Molecular Pathophysiological Mechanism of Arsenic Intoxication-Toward Molecular Forensic Toxicology-

为了阐明砷中毒的分子机制，我们于2005年以IFN-γ缺乏的小鼠为研究对象，研究了IFN-γ在砷酸盐性肾损伤中的致病作用。我们发现IFN-γ在砷酸盐诱导的肾损伤中起保护作用。在NaAs处理后10小时，IFN-γ缺陷小鼠的肾内砷浓度显著升高，与WT小鼠相比，多药耐药相关蛋白（MRP） 1的肾内表达减弱，MRP 1是NaAs外排的主要转运体。nf - e2相关因子（Nrf） 2蛋白，一种对MRP1基因表达至关重要的转录因子，在NaAs处理后，在两种小鼠的肾脏中相似地增加。相反，IFN-γ的缺失增强了转化生长因子-β-Smad3信号通路，并最终增强了激活转录因子3的表达，推测其抑制了nrf2介导的MRP1基因表达。因此，IFN-γ可能通过维持nrf2介导的肾内MRP1基因表达来保护NaAs-in - More诱导的急性肾损伤。2006年，我们研究了砷酸盐致肾损伤易感性的性别差异。在本研究中，我们发现雌性小鼠更容易受到砷酸盐引起的肾损伤。此外，我们还研究了卵巢切除术对雌性小鼠砷酸盐诱导的肾损伤易感性的影响，以及雄激素受体拮抗剂氟他胺对雄性小鼠砷酸盐诱导的肾损伤易感性的影响。本实验中，卵巢切除可减轻砷酸盐所致肾损伤，提示雌激素参与了砷酸盐所致肾损伤的发病机制。我们进一步研究了IL-6在砷酸盐致肾损伤中的致病作用。在本研究中，我们发现IL-6在砷酸盐诱导的肾损伤中起保护作用。有趣的是，IL-6缺乏小鼠对砷酸盐诱导的肾损伤的易感性没有性别差异，这表明雌激素通过IL-6信号传导在砷酸盐诱导的肾损伤中起不利作用。在接下来的项目中，我们将阐明雌激素和IL-6在砷酸盐性肾损伤中的作用机制。少

To clarify the molecular mechanisms of pathogenesis of arsenic intoxication, we have studied pathogenic roles of IFN-γ in arsenate-induced renal injury using IFN-γ deficient mouse in 2005. We found that IFN-γ played a protective role in arsenate-induced renal injury. The intrarenal arsenic concentration was significantly higher in IFN-γ deficient mice later than 10 hours after NaAs treatment, with attenuated intrarenal expression of multidrug resistance-associated protein (MRP) 1, a main transporter for NaAs efflux, compared with WT mice. NF-E2-related factor (Nrf) 2 protein, a transcription factor crucial for MRP1 gene expression, was similarly increased in the kidneys of both strains of mice after NaAs treatment. In contrast, the absence of IFN-γ augmented transforming growth factor-β-Smad3 signal pathway and eventually enhanced the expression of activating transcription factor 3, which is presumed to repress Nrf2-mediated MRP1 gene expression. Thus, IFN-γ can protect against NaAs-in … More duced acute renal injury, probably by maintaining Nrf2-mediated intrarenal MRP1 gene expression. In 2006, we have studied sex-based differences in susceptibility to arsenate-induced renal injury. In this study, we found that female mice were more susceptible to arsenate-induced renal injury. Moreover, we examined the effects of ovariectomy on susceptibility to arsenate-induced renal injury in female mice, and the effects of fltamide, an androgen receptor antagonist, on susceptibility to arsenate-induced renal injury in male mice. In this experiment, ovariectomy attenuated arsenate-induced renal injury, suggesting that estrogen was involved in pathogenesis of arsenate-induced renal injury. We further studied pathogenic roles of IL-6 in arsenate-induced renal injury. In this study, we found that IL-6 played a protective role in arsenate-induced renal injury. Interestingly, there was no sex-based difference of susceptibility to arsenate-induced renal injury in IL-6 deficient mice, which suggested that estrogen acts detrimentally in arsenate-induced renal injury through IL-6 signaling. In the next project, we will clarify the action mechanism of estrogen and IL-6 in arsenate-induced renal injury. Less