| First Author | Guo YC | Year | 2017 |
| Journal | Am J Pathol | Volume | 187 |
| Issue | 8 | Pages | 1736-1749 |
| PubMed ID | 28627412 | Mgi Jnum | J:244416 |
| Mgi Id | MGI:5913195 | Doi | 10.1016/j.ajpath.2017.04.007 |
| Citation | Guo YC, et al. (2017) 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-1alpha/Vascular Endothelial Growth Factor-C Expression. Am J Pathol 187(8):1736-1749 |
| abstractText | 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)-1alpha is downstream of PI3K-AKT-mTOR signaling. HIF-1alpha 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-1alpha expression, which then drives VEGF-C expression to promote lymphangiogenesis. |
