Lipopolysaccharide Induces Chronic Kidney Injury and Fibrosis through Activation of mTOR Signaling in Macrophages
Lipopolysaccharide Induces Chronic Kidney Injury and Fibrosis through Activation of mTOR Signaling in Macrophages
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脂多糖通过激活巨噬细胞中的 mTOR 信号传导诱导慢性肾损伤和纤维化。
DOI：
10.1159/000441506
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发表时间：
2015-01-01
影响因子：
4.2
通讯作者：
Chen, Guochun
中科院分区：
文献类型：
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作者：
Chen, Huihui;Zhu, Jiefu;Chen, Guochun
背景资料：脓毒性肾损伤是危重患者中最常见的并发症之一，具有发展为慢性肾脏病（CKD）的高风险。新兴的数据表明，哺乳动物雷帕霉素靶蛋白（mTOR）信号转导通过调节巨噬细胞的免疫反应在脓毒性炎症中起着重要作用。本研究旨在评价mTOR信号在内毒素血症诱导的慢性肾损伤和随后的纤维化发生中在肾巨噬细胞中的作用。方法：雄性C57 BL/6小鼠用于所有动物研究（每组n = 9）。每2天腹腔注射脂多糖（LPS）（1 mg/kg）以诱导持续性内毒素血症。在LPS处理前1天将雷帕霉素（1 mg/kg.day）给予小鼠亚组，并持续至实验结束。在离体实验中，培养RAW264.7细胞并用LPS（2 μ g/ml）处理48小时，同时在雷帕霉素（50 nmol）存在下孵育一个亚组的细胞2小时。结果：连续给予LPS可导致小鼠肾脏进行性巨噬细胞浸润、肾小管损伤和胶原沉积。雷帕霉素能明显改善LPS诱导的肾脏病理改变。在正常肾巨噬细胞中很少观察到pS 6 K的表达，但在LPS处理下，pS 6 K的表达随着时间的推移而显著增加。在离体研究中，LPS诱导培养的RAW264.7细胞中显著产生IL-1 β和MCP-1，其被雷帕霉素显著抑制。结论：总之，我们的研究结果表明，内毒素血症导致巨噬细胞中mTOR信号的激活，导致进行性肾脏炎性损伤和随后的纤维化。我们的研究可能揭示了脓毒症相关CKD和肾纤维化发展的机制。(C)2015 S. Karger AG，巴塞尔
Background: Septic kidney injury is one of the most common complications in critically ill patients with a high risk of developing chronic kidney disease (CKD). Emerging data indicate that mammalian target of rapamyci (mTOR) signaling plays a major role in septic inflammation by regulating the immune response of macrophage. This study was designed to evaluate the role of mTOR signaling in kidney macrophages during endotoxemia-induced chronic kidney injury and subsequent fibrogenesis. Methods: Male C57BL/6 mice were used for all animal studies (n = 9 for each group). Lipopolysaccharide (LPS) was injected intraperitoneally (1 mg/kg) every 2 days to induce persistent endotoxemia. Rapamycin (1 mg/kg.day) was administered to a subgroup of mice 1 day prior to LPS treatment and continued to termination of the experiment. In ex-vivo experiment, RAW264.7 cells were cultured and treated with LPS (2 mu g/ml) for 48 h while a subgroup of cells were incubated in the presence of rapamycin (50 nmol) for 2 h. Results: Continuous administration of LPS resulted in progressive macrophage infiltration, tubular injury and collagen deposition in mice kidneys. Rapamycin markedly ameliorated LPS-induced kidney pathological changes. Expression of pS6K was rarely observed in normal kidney macrophages, but significantly increased with time by LPS treatment. In ex-vivo study, LPS induced prominent production of IL-1 beta and MCP-1 in cultured RAW264.7 cells, which was significantly suppressed by rapamycin. Conclusion: Taken together, our findings show that endotoxemia results in activation of mTOR signaling in macrophages, leading to progressive kidney inflammatory injuries and subsequent fibrosis. Our study may reveal a mechanism involved in the development of sepsis-associated CKD and kidney fibrosis. (C) 2015 S. Karger AG, Basel