Chen A, Sheu L F, Ho Y S, Lin Y F, Chou W Y, Wang J Y, Lee W H
Department of Pathology, Tri-Service General Hospital, Taipei, Taiwan, ROC.
Am J Kidney Dis. 1998 Mar;31(3):443-52. doi: 10.1053/ajkd.1998.v31.pm9506681.
The administration of glucocorticoids has been reported to exacerbate proteinuria in a few patients with glomerulonephritis. This effect has not been well recognized, and the pathogenetic mechanism responsible for this phenomenon remains to be clarified. In this study, we observed that a high daily oral dose (0.5 mg/kg body weight) of dexamethasone was capable of inducing overt proteinuria in mice, beginning on day 5 and persisting for a 19-day duration. One fourth of mice also intermittently presented with slight hematuria beginning on day 12. Renal lesions in the dexamethasone-treated mice, which were killed on day 23, were characterized by mild mesangial expansion, segmental or global hyalinosis/sclerosis in deep cortical glomeruli, and focal tubular changes. No glomerular inflammatory cell infiltration or proliferative lesion was noted in any of the mice. Ultrastructural features of glomeruli included mesangial widening characterized by either an increase of mesangial matrix, dilated mesangial channels filled with slightly electron-dense material or mesangial lysis-like appearance showing intracytoplasmic microcysts filled with electron-lucent material, and evidence to support injury of endothelial cells, erythrocytes, and podocytes. An immunofluorescence study revealed enhanced glomerular deposition of IgG, IgA, IgM, and fibrinogen (P < 0.001, compared with normal control mice), but no glomerular C3 deposition was identified in any of the dexamethasone-treated mice. Charge analysis showed no impairment in anionic property of glomerular tufts in the dexamethasone-treated mice. In addition, the dexamethasone-induced proteinuria was greatly attenuated by treatment with a low molecular weight heparin, although it was not reduced by an angiotensin-converting enzyme inhibitor. Data from these experiments suggest that a large dose of glucocorticoids is potentially nephrotoxic. Alteration of a size-dependent permeability may predominantly contribute to the dexamethasone-induced proteinuria. However, the effect of glomerular hyperfiltration may be only partially involved in the pathogenesis of this dexamethasone-induced glomerulopathy in mice.
据报道，在一些肾小球肾炎患者中，使用糖皮质激素会加重蛋白尿。这种效应尚未得到充分认识，导致这一现象的发病机制仍有待阐明。在本研究中，我们观察到，每天口服高剂量（0.5毫克/千克体重）的地塞米松能够在小鼠中诱导明显的蛋白尿，从第5天开始，持续19天。四分之一的小鼠从第12天开始还间歇性出现轻微血尿。在第23天处死的地塞米松处理小鼠的肾脏病变特征为轻度系膜扩张、深部皮质肾小球节段性或全球性玻璃样变/硬化以及局灶性肾小管改变。在任何一只小鼠中均未观察到肾小球炎性细胞浸润或增殖性病变。肾小球的超微结构特征包括系膜增宽，表现为系膜基质增加、充满轻度电子致密物质的扩张系膜通道或类似系膜溶解的外观，显示充满电子透亮物质的胞浆内微囊肿，以及支持内皮细胞、红细胞和足细胞损伤的证据。免疫荧光研究显示IgG、IgA、IgM和纤维蛋白原在肾小球的沉积增强（与正常对照小鼠相比，P < 0.001），但在地塞米松处理的任何小鼠中均未发现肾小球C3沉积。电荷分析显示地塞米松处理小鼠的肾小球毛细血管襻阴离子特性无损害。此外，低分子量肝素治疗可大大减轻地塞米松诱导的蛋白尿，尽管血管紧张素转换酶抑制剂不能降低蛋白尿。这些实验数据表明，大剂量糖皮质激素可能具有肾毒性。大小依赖性通透性的改变可能主要导致地塞米松诱导的蛋白尿。然而，肾小球高滤过的作用可能仅部分参与小鼠地塞米松诱导的肾小球病的发病机制。
