Role of the complement membrane attack complex (C5b-9) in mediating experimental mesangioproliferative glomerulonephritis
Role of the complement membrane attack complex (C5b-9) in mediating experimental mesangioproliferative glomerulonephritis
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DOI：
10.1038/ki.1996.50
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发表时间：
1996-02-01
影响因子：
19.6
通讯作者：
Couser, WG
中科院分区：
文献类型：
--
作者：
Brandt, J;Pippin, J;Couser, WG
既往研究表明，系血管增殖性肾小球肾炎抗胸腺细胞血清（ATS）模型的大多数病理变化是补体依赖性的。这些包括系膜溶解、肾小球血小板浸润、系膜细胞增殖、系膜细胞产生生长因子和表达α -肌动蛋白的表型改变、肾小球巨噬细胞浸润、系膜基质扩张和蛋白尿。补体介导这些作用的机制尚未明确。由于中性粒细胞不参与ATS模型，我们假设观察到的补体效应是由于补体的C5b-9膜攻击复合物的肾小球细胞插入所致。这一假设是通过PVG大鼠来验证的，这些大鼠表现出C6基因常染色体隐性遗传的缺失。与正常补体（C+） PVG大鼠相比，酶酶酶激活的C6缺陷（C-） PVG大鼠血清产生正常数量的C5a，但不产生C5b-9。ATS诱导时，与C+对照组相比，C- PVG大鼠的系膜溶解、血小板浸润、系膜细胞增殖、α -肌动蛋白表达、巨噬细胞浸润、胶原IV沉积和蛋白尿显著减少。这些参数的减少与使用眼镜蛇毒因子的C+ PVG大鼠的全身性补体耗竭所达到的效果相当。这些发现确定了C5b-9在ATS模型中介导补体依赖性特征中的作用，并表明C5b-9解释了观察到的所有补体介导效应。这项研究首次证明了C5b-9在体内介导非膜性炎症型肾小球损伤中的功能作用。
Previous studies have demonstrated that most pathologic changes in the antithymocyte serum (ATS) model of mesangioproliferative glomerulonephritis are complement-dependent. These include mesangiolysis, glomerular platelet infiltration, mesangial cell proliferation, mesangial cell production of growth factors and phenotypic change to express alpha-actin, glomerular macrophage infiltrate, mesangial matrix expansion, and proteinuria. The mechanism by which complement mediates these effects has not been defined. Because neutrophils do not participate in the ATS model, we hypothesized that the complement effects observed are consequent to glomerular cell insertion of the C5b-9 membrane attack complex of complement. This hypothesis was tested utilizing PVG rats which exhibit an absence of C6 inherited in an autosomal recessive pattern. C6 deficient (C-) PVG rat serum activated by zymosan produced normal amounts of C5a compared to normocomplementemic (C+) PVG rat controls but no C5b-9. When ATS was induced, C- PVG rats had a significant and marked reduction in mesangiolysis, platelet infiltration, mesangial cell proliferation, alpha-actin expression, macrophage infiltration, collagen IV deposition, and proteinuria compared to C+ controls. The reduction in each of these parameters was comparable to that achieved by systemic complement depletion of C+ PVG rats with cobra venom factor. These findings establish the role of C5b-9 in mediating each of the complement-dependent features of the ATS model and indicate that C5b-9 accounts for all of the complement-mediated effects observed. This study provides the first documentation of a functional role for C5b-9 in mediating a non-membranous inflammatory type of glomerular injury in vivo.