Blockade of CCR2 ameliorates progressive fibrosis in kidney
Blockade of CCR2 ameliorates progressive fibrosis in kidney
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DOI：
10.1016/s0002-9440(10)63292-0
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发表时间：
2004-07-01
影响因子：
6
通讯作者：
Yokoyama, H
中科院分区：
文献类型：
--
作者：
Kitagawa, K;Wada, T;Yokoyama, H
纤维化是进行性器官疾病的标志。单核细胞趋化蛋白（MCP）-1，也称为巨噬细胞趋化和激活因子（MCAF/CCL 2）及其受体CCR 2被认为有助于进行性纤维化。然而，MCP-1/CCR 2阻断在进行性纤维化中的治疗功效仍有待研究。我们假设阻断CCR 2可能导致纤维化的改善。为了实现这一目标，我们研究了CCR 2基因靶向小鼠和用丙帕锗或RS-504393、CCR 2抑制剂治疗的小鼠中单侧输尿管梗阻诱导的肾间质纤维化。细胞浸润，其中大部分是F4/80阳性，减少了CCR 2基因敲除小鼠。此外，双重染色显示，CCR 2阳性细胞主要是F4/80阳性的巨噬细胞。重要的是，相对于野生型小鼠，CCR 2阻断减少了肾间质纤维化。与此同时，肾MCP-1，转化生长因子β和I型胶原蛋白的转录本和蛋白质在CCR 2基因敲除小鼠中减少。此外，通过在单侧输尿管梗阻模型中用CCR 2拮抗剂治疗证实了肾纤维化的这种CCR 2依赖性环。这些发现表明，阻断CCR 2的治疗策略可能通过减少患病肾脏中巨噬细胞的浸润和活化而对进行性纤维化有益。
Fibrosis is a hallmark of progressive organ diseases. Monocyte chemoattractant protein (MCP)-1, also termed as macrophage chemotactic and activating factor (MCAF/CCL2) and its receptor, CCR2 are presumed to contribute to progressive fibrosis. However, the therapeutic efficacy of MCP-1/CCR2 blockade in progressive fibrosis remains to be investigated. We hypothesized that blockade of CCR2 may lead to the improvement of fibrosis. To achieve this goal, we investigated renal interstitial fibrosis induced by a unilateral ureteral obstruction in CCR2 gene-targeted mice and mice treated with propagermanium or RS-504393, CCR2 inhibitors. Cell infiltrations, most of which were F4/80-positive, were reduced in CCR2 knockout mice. In addition, dual staining revealed that CCR2-positive cells were mainly F4/80-positive macrophages. importantly, CCR2 blockade reduced renal interstitial fibrosis relative to wild-type mice. Concomitantly, renal transcripts and protein of MCP-1, transforming growth factor-beta, and type I collagen were decreased in CCR2-null mice. Further, this CCR2-dependent loop for renal fibrosis was confirmed by treatment with CCR2 antagonists in a unilateral ureteral obstruction model. These findings suggest that the therapeutic strategy of blocking CCR2 may prove beneficial for progressive fibrosis via the decrease in infiltration and activation of macrophages in the diseased kidneys.