Sirtuin1 inhibits calcium oxalate crystal-induced kidney injury by regulating TLR4 signaling and macrophage-mediated inflammatory activation.
Sirtuin1 inhibits calcium oxalate crystal-induced kidney injury by regulating TLR4 signaling and macrophage-mediated inflammatory activation.
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DOI：
10.1016/j.cellsig.2023.110887
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发表时间：
2023-09
影响因子：
4.8
通讯作者：
C. Duan;Haoran Liu;Xiaoqi Yang;Jianhe Liu;Yao-liang Deng;Tao Wang;J. Xing;Zhiquan Hu;
中科院分区：
文献类型：
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作者：
C. Duan;Haoran Liu;Xiaoqi Yang;Jianhe Liu;Yao-liang Deng;Tao Wang;J. Xing;Zhiquan Hu;
Sirtuin 1（Sirt 1）的激活通过调节肾脏免疫微环境，显著减轻草酸钙（CaOx）结晶沉积和肾脏炎性损伤。为了阐明Sirt 1对巨噬细胞相关炎症和肾小管上皮细胞（TECs）坏死治疗作用的分子机制，我们构建了巨噬细胞和CaOx一水合物（COM）刺激的肾小管细胞共培养系统来模拟肾脏中的免疫微环境，并在野生型和骨髓特异性Sirt 1敲除小鼠中建立了CaOx肾钙质沉着症小鼠模型。Gene Expression Omnibus Datasets的靶点预测分析显示，只有miR-34 b-5 p受脂多糖调控，并被SRT 1720上调，靶向TLR 4 3′-非翻译区。在体外，SRT 1720通过靶向miR-34 b-5 p抑制了COM刺激的TEC中TLR 4表达和M1巨噬细胞极化，并减少了活性氧（ROS）产生和线粒体损伤。在机制上，Sirt 1通过抑制H3 K27的三甲基化来促进miR-34 b-5 p的表达，H3 K27直接与miR-34 b-5 p启动子结合并消除miR-34 b-5 p的转录。此外，Sirt 1的缺失加重了CaOx肾钙沉着症诱导的炎症和氧化性肾损伤，而AgomiR-34 b逆转了这些作用。因此，我们的数据表明，Sirt 1抑制TLR 4信号转导和M1巨噬细胞极化，并减少体外和体内TEC的炎症和氧化损伤。
Sirtuin1 (Sirt1) activation significantly attenuated calcium oxalate (CaOx) crystal deposition and renal inflammatory injury by regulating renal immune microenvironment. Here, to elucidate the molecular mechanism underlying the therapeutic effects of Sirt1 on macrophage related inflammation and tubular epithelial cells (TECs) necrosis, we constructed a macrophage and CaOx monohydrate (COM)-stimulated tubular cell co-culture system to mimic immune microenvironment in kidney and established a mouse model of CaOx nephrocalcinosis in wild-type and myeloid-specific Sirt1 knockout mice. Target prediction analyses of Gene Expression Omnibus Datasets showed that only miR-34b-5p is regulated by lipopolysaccharides and upregulated by SRT1720 and targets the TLR4 3′-untranslated region. In vitro, SRT1720 suppressed TLR4 expression and M1 macrophage polarization and decreased reactive oxygen species (ROS) production and mitochondrial damage in COM-stimulated TECs by targeting miR-34b-5p. Mechanically, Sirt1 promoted miR-34b-5p expression by suppressing the tri-methylation of H3K27, which directly bound to the miR-34b-5p promoter and abolished the miR-34b-5p transcription. Furthermore, loss of Sirt1 aggravated CaOx nephrocalcinosis-induced inflammatory and oxidative kidney injury, while AgomiR-34b reversed these effects. Therefore, our data suggested that Sirt1 inhibited TLR4 signaling and M1 macrophage polarization and decreased inflammatory and oxidative injury of TECs in vitro and in vivo.