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
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
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巨噬细胞通过 C-C 基序趋化因子受体 2 依赖性磷脂酰肌醇 3-激酶-AKT 雷帕霉素信号传导和缺氧诱导因子 1 的机制靶标调节单侧输尿管梗阻诱导的肾淋巴管生成
DOI：
10.1016/j.ajpath.2017.04.007
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发表时间：
2017-08-01
影响因子：
6
通讯作者：
Wang, Cong-Yi
中科院分区：
文献类型：
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作者：
Guo, Yan-Chao;Zhang, Meng;Wang, Cong-Yi
慢性肾脏病患者的肾纤维化过程中会发生淋巴管生成，淋巴管的形成需要血管内皮生长因子（VEGF）-C；然而，其根本机制仍不清楚。我们证明巨噬细胞可以通过 C-C 基序趋化因子受体 2 (CCR2) 介导的信号传导表达高水平的 VEGF-C，从而调节单侧输尿管梗阻 (UUO) 诱导的肾淋巴管生成。 Ccr2 缺陷的小鼠在 UUO 诱导后表现出淋巴管生成受抑制以及肾损伤和纤维化减弱。 UUO 诱导后浸润的巨噬细胞产生了有利于淋巴管生成的微环境，这可能取决于 Ccr2 的表达。机制研究表明，CCR2 是巨噬细胞响应其配体单核细胞趋化蛋白 1 刺激而激活磷脂酰肌醇 3 激酶 (PI3K)-AKT 机械靶标雷帕霉素 (mTOR) 信号传导所必需的，而缺氧诱导因子 (HIF)-1 α 是 PI3K-AKT-mTOR 信号传导的下游。 HIF-1α直接与VEGF-C启动子结合，驱动其表达，增强淋巴管生成。总的来说，我们描述了巨噬细胞中的一种新型调控网络，其中 CCR2 激活 PI3K-AKT-mTOR 信号传导以介导 HIF-1 α 表达，然后驱动 VEGF-C 表达以促进淋巴管生成。
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)-1 alpha is downstream of PI3K-AKT-mTOR signaling. HIF-1 alpha 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-1 alpha expression, which then drives VEGF-C expression to promote lymphangiogenesis.