Hatanaka Y, Yuzawa Y, Nishikawa K, Fukatsu A, Okada N, Okada H, Mizuno M, Matsuo S
Third Department of Internal Medicine, Nagoya University School of Medicine, Japan.
Kidney Int. 1995 Dec;48(6):1728-37. doi: 10.1038/ki.1995.471.
In the kidneys of anti-glomerular basement membrane (anti-GBM) antibody disease, binding of antibodies to tubular basement membrane (TBM) is often observed. The present work was performed to explore the mechanisms of binding of anti-GBM antibodies to TBM in vivo with special reference to 5I2Ag, a rat membrane inhibitor of complement which regulates complement activation at C3 convertase level. To suppress functions of renal 5I2Ag, F(ab')2 fragment of 5I2 (a neutralizing mAb against 5I2Ag) was perfused in the left kidney and then blood circulation was restored. Mild proteinuria ( < 10 mg/16 hr) was observed during first several days. Five days later, there were tubulointerstitial injuries defined by tubular vimentin staining and leukocyte infiltration. Significant deposition of C3 was observed in the capillaries and in TBM. In rats intravenously injected with rabbit anti-rat GBM antibodies five minutes after kidney perfusion with 5I2, strong binding of rabbit IgG to TBM was observed at one and five days after injection. Although these rats showed mild proteinuria comparable to those perfused with 5I2 and those injected with normal rabbit serum, tubulointerstitial injury was significantly enhanced at Day 5. In contrast, rats perfused with irrelevant mAb and injected with anti-GBM antibodies did not show any significant binding of antibodies to TBM nor tubulointerstitial injury. Furthermore, rats which were made proteinuric by puromycin aminonucleoside and injected with anti-GBM antibodies did not show any significant binding of rabbit IgG to TBM. These results indicate that 5I2Ag, a rat membrane inhibitor of complement at the C3 convertase level, regulates vascular permeability in the living kidney, and that dysfunction or decreased expression of this molecule leads to increased accessibility of anti-GBM antibodies to TBM.
在抗肾小球基底膜（anti-GBM）抗体疾病的肾脏中，常观察到抗体与肾小管基底膜（TBM）的结合。本研究旨在探讨抗GBM抗体在体内与TBM结合的机制，特别参考5I2Ag，一种大鼠补体膜抑制剂，它在C3转化酶水平调节补体激活。为抑制肾脏5I2Ag的功能，将5I2的F(ab')2片段（一种针对5I2Ag的中和单克隆抗体）灌注到左肾，然后恢复血液循环。最初几天观察到轻度蛋白尿（<10 mg/16小时）。五天后，出现由肾小管波形蛋白染色和白细胞浸润定义的肾小管间质损伤。在毛细血管和TBM中观察到C3的显著沉积。在用5I2灌注肾脏五分钟后静脉注射兔抗大鼠GBM抗体的大鼠中，注射后一天和五天观察到兔IgG与TBM的强烈结合。尽管这些大鼠表现出与用5I2灌注的大鼠和注射正常兔血清的大鼠相当的轻度蛋白尿，但在第5天肾小管间质损伤明显加重。相比之下，用无关单克隆抗体灌注并注射抗GBM抗体的大鼠未显示抗体与TBM的任何显著结合，也未出现肾小管间质损伤。此外，用嘌呤霉素氨基核苷诱导蛋白尿并注射抗GBM抗体的大鼠未显示兔IgG与TBM的任何显著结合。这些结果表明，5I2Ag作为一种在C3转化酶水平的大鼠补体膜抑制剂，调节活体肾脏中的血管通透性，并且该分子的功能障碍或表达降低导致抗GBM抗体更容易接触到TBM。
