Theranostics 2020; 10(26):12011-12025. doi:10.7150/thno.51144 This issue Cite

Research Paper

AhR activation attenuates calcium oxalate nephrocalcinosis by diminishing M1 macrophage polarization and promoting M2 macrophage polarization

Xiaoqi Yang1#, Haoran Liu1,2#, Tao Ye1, Chen Duan1, Peng Lv1, Xiaoliang Wu1, Jianhe Liu2, Kehua Jiang3, Hongyan Lu4, Huan Yang1, Ding Xia1, Ejun Peng1, Zhiqiang Chen1, Kun Tang1✉, Zhangqun Ye1

1. Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
2. Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
3. Department of Urology, Guizhou Provincial People's Hospital, Guiyang, China.
4. Department of Urology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
#These authors contributed equally to this work.

Citation:
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. AhR activation attenuates calcium oxalate nephrocalcinosis by diminishing M1 macrophage polarization and promoting M2 macrophage polarization. Theranostics 2020; 10(26):12011-12025. doi:10.7150/thno.51144. https://www.thno.org/v10p12011.htm
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Abstract

Graphic abstract

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.

Keywords: AhR, IRF1, HIF-1α, Macrophage, Nephrocalcinosis


Citation styles

APA
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. (2020). AhR activation attenuates calcium oxalate nephrocalcinosis by diminishing M1 macrophage polarization and promoting M2 macrophage polarization. Theranostics, 10(26), 12011-12025. https://doi.org/10.7150/thno.51144.

ACS
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. AhR activation attenuates calcium oxalate nephrocalcinosis by diminishing M1 macrophage polarization and promoting M2 macrophage polarization. Theranostics 2020, 10 (26), 12011-12025. DOI: 10.7150/thno.51144.

NLM
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. AhR activation attenuates calcium oxalate nephrocalcinosis by diminishing M1 macrophage polarization and promoting M2 macrophage polarization. Theranostics 2020; 10(26):12011-12025. doi:10.7150/thno.51144. https://www.thno.org/v10p12011.htm

CSE
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. 2020. AhR activation attenuates calcium oxalate nephrocalcinosis by diminishing M1 macrophage polarization and promoting M2 macrophage polarization. Theranostics. 10(26):12011-12025.

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