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

砷中毒的分子病理生理机制-走向分子法医毒理学-

• 批准号: 17590582
• 负责人: KIMURA Akihiko
• 金额: $ 2.18万
• 依托单位: Wakayama Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590582/
• 关键词: arsenic intoxication; renal injury; IFN-γ; MRP1; TGF-β; sex difference; estrogen; IL-6; Nrf2; ATF3; シグナルクロストーク

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

为了阐明砷中毒发病的分子机制，我们于2005年利用干扰素-γ缺陷小鼠研究了干扰素-γ在砷中毒小鼠肾损伤中的致病作用。我们发现干扰素-γ对砷中毒所致的肾损伤有保护作用。与WT小鼠相比，干扰素-γ缺陷小鼠在NaAS治疗后10h肾内砷浓度显著升高，肾内多药耐药相关蛋白1的表达减弱。核因子-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治疗后，在两个品系的小鼠肾脏中类似地增加。相反，缺乏干扰素-γ增强了转化生长因子-β-Smad3信号通路，最终增强了激活转录因子3的表达，这可能抑制了Nrf2介导的MRP1基因的表达。因此，干扰素-γ对NaAS-in…具有保护作用。更多地减少急性肾损伤，可能是通过维持Nrf2介导的肾内MRP1基因的表达。2006年，我们研究了砷酸盐所致肾损伤易感性的性别差异。在这项研究中，我们发现雌性小鼠更容易受到砷盐诱导的肾脏损伤。此外，我们还研究了卵巢切除对雌性小鼠砷中毒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中毒肾损伤易感性的影响。在本实验中，卵巢切除减轻了砷酸盐所致的肾损伤，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在砷中毒肾损伤中的致病作用。在本研究中，我们发现IL-6在砷中毒所致的肾损伤中起到保护作用。有趣的是，在IL-6缺乏的小鼠中，对砷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信号在砷诱导的肾损伤中起有害作用。在下一个项目中，我们将阐明雌激素和IL-6在砷中毒肾损伤中的作用机制。较少

项目成果

MRP-1 expression levels determine strain-specific susceptibility to sodium arsenic-induced renal injury between C57BL/6 and BALB/c mice

• DOI: 10.1016/j.taap.2004.07.013
• 发表时间: 2005-02-15
• 期刊: TOXICOLOGY AND APPLIED PHARMACOLOGY
• 影响因子: 3.8
• 作者: Kimura, A;Ishida, Y;Kondo, T
• 通讯作者: Kondo, T

Interferon-gamma plays protective roles in sodium arsenite-induced renal injury by up-regulating intrarenal multidrug resistance-associated protein 1 expression.

干扰素-γ 通过上调肾内多药耐药相关蛋白 1 的表达，在亚砷酸钠诱导的肾损伤中发挥保护作用。

• 发表时间: 2006
• 期刊: The American Journal of Pathology 169
• 作者: Kimura;Kondo;他6名
• 通讯作者: 他6名

Interferon-gamma plays protective roles in sodium arsenate-induced renal injury by up-regulating intrarenal multidrug resistance-associated protein 1 expression.

干扰素-γ 通过上调肾内多药耐药相关蛋白 1 的表达，在砷酸钠诱导的肾损伤中发挥保护作用。

• 发表时间: 2006
• 期刊: American Journal of Pathology 169, 4
• 作者: Ogata;Mamoru;Akihiko Kimura
• 通讯作者: Akihiko Kimura

Interferon-gamma plays protective roles in sodium arseniteinduced renal injury by up-regulating intrarenal multidrug resistance-associated protein expression.

干扰素-γ通过上调肾内多药耐药相关蛋白的表达，在亚砷酸钠诱导的肾损伤中发挥保护作用。

• 发表时间: 2006
• 期刊: American Journal of Pathology 169・4
• 作者: OGATA;Mamoru;Akihiko Kimura
• 通讯作者: Akihiko Kimura