CCR2 signaling contributes to ischemia-reperfusion injury in kidney
CCR2 signaling contributes to ischemia-reperfusion injury in kidney
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DOI：
10.1097/01.asn.0000089563.63641.a8
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发表时间：
2003-10-01
影响因子：
13.6
通讯作者：
Yokoyama, H
中科院分区：
文献类型：
--
作者：
Furuichi, K;Wada, T;Yokoyama, H
以CCR2基因缺陷小鼠为研究对象，探讨巨噬细胞通过单核细胞趋化蛋白I(MCP-1或CCL2)/CCR2信号通路在肾缺血再灌注损伤发病机制中的作用。用普罗曼(3-氧胚基丙酸聚合物)和RS-504393抑制单核细胞趋化蛋白-1/CCR2信号转导系统的治疗效果。用血管夹夹闭左肾动、静脉60min。肾缺血再灌注损伤后，外髓可见大量浸润性细胞和明显的急性肾小管坏死。野生型小鼠肾脏缺血再灌流后，损伤肾组织中MCP-1mRNA和蛋白表达增强，间质中CCR2阳性巨噬细胞表达增强。CCR2基因缺陷小鼠与野生型小鼠相比，MCP-1的表达降低。CCR2基因缺陷小鼠脑缺血再灌流后，间质巨噬细胞数量明显减少。CCR2基因缺陷小鼠缺血再灌注后间质诱导型一氧化氮合酶阳性细胞数减少。CCR2基因缺陷小鼠肾小管缺血再灌注后肾小管坏死面积明显小于野生型小鼠。此外，与野生型小鼠相比，CCR2基因缺陷小鼠KC、巨噬细胞炎性蛋白2、上皮细胞来源的中性粒细胞激活肽78和中性粒细胞激活肽2的表达减少，并伴随着间质粒细胞浸润的减少。类似地，普罗曼和RS-504393可减少缺血再灌注后96h的间质浸润性细胞数和肾小管坏死。这些结果表明，MCP-1通过CCR2信号通路在肾缺血再灌注损伤中通过巨噬细胞的浸润和激活发挥重要作用，为肾缺血再灌注损伤提供了治疗靶点。
Examined were CCR2-deficient mice to clarify the contribution of macrophages via monocyte chemoattractant protein I (MCP-1 or CCL2)/CCR2 signaling to the pathogenesis of renal ischemia-reperfusion injury. Also evaluated was the therapeutic effects via the inhibition of MCP-1/CCR2 signaling with propagermanium (3-oxygermylpropionic acid polymer) and RS-504393. Renal artery and vein of the left kidney were occluded with a vascular clamp for 60 min. A large number of infiltrated cells and marked acute tubular necrosis in outer medulla after renal ischemia-reperfusion injury was observed. Ischemia-reperfusion induced the expression of MCP-1 mRNA and protein in injured kidneys, followed by CCR2-positive macrophages in interstitium in wild-type mice. The expression of MCP-1 was decreased in CCR2-deficient mice compared with wild-type mice. The number of interstitial infiltrated macrophages was markedly smaller in the CCR2-deficient mice after ischemia-reperfusion. CCR2-deficient mice decreased the number of interstitial inducible nitric oxide synthase-positive cells after ischemia-reperfusion. The area of tubular necrosis in CCR2-deficient mice was significantly lower than that of wild-type mice after ischemia-reperfusion. In addition, CCR2-deficient mice diminished KC, macrophage inflammatory protein 2, epithelial cell-derived neutrophil-activating peptide 78, and neutrophil-activating peptide 2 expression compared with wild-type mice accompanied with the reduction of interstitial granulocyte infiltration. Similarly, propagermanium and RS-504393 reduced the number of interstitial infiltrated cells and tubular necrosis up to 96 h after ischemia-reperfusion injury. These results revealed that MCP-1 via CCR2 signaling plays a key role in the pathogenesis of renal ischemia-reperfusion injury through infiltration and activation of macrophages, and it offers a therapeutic target for ischemia-reperfusion.