Myeloid-specific targeting of Notch ameliorates murine renal fibrosis via reduced infiltration and activation of bone marrow-derived macrophage
| Autor: | Shi-Qian Liang, Hong-Yan Qin, Hua Han, Yu-Chen Ye, Peng Zhang, Jun-Long Zhao, Peng-Fei Ma, Yuanyuan Wang, Dong-Jie An, Xiaowei Liu, Ying-Ying Lu, Yali Jiang |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
CCR2 Epithelial-Mesenchymal Transition Receptors CCR2 Population lcsh:Animal biochemistry Notch signaling pathway Bone marrow-derived macrophage Kidney Biochemistry 03 medical and health sciences Mice 0302 clinical medicine Drug Discovery Renal fibrosis medicine Animals lcsh:QH573-671 education lcsh:QP501-801 Notch signaling Cells Cultured education.field_of_study Receptors Notch lcsh:Cytology Chemistry Monocyte Macrophages EMT Epithelial Cells Cell Biology renal fibrosis Fibrosis Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Immunoglobulin J Recombination Signal Sequence-Binding Protein Cancer research Kidney Diseases heterogeneity Myofibroblast Biotechnology Research Article Ureteral Obstruction |
| Zdroj: | Protein & Cell Protein & Cell, Vol 10, Iss 3, Pp 196-210 (2018) |
| ISSN: | 1674-8018 1674-800X |
| Popis: | Macrophages play critical roles in renal fibrosis. However, macrophages exhibit ontogenic and functional heterogeneities, and which population of macrophages contributes to renal fibrosis and the underlying mechanisms remain unclear. In this study, we genetically targeted Notch signaling by disrupting the transcription factor recombination signal binding protein-Jκ (RBP-J), to reveal its role in regulation of macrophages during the unilateral ureteral obstruction (UUO)-induced murine renal fibrosis. Myeloid-specific disruption of RBP-J attenuated renal fibrosis with reduced extracellular matrix deposition and myofibroblast activation, as well as attenuated epithelial-mesenchymal transition, likely owing to the reduced expression of TGF-β. Meanwhile, RBP-J deletion significantly hampered macrophage infiltration and activation in fibrotic kidney, although their proliferation appeared unaltered. By using macrophage clearance experiment, we found that kidney resident macrophages made negligible contribution, but bone marrow (BM)-derived macrophages played a major role in renal fibrogenesis. Further mechanistic analyses showed that Notch blockade reduced monocyte emigration from BM by down-regulating CCR2 expression. Finally, we found that myeloid-specific Notch activation aggravated renal fibrosis, which was mediated by CCR2+ macrophages infiltration. In summary, our data have unveiled that myeloid-specific targeting of Notch could ameliorate renal fibrosis by regulating BM-derived macrophages recruitment and activation, providing a novel strategy for intervention of this disease. Electronic supplementary material The online version of this article (10.1007/s13238-018-0527-6) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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