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Role of interstitial inflammation and chronic hypoxia in drug-induced progressive renal diseases. Its therapeutic strategies

间质炎症和慢性缺氧在药物引起的进行性肾病中的作用。

基本信息

批准号：
18590514
负责人：
MIURA Katsuyuki
金额：
$ 2.55万
依托单位：
Osaka City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590514/
关键词：
renal fibrosis heme oxygenase erythropoietin hypoxia

项目摘要

This research project was conducted to clarify the role of hypoxia-responsive molecule and existing inflammation in the development of renal interstitial fibrosis. Induction of heme oxygenase-1 (HO-1), a well-known hypoxia-inducible molecule, attenuated renal fibrosis in rat obstructive uropathy whereas interstitial infiltration of macrophages increased unexpectedly. In contrast, T cell influx was markedly attenuated. Immunohistochemical localization of HO-1 revealed its expression in the infiltrating macrophages, suggesting that these cells may be protective to fibrosis. Erythropoietin (EPO), another hypoxia-inducible molecule, was tested in the obstructive uropathy. Although EPO increased blood hemoglobin concentration, it did not affect renal fibrosis. These results suggested that hypoxia-inducible molecules, HO-1 but not EPO has ability to attenuate renal fibrosis. Next, we examined to determine gene expression profile associated with inflammatory cell influx and also the effects of anti-inflammatory drug. For this sake, glomerular gene expression of mouse model of lupus nephritis was assessed by microarray. These glomeruli showed high expression of various chemokines and their receptors that was accompanied by marked influx of macrophages, T cells and neutrophils. Prednisolone markedly attenuated all of these responses. Taken together, it is suggested that hypoxia-inducible HO-1 is anti-fibrotic but its action on infiltrating cells depends on the species of the inflammatory cells that is in marked contrast to the action of anti-inflammatory gluco-corticoid.

该研究项目旨在阐明缺氧反应分子和现有炎症在肾间质纤维化发展中的作用。血红素加氧酶-1 (HO-1)（一种众所周知的缺氧诱导分子）的诱导可减轻大鼠梗阻性尿路病中的肾纤维化，而巨噬细胞的间质浸润却意外增加。相反，T细胞流入明显减弱。 HO-1 的免疫组织化学定位揭示了其在浸润巨噬细胞中的表达，表明这些细胞可能对纤维化具有保护作用。促红细胞生成素（EPO）是另一种缺氧诱导分子，在阻塞性尿路病中进行了测试。 EPO虽然增加血液中血红蛋白浓度，但并不影响肾纤维化。这些结果表明缺氧诱导分子 HO-1 而不是 EPO 具有减轻肾纤维化的能力。接下来，我们检查以确定与炎症细胞流入相关的基因表达谱以及抗炎药物的作用。为此，通过微阵列评估狼疮性肾炎小鼠模型的肾小球基因表达。这些肾小球显示出各种趋化因子及其受体的高表达，并伴有巨噬细胞、T 细胞和中性粒细胞的显着流入。泼尼松龙显着减弱所有这些反应。综上所述，缺氧诱导的 HO-1 具有抗纤维化作用，但其对浸润细胞的作用取决于炎症细胞的种类，这与抗炎糖皮质激素的作用形成鲜明对比。