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./nMethods: 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./nResults: 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./nConclusions: 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.

中文翻译：

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AhR激活通过减少M1巨噬细胞极化并促进M2巨噬细胞极化来减轻草酸钙肾钙化病

草酸钙（CaOx）晶体可引发肾脏损伤，从而导致肾钙化病的发病机理。浸润性巨噬细胞的表型可能影响CaOx介导的肾炎性损伤以及晶体沉积。芳烃受体（AhR）如何调节炎症和巨噬细胞极化已广为人知。然而，如何调节CaOx肾钙化病尚不清楚。小鼠腹膜内注射乙醛酸，建立或不治疗AhR激活剂6-甲酰基吲哚（3,2-b）咔唑（FICZ）的CaOx肾钙化模型。正电子发射断层扫描计算机断层扫描（PET-CT）成像，高碘酸席夫（PAS）染色和偏光光学显微镜用于评估小鼠肾脏的肾脏损伤和晶体沉积。Western印迹，免疫荧光，染色质免疫沉淀，微小RNA-荧光原位杂交，以及萤光素酶报道测定法用于分析偏振状态和macrophage./n的调控机制结果：给予FICZ后，在鼠CaOx肾钙化病模型中，AhR表达显着上调，并与干扰素调节因子1（IRF1）和低氧诱导因子1-α（HIF-1α）水平负相关。此外，AhR激活抑制体外IRF1和HIF-1α水平并降低M1巨噬细胞极化。在机理上，生物信息学分析和染色质免疫沉淀试验证实，AhR可以与miR-142a启动子结合以转录激活miR-142a。此外，荧光素酶报告基因测定验证了miR-142A通过直接靶向它们的3'非翻译regions./n抑制IRF1和HIF-1α表达结论： 我们的结果表明，AhR激活可通过AhR-miR-142a-IRF1 /HIF-1α途径减少M1巨噬细胞极化并促进M2巨噬细胞极化，从而抑制CaOx肾钙化。