Macrophages Regulate Unilateral Ureteral Obstruction-Induced Renal Lymphangiogenesis through C-C Motif Chemokine Receptor 2-Dependent Phosphatidylinositol 3-Kinase-AKT-Mechanistic Target of Rapamycin Signaling and Hypoxia-Inducible Factor-1α/Vascular Endothelial Growth Factor-C Expression
| Autor: | Fa-Xi Wang, Jing Liu, Meng Zhang, Kun Huang, Yan-Chao Guo, Guang-Chang Pei, Ying Yao, Fei Sun, Jia Song, Yi Wang, Shu Zhang, Fengming Zhu, Nuruliarizki Shinta Pandupuspitasari, Cong-Yi Wang, Ying Zhang, Qilin Yu, Fei Xiong, Xiaoyu He, Ping Yang |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
CCR2 Receptors CCR2 Vascular Endothelial Growth Factor C Biology urologic and male genital diseases Kidney Pathology and Forensic Medicine 03 medical and health sciences chemistry.chemical_compound Chemokine receptor Mice Phosphatidylinositol 3-Kinases Animals Lymphangiogenesis Mechanistic target of rapamycin PI3K/AKT/mTOR pathway Mice Knockout Macrophages TOR Serine-Threonine Kinases Hypoxia-Inducible Factor 1 alpha Subunit Fibrosis Vascular endothelial growth factor 030104 developmental biology Hypoxia-inducible factors chemistry Vascular endothelial growth factor C Immunology biology.protein Cancer research Proto-Oncogene Proteins c-akt Signal Transduction Ureteral Obstruction |
| Zdroj: | The American journal of pathology. 187(8) |
| ISSN: | 1525-2191 |
| Popis: | Lymphangiogenesis occurs during renal fibrosis in patients with chronic kidney diseases and vascular endothelial growth factor (VEGF)-C is required for the formation of lymphatic vessels; however, the underlying mechanisms remain unclear. We demonstrate that macrophages can regulate unilateral ureteral obstruction (UUO)-induced renal lymphangiogenesis by expressing high levels of VEGF-C by C-C motif chemokine receptor 2 (CCR2)-mediated signaling. Mice deficient in Ccr2 manifested repressed lymphangiogenesis along with attenuated renal injury and fibrosis after UUO induction. The infiltrated macrophages after UUO induction generated a microenvironment in favor of lymphangiogenesis, which likely depended on Ccr2 expression. Mechanistic studies revealed that CCR2 is required for macrophages to activate phosphatidylinositol 3-kinase (PI3K)-AKT-mechanistic target of rapamycin (mTOR) signaling in response to its ligand monocyte chemoattractant protein 1 stimulation, whereas hypoxia-inducible factor (HIF)-1α is downstream of PI3K-AKT-mTOR signaling. HIF-1α directly bound to the VEGF-C promoter to drive its expression to enhance lymphangiogenesis. Collectively, we characterized a novel regulatory network in macrophages, in which CCR2 activates PI3K-AKT-mTOR signaling to mediate HIF-1α expression, which then drives VEGF-C expression to promote lymphangiogenesis. |
| Databáze: | OpenAIRE |
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