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

本课题旨在阐明缺氧反应分子和存在的炎症在肾间质纤维化发生中的作用。血红素加氧酶-1 （HO-1）是一种众所周知的缺氧诱导分子，其诱导可减轻大鼠梗阻性尿病的肾纤维化，而间质巨噬细胞的浸润却意外增加。相反，T细胞内流明显减弱。免疫组化定位发现HO-1在浸润的巨噬细胞中表达，提示这些细胞可能对纤维化具有保护作用。研究了另一种缺氧诱导分子促红细胞生成素（EPO）在梗阻性尿病中的作用。EPO虽使血血红蛋白浓度升高，但对肾纤维化无影响。这些结果提示缺氧诱导分子HO-1而非EPO具有减轻肾纤维化的能力。接下来，我们检查确定与炎症细胞内流相关的基因表达谱以及抗炎药物的作用。为此，采用芯片技术检测狼疮性肾炎小鼠模型肾小球基因表达。这些肾小球显示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著涌入。强的松龙明显减弱了所有这些反应。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明显相反。

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.