Complement factor C5a mediates renal ischemia-reperfusion injury independent from neutrophils
Complement factor C5a mediates renal ischemia-reperfusion injury independent from neutrophils
复制标题
DOI：
10.4049/jimmunol.170.7.3883
复制
发表时间：
2003-04-01
影响因子：
4.4
通讯作者：
Buurman, WA
中科院分区：
文献类型：
--
作者：
de Vries, B;Köhl, J;Buurman, WA
补体系统已被证明介导肾缺血-再灌注（I/R）损伤。然而，补体因子C5 a对I/R损伤的贡献，特别是在肾脏中，仍有待确定。在这项研究中，我们研究了阻断C5 aR通路对炎症反应和肾功能的影响，在小鼠模型的I/R损伤。首先，我们分析了C5 aR在健康小鼠肾脏中的表达。有趣的是，我们发现表达系膜，以及对肾小管上皮细胞。I/R损伤后，肾小管上皮细胞C5 aR表达上调。此外，CXC趋化因子和TNF-α的mRNA水平显著增加，肾脏被中性粒细胞严重浸润。通过特异性C5 a受体拮抗剂（C5 aRA）阻断C5 aR途径消除了CXC趋化因子的上调，但没有消除TNF-α的上调，并使中性粒细胞浸润减少> 50%。此外，C5 aRA的应用显著减少了肾功能的丧失。这种功能的改善与中性粒细胞的存在无关，因为mAb NIMP-R14的中性粒细胞消耗不影响C5 aRA治疗的保护作用。此外，阻断C5 aR通路对肾细胞凋亡没有影响。这些数据提供的证据表明，C5 a是至关重要的参与肾I/R损伤的发病机制，通过调节嗜中性粒细胞依赖性以及嗜中性粒细胞非依赖性途径，其中包括CXC趋化因子的调节，但不TNF-α或凋亡途径。
The complement system has been shown to mediate renal ischemia-reperfusion (I/R) injury. However, the contribution of complement factor C5a to I/R injury, in particular in the kidney, remains to be established. In this study, we investigated the impact of blocking the C5aR pathway on the inflammatory response and on the renal function in a murine model of I/R injury. First, we analyzed C5aR expression in kidneys of healthy mice. Intriguingly, we found expression on mesangial, as well as on tubular epithelial, cells. After I/R injury, C5aR expression was up-regulated in tubular epithelial cells. In addition, mRNA levels of CXC chemokines and TNF-alpha increased significantly and kidneys were heavily infiltrated by neutrophils. Blocking the C5aR pathway by a specific C5a receptor antagonist (C5aRA) abrogated up-regulation of CXC chemokines but not of TNF-alpha and reduced neutrophil infiltration by >50%. Moreover, application of the C5aRA significantly reduced loss of renal function. This improvement of function was independent of the presence of neutrophils because neutrophil depletion by mAb NIMP-R14 did not affect the protective effect of C5aRA treatment. Furthermore, blocking of the C5aR pathway had no influence on renal apoptosis. These data provide evidence that C5a is crucially involved in the pathogenesis of renal I/R injury by modulation of neutrophil-dependent as well as neutrophil-independent pathways, which include the regulation of CXC chemokines but not TNF-alpha or apoptotic pathways.