tert-Butylhydroquinone Treatment Alleviates Contrast-Induced Nephropathy in Rats by Activating the Nrf2/Sirt3/SOD2 Signaling Pathway
tert-Butylhydroquinone Treatment Alleviates Contrast-Induced Nephropathy in Rats by Activating the Nrf2/Sirt3/SOD2 Signaling Pathway
复制标题
叔丁基氢醌治疗通过激活 Nrf2/Sirt3/SOD2 信号通路减轻大鼠造影剂肾病
DOI：
10.1155/2019/4657651
复制
发表时间：
2019-12-20
影响因子：
--
通讯作者：
Zou, Hequn
中科院分区：
文献类型：
--
作者：
Zhou, Qin;Wang, Xin;Zou, Hequn
氧化应激在造影剂肾病（CIN）的病理生理学中起关键作用。由于CIN的特异性治疗仍然是未满足的医疗需求，因此必须找到针对CIN临床管理的有效策略。已知转录因子Nrf 2调节抗氧化应激反应。本研究的目的是评估Nrf 2激活剂叔丁基对苯二酚（t-BHQ）在预防CIN中的作用，并阐明其体外和体内作用的潜在机制。我们建立了CIN大鼠模型，并用t-BHQ（25 mg/kg）治疗动物。通过评估肾功能、HE染色、免疫组织化学和蛋白质印迹来阐明t-BHQ治疗对CIN大鼠的影响。我们还研究了氧化应激相关标志物的活性，如细胞内ROS水平，MDA水平，SOD 2活性和GSH/GSSG比值。我们通过siRNA介导的暴露于放射性造影剂的HK-2细胞中Nrf 2的沉默来验证我们的结果。t-BHQ治疗可明显改善CIN大鼠的肾功能和组织病理学改变。此外，预处理t-BHQ显着增加SOD 2活性和GSH/GSSG的比例，并降低ROS和MDA的水平，在动物进行碘佛醇暴露。此外，t-BHQ处理增加了Nrf 2、Sirt 3和SOD 2的表达，同时降低了乙酰化SOD 2的表达。当Nrf 2沉默的HK-2细胞暴露于放射性造影剂时，它们遭受严重的细胞氧化应激，表现出较低的Sirt 3和SOD 2表达，并表达较高水平的乙酰化SOD 2;然而，t-BHQ处理不影响si-Nrf 2 HK-2细胞中这些指标的蛋白质表达。我们的研究结果表明，Nrf 2在调节Sirt 3/SOD 2抗氧化通路中起着重要作用，t-BHQ可能是一种潜在的药物，通过激活Nrf 2/Sirt 3/SOD 2信号通路在体外和体内改善放射造影剂诱导的肾病。
Oxidative stress plays a critical role in the pathophysiology of contrast-induced nephropathy (CIN). Since the specific treatment of CIN remains an unmet medical need, it is imperative to find an effective strategy against the clinical management of CIN. The transcription factor Nrf2 is known to regulate antioxidative stress response. The aim of the present study was to assess the effects of tert-butylhydroquinone (t-BHQ), an activator of Nrf2, in the prevention of CIN and elucidate the underlying mechanism of its action in vitro and in vivo. We established a rat model of CIN and treated the animals with t-BHQ (25 mg/kg). The effects of t-BHQ treatment on CIN rats were elucidated by assessing renal function, HE staining, immunohistochemistry, and western blotting. We also studied the activity of oxidative stress-related markers, such as intracellular ROS level, MDA level, SOD2 activity, and GSH/GSSG ratio. We validated our results by siRNA-mediated silencing of Nrf2 in HK-2 cells exposed to the radiocontrast agent. Treatment with t-BHQ significantly ameliorated the renal function and the histopathological lesions in CIN rats. Further, pretreatment with t-BHQ significantly increased the SOD2 activity and GSH/GSSG ratio and decreased the levels of ROS and MDA in animals subjected to ioversol exposure. In addition, t-BHQ treatment increased the expression of Nrf2, Sirt3, and SOD2 and concomitantly decreased the expression of acetylated-SOD2. When Nrf2-silenced HK-2 cells were exposed to radiocontrast agent, they suffered severe cell oxidative stress, exhibited lower expression of Sirt3 and SOD2, and expressed higher levels of acetylated-SOD2; however, t-BHQ treatment did not affect the protein expression of these indicators in si-Nrf2 HK-2 cells. Our findings suggested that Nrf2 plays an important role in the regulation of the Sirt3/SOD2 antioxidative pathway, and t-BHQ may be a potential agent to ameliorate radiocontrast-induced nephropathy via activating the Nrf2/Sirt3/SOD2 signaling pathway in vitro and in vivo.