Complement membrane attack complex (C5b-9) mediates interstitial disease in experimental nephrotic syndrome.
Complement membrane attack complex (C5b-9) mediates interstitial disease in experimental nephrotic syndrome.
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发表时间：
1999-11
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通讯作者：
Masaomi Nangaku;J. Pippin;W. Couser
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作者：
Masaomi Nangaku;J. Pippin;W. Couser
越来越多的证据表明，非选择性蛋白尿患者尿液中滤过的补体成分产生补体活化产物，导致肾小管间质疾病，导致肾功能进行性丧失。为了阐明C5 b-9在补体介导的对暴露于蛋白尿的肾小管细胞的影响中的作用，在正常补体血症和遗传上C6缺陷的花斑病毒glaxo（PVG）大鼠中诱导相等水平的蛋白尿（使用嘌呤霉素的氨基糖苷）。半定量组织学分析显示，补体充足的动物比C6缺乏大鼠更严重的肾小管间质疾病。C6缺陷动物中肾小管间质损伤的改善通过使用三种独立的肾小管损伤标志物的研究得到证实，波形蛋白、骨桥蛋白和增殖细胞核抗原。更多的肾小管上皮细胞表达骨桥蛋白（肾小管损伤的早期标志物）在normocomplementemic大鼠，与C6缺乏大鼠相比，在第7和12天。在第12天，在正常补体血症大鼠中，肾小管损伤区域附近的波形蛋白染色增加，在第12天，在补体充足的动物中观察到更多的增殖细胞核抗原阳性肾小管细胞。在补体充足的大鼠中，肾小管间质损伤也与第12天细胞外基质（纤连蛋白）的大量积累有关。这些研究首次证明了C6，因此C5 b-9在蛋白尿诱导的非免疫性肾小管间质损伤的发病机制中的重要作用。这些发现表明，由蛋白尿引起的C5 b-9形成通过损害肾小管上皮细胞而导致肾单位功能的丧失，并且预防肾小管中的C5 b-9形成可以减缓肾功能的恶化。
Accumulating evidence suggests that the generation of complement activation products from filtered complement components in urine with nonselective proteinuria leads to tubulointerstitial disease, resulting in progressive loss of renal function. To elucidate the role of C5b-9 in complement-mediated effects on renal tubular cells exposed to proteinuric urine, equivalent levels of proteinuria were induced (using the aminonucleoside of puromycin) in normocomplementemic and genetically C6-deficient piebald viral glaxo (PVG) rats. Semiquantitative histologic analysis revealed that complement-sufficient animals developed more severe tubulointerstitial disease than did C6-deficient rats. Amelioration of tubulointerstitial damage in C6-deficient animals was confirmed by studies with three independent markers of tubular damage, i.e., vimentin, osteopontin, and proliferating cell nuclear antigen. More tubular epithelial cells expressed osteopontin (an early marker of tubular injury) in normocomplementemic rats, compared with C6-deficient rats, at both days 7 and 12. Staining of vimentin in the tubules, near areas of tubular damage, was increased in normocomplementemic rats at day 12, and more proliferating cell nuclear antigen-positive tubular cells were observed at day 12 in complement-sufficient animals. The tubulointerstitial damage in complement-sufficient rats was also associated with greater accumulation of extracellular matrix (fibronectin) at day 12. These studies document for the first time an important role for C6, and therefore C5b-9, in the pathogenesis of nonimmunologic tubulointerstitial injury induced by proteinuria. These findings suggest that C5b-9 formation resulting from proteinuria contributes to the loss of nephron function by damaging the tubulointerstitium and that prevention of C5b-9 formation in tubules could slow the deterioration of renal function.