径和 GSH 浓度。将小鼠分为四组：对照组和三组，用不同浓度（5、50和200毫克/千克体重）的DEHP治疗30天。我们的结果表明，DEHP 改变了血清生化参数肌酐 (CREA)、尿素和乳酸脱氢酶 (LDH) 的正常水平。这种邻苯二甲酸盐通过诱导脂质过氧化和蛋白质氧化造成氧化损伤，其特征是蛋白质羰基 (PC) 增加和蛋白质结合巯基 (PSH) 损失。同时，DEHP 处理降低了 Nrf-2、HO-1 和 GCLC（负责 GSH 合成）的蛋白质水平，并降低了 GSH 水平。 Nrf2途径的抑制与细胞凋亡线粒体途径的激活有关。除了 Bcl-2 的下调之外，p53 和 Bax 蛋白水平的上调也证明了这种凋亡过程。总的来说，我们的数据表明，Nrf2 和 GSH 的消耗与 DEHP 处理的小鼠肾脏氧化应激的升高和内在细胞凋亡的激活有关。