Vascular endothelial growth factor-C and -D are involved in lymphangiogenesis in mouse unilateral ureteral obstruction

Kidney Int. 2013 Jan;83(1):50-62. doi: 10.1038/ki.2012.312. Epub 2012 Aug 29.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Clodronic Acid / pharmacology
  • Disease Models, Animal
  • Endothelium, Lymphatic / pathology
  • Fibrosis
  • Kidney / metabolism
  • Kidney / pathology
  • Lymphangiogenesis / physiology*
  • Macrophages / drug effects
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Signal Transduction / physiology*
  • Transforming Growth Factor beta1 / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology
  • Ureteral Obstruction / pathology*
  • Ureteral Obstruction / physiopathology*
  • Vascular Endothelial Growth Factor C / physiology*
  • Vascular Endothelial Growth Factor D / physiology*


  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor D
  • Clodronic Acid