Transforming growth factor-β induces vascular endothelial growth factor-C expression leading to lymphangiogenesis in rat unilateral ureteral obstruction

Kidney Int. 2012 May;81(9):865-79. doi: 10.1038/ki.2011.464. Epub 2012 Jan 18.

Abstract

Inflammation is recognized as an important contributor to lymphangiogenesis; however, in tubulointerstitial lesions in human chronic kidney diseases, this process is better correlated with the presence of myofibroblasts rather than macrophages. As little is known about the interaction between lymphangiogenesis and renal fibrosis, we utilized the rat unilateral ureteral obstruction model to analyze inflammation, fibrosis, lymphangiogenesis, and growth factor expression. Additionally, we determined the relationship between vascular endothelial growth factor-C (VEGF-C), an inducer of lymphangiogenesis, and the profibrotic factor, transforming growth factor-β1 (TGF-β1). The expression of both TGF-β1 and VEGF-C was detected in tubular epithelial and mononuclear cells, and gradually increased, peaking 14 days after ureteral obstruction. The kinetics and localization of VEGF-C were similar to those of TGF-β1, and the expression of these growth factors and lymphangiogenesis were linked with the progression of fibrosis. VEGF-C expression was upregulated by TGF-β1 in cultured proximal tubular epithelial cells, collecting duct cells, and macrophages. Both in vitro and in vivo, the induction of VEGF-C along with the overall appearance of lymphatics in vivo was specifically suppressed by the TGF-β type I receptor inhibitor LY364947. Thus, TGF-β1 induces VEGF-C expression, which leads to lymphangiogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Disease Models, Animal
  • Fibroblasts / metabolism
  • Fibrosis
  • Humans
  • Kidney Tubules / drug effects
  • Kidney Tubules / metabolism*
  • Kidney Tubules / pathology
  • Kidney Tubules / physiopathology
  • Lymphangiogenesis* / drug effects
  • Macrophages / metabolism
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyrazoles / pharmacology
  • Pyrroles / pharmacology
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Real-Time Polymerase Chain Reaction
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors
  • Receptors, Transforming Growth Factor beta / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Time Factors
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism*
  • Up-Regulation
  • Ureteral Obstruction / genetics
  • Ureteral Obstruction / metabolism*
  • Ureteral Obstruction / pathology
  • Ureteral Obstruction / physiopathology
  • Vascular Endothelial Growth Factor C / genetics
  • Vascular Endothelial Growth Factor C / metabolism*

Substances

  • Ly-364947
  • Lyve1 protein, rat
  • Membrane Glycoproteins
  • Pdpn protein, rat
  • Pyrazoles
  • Pyrroles
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, Transforming Growth Factor beta
  • TGFB1 protein, human
  • Tgfb1 protein, rat
  • Transforming Growth Factor beta1
  • Vascular Endothelial Growth Factor C
  • vascular endothelial growth factor C, mouse
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • Tgfbr1 protein, rat