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

Abstract

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.

VEGFC negatively regulates the growth and aggressiveness of medulloblastoma cells

“…Our results seem inconsistent with gene expression in patients. This demonstrates the complexity of a whole tumor, the role of the tumor microenvironment, blood, lymphatic and immune systems and of phenomena such as hypoxia, which are not totally understood yet [59][60][61] . The effect of tumor microenvironment has previously been demonstrated in the lab.…”

Hypoxia: Overview on Hypoxia-Mediated Mechanisms with a Focus on the Role of HIF Genes

“…The two molecules have also been significantly associated with HIF-1α expression in various cancers through immunohistochemical techniques [106,107]. Molecular analysis showed that hypoxic conditions determines the transcription at mRNA level of VEGF-C and VEGF-D in lymphatic endothelial cells [108], where in macrophages, HIF-1α can manage the expression of VEGF-C via a hypoxia response element (HRE) sequence located within the promoter of the VEGF-C gene [109]. The expression of the same gene in hypoxia can be induced also independently of HIF-1α regulation through a mechanisms dependent of an internal ribosome entry site [110].…”

Upregulation of p16, Bax and Bcl-2 mRNAExpression Associated with Epithelial Apoptosis and Myofibroblast Proliferation in Kidney Fibrosis Model in Mice

“…There is a decrease in renal blood flow and glomerular filtration rate (GFR) during the first 3 h after UUO, followed by a progressive increase in interstitial inflammatory cell inflltration occurring 12 h to 14 days after the obstruction and by day 3, inflammation, microvascular damage and increased numbers of fibroblasts are apparent ( 12 ). Interstitial fibrosis occurs between days 5 and 12 and reaches its peak on day 19 ( 13 ).…”