C6 mediates chronic progression of tubulointerstitial damage in rats with remnant kidneys
C6 mediates chronic progression of tubulointerstitial damage in rats with remnant kidneys
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DOI：
10.1681/asn.v134928
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发表时间：
2002-04-01
影响因子：
13.6
通讯作者：
Couser, WG
中科院分区：
文献类型：
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作者：
Nangaku, M;Pippin, J;Couser, WG
尽管蛋白尿曾经被认为只是肾小球损伤的标志物，但越来越多的证据表明蛋白尿本身具有肾毒性，并会导致肾损伤的进展。多项研究表明，蛋白尿中补体的激活会导致肾小管和间质损伤。先前已证明，急性补体介导的间质性疾病是由 C5b-9 诱导的。本文在非免疫残肾模型中研究了 C5b-9 在慢性蛋白尿肾病进展中的作用。对正常补体对照和 C6 缺陷 PVG 大鼠进行六分之五肾切除术。通过测量肾小管损伤的两种独立标志物（即波形蛋白和骨桥蛋白）、细胞外基质成分 I 型胶原、IV 型胶原和层粘连蛋白的间质积累、间质巨噬细胞浸润和肾功能来评估肾小管间质损伤。两组的蛋白尿和血压水平相似。虽然两组大鼠刷状缘上的 C3 沉积是相同的，但仅在补体正常的大鼠中观察到 C5b-9 沉积。第35天时，两组的肾小管间质损伤和肾衰竭程度相同。补体正常大鼠的肾小管间质损伤在第 70 天时仍然很严重。相比之下，C6 缺陷大鼠的肾小管间质损伤在第 70 天时明显改善，肾功能也有所改善。在继发于肾单位损失的慢性进行性肾病的大鼠模型中，最初的间质变化是补体独立的并且很大程度上是可逆的，而进行性间质纤维化主要由 C5b-9 介导。减少肾小管细胞中 C5b-9 攻击的治疗可能会减缓进展并促进恢复。
Although it was once considered only a marker of glomerular damage, accumulating evidence indicates that proteinuria per se is nephrotoxic and contributes to the progression of renal injury. Several studies have demonstrated that activation of complement in proteinuric urine results in tubular and interstitial damage. It was previously demonstrated that acute complement-mediated interstitial disease is induced by C5b-9. Here the role of C5b-9 in the progression of chronic proteinuric renal disease was investigated in a nonimmunologic remnant kidney model. Five-sixths nephrectomies were performed for normocomplementernic control and C6-deficient PVG rats. Tubulointerstitial injury was assessed by measurement of two independent markers of tubular injury (i.e., vimentin and osteopontin), interstitial accumulation of the extracellular matrix components collagen type I, collagen type IV, and laminin, interstitial macrophage infiltration, and renal function. The two groups developed similar levels of proteinuria and BP. Whereas C3 deposition on the brush border was equivalent for rats in the two groups, C5b-9 deposition was observed only for normocomplementemic rats. At day 35, the degrees of both tubulointerstitial injury and renal failure were the same for the two groups. Tubulointerstitial injury in normocomplementemic rats was still severe at day 70. In contrast, interstitial injury in C6-deficient rats had improved markedly at day 70, with improvements in renal function. In a rat model of chronic progressive renal disease secondary to nephron loss, the initial interstitial changes are complement-independent and largely reversible, whereas progressive interstitial fibrosis is mediated predominantly by C5b-9. Treatment to reduce C5b-9 attack in tubular cells may slow progression and facilitate recovery.