Lymphatic remodeling in
inflammation has been found in tracheal
mycoplasma infection, human kidney transplant, skin
inflammation,
peritonitis, and corneal
inflammation. Here we investigated lymphangiogenesis in fibrotic area in unilateral
ureteral obstruction, a model of progressive renal
fibrosis, and evaluated the roles of
vascular endothelial growth factor (
VEGF)-C and -D in the obstructed kidney. Compared to
sham-operated mice, the number of LYVE-1-positive lymphatic vessels, the proliferation of LYVE-1-positive lymphatic endothelial cells, along with
VEGF-C and -D
mRNA expression were all significantly increased following
ureteral obstruction. Depletion of macrophages with
clodronate decreased lymphangiogenesis in the obstructed kidney.
VEGF-C expression was higher in M2- than in M1-polarized macrophages from bone marrow-derived macrophages, and also increased in Raw 264.7 or renal proximal tubule cells by stimulation with TGF-β1 or TNF-α.
VEGF-D reversed the inhibitory effect of TGF-β1 on
VEGF-C-induced migration, capillary-like tube formation, and proliferation of human lymphatic endothelial cells. Additionally, the blockade of
VEGF-C and
VEGF-D signaling decreased obstruction-induced lymphangiogenesis. Thus,
VEGF-C and
VEGF-D are associated with lymphangiogenesis in the fibrotic kidney in a mouse model of
ureteral obstruction.