Macrophages contribute to the initiation of ischaemic acute renal failure in rats
Macrophages contribute to the initiation of ischaemic acute renal failure in rats
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DOI：
10.1093/ndt/gfk047
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发表时间：
2006-05-01
影响因子：
6.1
通讯作者：
Kim, HK
中科院分区：
文献类型：
--
作者：
Jo, SK;Sung, SA;Kim, HK
背景虽然中性粒细胞和T细胞在介导缺血/再灌注后的肾损伤中是重要的，但巨噬细胞的作用仍然未知。采用脂质体氯膦酸二钠（LC），我们研究了系统性单核-巨噬细胞耗竭对大鼠缺血性急性肾功能衰竭肾损害的影响。通过LC或脂质体载体注射雄性Sprague-Dawley大鼠，并进行双侧肾蒂钳夹（40 min）或假缺血。在再灌注后4、24和72 h，评估生化和组织学肾损伤，并使用定量实时逆转录聚合酶链反应进行肿瘤坏死因子-α（TNF-α）、白细胞介素-1 β（IL-1 β）、IL-6和单核细胞趋化蛋白-1（MCP-1）的基因表达动力学。LC处理24 h后，外周血单核细胞和肝脏外胚层发育不良蛋白-1阳性细胞百分比显著降低。系统性单核细胞-巨噬细胞耗竭导致（a）不太严重的肾小管坏死，（B）炎症减少和（c）肾小管上皮细胞凋亡减少。基因表达动力学显示IL-6基因表达在再灌注后4 h达到高峰，随后是TNF-α、IL-1 β和MCP-1的表达，在再灌注后24 h达到高峰。系统性单核-巨噬细胞耗竭显著降低这些细胞因子和趋化因子基因表达。这些结果表明，巨噬细胞是缺血/再灌注损伤起始期的重要介质，限制初始巨噬细胞浸润或活化的策略可用于治疗急性肾衰竭。
Background. Although neutrophils and T cells are important in mediating renal injury following ischaemia/reperfusion, the role of macrophages is still unknown. Using liposomal clodronate (LC), we investigated the effect of systemic monocyte-macrophage depletion on renal damage in ischaemic acute renal failure in rats.Methods. Male Sprague-Dawley rats were injected by LC or liposomal vehicle and underwent bilateral renal pedicle clamping (40 min) or sham ischaemia. Biochemical and histological renal damage was assessed and gene expression kinetics of tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), IL-6 and monocyte chemoattractant protein-1 (MCP-1) using quantitative real-time reverse transcription-polymerase chain reaction were conducted at 4, 24 and 72 h after reperfusion.Results. The percentage of peripheral blood monocytes and ectodysplasin-1-positive cells in liver decreased significantly in LC-treated animals at 24 h. Systemic monocyte-macrophage depletion resulted in (a) less severe tubular necrosis, (b) reduced inflammation and (c) reduced apoptosis of renal tubular epithelial cells. Gene expression kinetics showed that IL-6 gene expression peaked early at 4 h after reperfusion, followed by TNF-alpha, IL-1 beta and MCP-1 expressions, which peaked at 24 h. Systemic monocyte-macrophage depletion significantly reduced these cytokine and chemokine gene expressions.Conclusions. These results suggest that macrophages are an important mediator in the initiation period of ischaemia/reperfusion injury and strategies that limit initial macrophage infiltration or activation can be useful in the treatment of acute renal failure.