Rapamycin ameliorates kidney fibrosis by inhibiting the activation of mTOR signaling in interstitial macrophages and myofibroblasts.
Rapamycin ameliorates kidney fibrosis by inhibiting the activation of mTOR signaling in interstitial macrophages and myofibroblasts.
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雷帕霉素通过抑制间质巨噬细胞和肌成纤维细胞中 mTOR 信号传导的激活来改善肾脏纤维化
DOI：
10.1371/journal.pone.0033626
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Liu F
中科院分区：
文献类型：
--
作者：
Chen G;Chen H;Wang C;Peng Y;Sun L;Liu H;Liu F
间质纤维化是各种进行性慢性肾脏疾病（CKD）的必然结果。新出现的数据表明，雷帕霉素可以通过减少间质浸润和细胞外基质（ECM）的积累来改善肾纤维化。然而，调控这些变化的细胞机制还没有得到很好的理解。在这项研究中，我们揭示了哺乳动物间质巨噬细胞和肌成纤维细胞中雷帕霉素靶点（mTOR）信号的持续激活，但在肾纤维化的发展过程中，损伤的近端上皮细胞、CD4+ T细胞、中性粒细胞或内皮细胞中很少激活。单侧输尿管梗阻（UUO）小鼠给予雷帕霉素可显著抑制mTOR信号的免疫反应性，从而降低梗阻肾脏的炎症反应和ECM积累。来自雷帕霉素处理的梗阻肾脏的分离巨噬细胞的炎症活性比对照组低。体外研究证实，雷帕霉素显著抑制培养成纤维细胞（NIH3T3细胞）由TGF-β1刺激诱导的成纤维活化。进一步实验发现，雷帕霉素对马兜铃酸处理的HK2细胞的纤维生成没有直接的抑制作用。我们的研究结果表明，雷帕霉素可以通过阻断间质巨噬细胞和肌成纤维细胞的mTOR信号来改善肾纤维化。
Interstitial fibrosis is an inevitable outcome of all kinds of progressive chronic kidney disease (CKD). Emerging data indicate that rapamycin can ameliorate kidney fibrosis by reducing the interstitial infiltrates and accumulation of extra cellular matrix (ECM). However, the cellular mechanism that regulates those changes has not been well understood yet. In this study, we revealed the persistent activation of mammalian target of rapamycin (mTOR) signaling in the interstitial macrophages and myofibroblasts, but rarely in injured proximal epithelial cells, CD4+ T cells, neutrophils, or endothelial cells, during the development of kidney fibrosis. Administration of rapamycin to unilateral ureteral obstruction (UUO) mice significantly suppressed the immunoreactivity of mTOR signaling, which decreased the inflammatory responses and ECM accumulation in the obstructed kidneys. Isolated macrophages from rapamycin-treated obstructed kidneys presented less inflammatory activity than vehicle groups. In vitro study confirmed that rapamycin significantly inhibited the fibrogenic activation of cultured fibroblasts (NIH3T3 cells), which was induced by the stimulation of TGF-β1. Further experiment revealed that rapamycin did not directly inhibit the fibrogenesis of HK2 cells with aristolochic acid treatment. Our findings clarified that rapamycin can ameliorate kidney fibrosis by blocking the mTOR signaling in interstitial macrophages and myofibroblasts.
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影响因子：
13.6
作者：
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通讯作者：
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作者：
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DOI：
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