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

本研究旨在阐明低氧反应分子和存在的炎症在肾间质纤维化发生发展中的作用。血红素氧合酶-1(HO-1)是一种众所周知的低氧诱导分子，它的诱导可减轻梗阻性尿路病变大鼠的肾脏纤维化，而巨噬细胞间质的浸润却意外增加。相反，T细胞内流明显减弱。HO-1的免疫组织化学定位显示其在浸润性巨噬细胞中的表达，提示这些细胞可能对纤维化具有保护作用。另一种低氧诱导分子促红细胞生成素(EPO)在梗阻性尿路疾病中被检测。促红细胞生成素虽然增加了血液中的血红蛋白浓度，但不影响肾纤维化。这些结果表明，低氧诱导的分子HO-1，而不是EPO，具有减轻肾纤维化的能力。接下来，我们研究了与炎性细胞内流相关的基因表达谱，以及抗炎药物的作用。为此，应用基因芯片技术检测狼疮性肾炎小鼠模型肾小球基因的表达。这些肾小球高表达各种趋化因子及其受体，并伴有明显的巨噬细胞、T细胞和中性粒细胞的内流。强的松龙显著减弱所有这些反应。综上所述，我们认为低氧诱导的HO-1具有抗纤维化作用，但其对浸润细胞的作用依赖于炎症细胞的种类，这与抗炎性糖皮质激素的作用截然不同。

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.