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IFN-γ缺陷小鼠研究了IFN-γ在砷致肾损伤中的致病作用。我们发现IFN-γ在砷致肾损伤中起保护作用。与WT小鼠相比，NaAs处理后10小时后IFN-γ缺陷小鼠肾内砷浓度显著升高，多药耐药相关蛋白（MRP）1（NaAs外排的主要转运蛋白）的肾内表达减弱。NF-E2相关因子（Nrf）2蛋白，一种对MRP 1基因表达至关重要的转录因子，在NaAs治疗后两种小鼠的肾脏中也同样增加。相反，IFN-γ的缺乏增强了转化生长因子-β-Smad 3信号通路，并最终增强了转录激活因子3的表达，推测转录激活因子3抑制Nrf 2介导的MRP 1基因表达。因此，IFN-γ可以保护抗NaAs-in ...更多信息 可能通过维持Nrf 2介导的肾内MRP 1基因表达而引起急性肾损伤。在2006年，我们研究了砷致肾损伤的易感性的性别差异。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florone对雄性小鼠砷酸盐诱导的肾损伤易感性的影响。在本实验中，卵巢切除减轻砷引起的肾损伤，提示雌激素参与了砷引起的肾损伤的发病机制。我们进一步研究了IL-6在砷致肾损伤中的致病作用。在本研究中，我们发现IL-6在砷致肾损伤中起保护作用。有趣的是，在IL-6缺陷小鼠中，砷诱导的肾损伤的易感性没有基于性别的差异，这表明雌激素通过IL-6信号传导在砷诱导的肾损伤中起预防性作用。在接下来的项目中，我们将阐明雌激素和IL-6在砷中毒性肾损伤中的作用机制。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