AhR activation attenuates calcium oxalate nephrocalcinosis by diminishing M1 macrophage polarization and promoting M2 macrophage polarization.
AhR activation attenuates calcium oxalate nephrocalcinosis by diminishing M1 macrophage polarization and promoting M2 macrophage polarization.
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AhR 激活通过减少 M1 巨噬细胞极化和促进 M2 巨噬细胞极化来减轻草酸钙肾钙质沉着症
作者：
Yang X;Liu H;Ye T;Duan C;Lv P;Wu X;Liu J;Jiang K;Lu H;Yang H;Xia D;Peng E;Chen Z;Tang K;Ye Z
草酸钙(CaOx)晶体可引发肾脏损伤，参与肾钙质沉着症的发病机制。浸润性巨噬细胞的表型可能影响CaOx介导的肾脏炎症损伤和晶体沉积。芳香烃受体(AhR)如何调节炎症和巨噬细胞极化是众所周知的；然而，它如何调节CaOx肾钙质沉积仍不清楚。方法：给小鼠腹腔注射乙醛，建立CaOx肾钙质沉着症模型，同时给予AhR激活剂6-甲酰吲哚(3，2-b)咔唑(FICZ)治疗。用正电子发射计算机断层扫描(PET-CT)、高碘酸-席夫(PAS)染色和偏光显微镜观察小鼠肾脏损伤和肾脏晶体沉积情况。采用Western blotting、免疫荧光、染色质免疫沉淀、microRNA-荧光原位杂交、荧光素酶报告基因分析等方法分析巨噬细胞的极化状态及其调控机制。结果：在小鼠CaOx肾钙质沉着症模型中，肾上腺皮质激素受体的表达显著上调，并与干扰素调节因子1和缺氧诱导因子1-α(α)水平呈负相关。此外，在体外，AhR激活可抑制IRF1和HIF-1α水平，并降低M1巨噬细胞极化。在作用机制方面，生物信息学分析和染色质免疫沉淀分析证实AhR可以结合miR-142a启动子转录激活miR-142a。此外，荧光素酶报告实验证实，miR-142a通过直接靶向IRF1和HIF-1的3‘非翻译区来抑制α的表达。结论：AhR激活可通过AhR-miR-142a-irf1/HIF-1α途径减弱M1巨噬细胞极化，促进M2巨噬细胞极化，从而抑制CaOx肾钙化。
Calcium oxalate (CaOx) crystal can trigger kidney injury, which contributes to the pathogenesis of nephrocalcinosis. The phenotypes of infiltrating macrophage may impact CaOx-mediated kidney inflammatory injury as well as crystal deposition. How aryl hydrocarbon receptor (AhR) regulates inflammation and macrophage polarization is well understood; however, how it modulates CaOx nephrocalcinosis remains unclear. Methods: Mice were intraperitoneally injected with glyoxylate to establish CaOx nephrocalcinosis model with or without the treatment of AhR activator 6-formylindolo(3,2-b)carbazole (FICZ). Positron emission tomography computed tomography (PET-CT) imaging, Periodic acid-Schiff (PAS) staining, and polarized light optical microscopy were used to evaluate kidney injury and crystal deposition in mice kidney. Western blotting, immunofluorescence, chromatin immunoprecipitation, microRNA-fluorescence in situ hybridization, and luciferase reporter assays were applied to analyze polarization state and regulation mechanism of macrophage. Results: AhR expression was significantly upregulated and negatively correlated with interferon-regulatory factor 1 (IRF1) and hypoxia inducible factor 1-alpha (HIF-1α) levels in a murine CaOx nephrocalcinosis model following administration of FICZ. Moreover, AhR activation suppressed IRF1 and HIF-1α levels and decreased M1 macrophage polarization in vitro. In terms of the mechanism, bioinformatics analysis and chromatin immunoprecipitation assay confirmed that AhR could bind to miR-142a promoter to transcriptionally activate miR-142a. In addition, luciferase reporter assays validated that miR-142a inhibited IRF1 and HIF-1α expression by directly targeting their 3'-untranslated regions. Conclusions: Our results indicated that AhR activation could diminish M1 macrophage polarization and promote M2 macrophage polarization to suppress CaOx nephrocalcinosis via the AhR-miR-142a-IRF1/HIF-1α pathway.
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DOI：
10.1038/s41581-018-0103-6
发表时间：
2019-04
期刊：
Nature reviews. Nephrology
影响因子：
--
作者：
Guo C;Dong G;Liang X;Dong Z
通讯作者：
Dong Z
影响因子：
6.1
作者：
Busbee PB;Rouse M;Nagarkatti M;Nagarkatti PS
通讯作者：
Nagarkatti PS
影响因子：
11.4
作者：
Idelman G;Smith DLH;Zucker SD
通讯作者：
Zucker SD
影响因子：
3
作者：
Evan, Andrew P.
通讯作者：
Evan, Andrew P.
升高的内皮缺氧诱导因子1α有助于肾小球损伤，并促进高血压慢性肾脏疾病。
DOI：
10.1161/hypertensionaha.115.05578
发表时间：
2015-07
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Luo R;Zhang W;Zhao C;Zhang Y;Wu H;Jin J;Zhang W;Grenz A;Eltzschig HK;Tao L;Kellems RE;Xia Y
通讯作者：
Xia Y