Critical role of cyclooxygenase-2 activation in pathogenesis of hydronephrosis caused by lactational exposure of mice to dioxin
Critical role of cyclooxygenase-2 activation in pathogenesis of hydronephrosis caused by lactational exposure of mice to dioxin
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DOI：
10.1016/j.taap.2008.05.012
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发表时间：
2008-09-15
影响因子：
3.8
通讯作者：
Tohyama, Chiharu
中科院分区：
文献类型：
--
作者：
Nishimura, Noriko;Matsumura, Fumio;Tohyama, Chiharu
先天性肾积水是除先天性肾积水外，在婴幼儿中常见的一种严重疾病。遗传因素，在子宫内暴露于异物2，3，7，8-四氯二苯并-对二恶英(TCDD)，被认为是由于输尿管解剖梗阻而导致啮齿动物肾积水。在这里，我们报告了乳期暴露于TCDD的小鼠所致的肾积水与解剖梗阻无关，而与输尿管上皮下间充质的异常改变有关。在这些仔鼠的肾脏中，包括单核细胞趋化蛋白(MCP)-1、肿瘤坏死因子α(TNFα)和白介素1β(IL)-1β在内的一系列炎性细胞因子的表达早在出生后7天就上调了。在TCDD诱导的肾积水中，环氧合酶(COX)-2mRNA和蛋白以及前列腺素E2(PGE(2))的表达明显上调，这是一种芳烃受体依赖的方式，随后Na(+)和K(+)转运体、NKCC2和ROMK的基因表达明显上调。每天给新生儿使用COX-2选择性抑制剂，直到PND7完全阻断TCDD诱导的PGE2合成和炎性细胞因子和电解质转运蛋白的基因表达，最终阻止肾积水的发生。这些发现表明，COX-2在TCDD中的重要作用是通过功能损害而不是通过解剖阻断输尿管而导致肾积水。(C)2008 Elsevier Inc.保留所有权利。
Congenital hydronephrosis is a serious disease occurring among infants and children Besides the intrinsic. genetic factors, in utero exposure to a xenobiotic, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has been suggested to induce hydronephrosis in rodents owing to anatomical obstruction in the ureter. Here, we report that hydronephrosis induced in mouse pups exposed lactationally to TCDD is not associated with anatomical obstruction, but with abnormal alterations in the subepithelial mesenchyma of the ureter. In the kidneys of these pups, the expressions of a battery of inflammatory cytokines including monocyte chemoattractant protein (MCP)-1, tumor necrosis factor alpha (TNF alpha) and interleukin (IL) -1 beta were Up-regulated as early as postnatal day (PND) 7. The amounts of cyclooxygenase (COX) -2 mRNA and protein as well as prostaglandin E2 (PGE(2)) were conspicuously up-regulated in an arylhydrocarbon-receptor-dependent manner in the TCDD-induced hydronephrotic kidney, with a subsequent clown-regulation of the gene expressions of Na(+) and K(+) transporters, NKCC2 and ROMK. Daily administration of a COX-2 selective inhibitor to newborns until PND 7 completely abrogated the TCDD-induced PGE2 synthesis and gene expressions of inflammatory cytokines and electrolyte transporters, and eventually prevented the onset of hydronephrosis. These findings suggest an essential role of COX-2 in mediating the TCDD action of inducing hydronephrosis through the functional impairment rather than the anatomical blockade of the ureter. (C) 2008 Elsevier Inc. All rights reserved.