Renal heparan sulfate proteoglycans modulate fibroblast growth factor 2 signaling in experimental chronic transplant dysfunction

Am J Pathol. 2013 Nov;183(5):1571-1584. doi: 10.1016/j.ajpath.2013.07.030. Epub 2013 Sep 11.


Depending on the glycan structure, proteoglycans can act as coreceptors for growth factors. We hypothesized that proteoglycans and their growth factor ligands orchestrate tissue remodeling in chronic transplant dysfunction. We have previously shown perlecan to be selectively up-regulated in the glomeruli and arteries in a rat renal transplantation model. Using the same model, here we present quantitative RT-PCR profiling data on proteoglycans and growth factors from laser-microdissected glomeruli, arterial tunicae mediae, and neointimae at 12 weeks after transplantation. In glomeruli and neointimae of allografts, selective induction of the matrix heparan sulfate proteoglycan perlecan was observed, along with massive accumulation of fibroblast growth factor 2 (FGF2). Profiling the heparan sulfate polysaccharide side chains revealed conversion from a non-FGF2-binding heparan sulfate phenotype in control and isografted kidneys toward a FGF2-binding phenotype in allografts. In vitro experiments with perlecan-positive rat mesangial cells showed that FGF2-induced proliferation is dependent on sulfation and can be inhibited by exogenously added heparan sulfate. These findings indicate that matrix proteoglycans such as perlecan serve as functional docking platforms for FGF2 in chronic transplant dysfunction. We speculate that heparin-like glycomimetics could be a promising intervention to retard development of glomerulosclerosis and neointima formation in chronic transplant dysfunction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allografts / metabolism
  • Allografts / pathology
  • Amino Acid Motifs
  • Animals
  • Cell Membrane / metabolism
  • Cell Proliferation
  • Chronic Disease
  • Female
  • Fibroblast Growth Factor 2 / metabolism*
  • Heparan Sulfate Proteoglycans / metabolism
  • Heparitin Sulfate / metabolism*
  • Kidney / metabolism*
  • Kidney / pathology*
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / pathology
  • Kidney Transplantation / adverse effects*
  • Mesangial Cells / metabolism
  • Mesangial Cells / pathology
  • Protein Binding
  • Proteoglycans / metabolism*
  • Rats
  • Signal Transduction*
  • Up-Regulation


  • Heparan Sulfate Proteoglycans
  • Proteoglycans
  • Fibroblast Growth Factor 2
  • perlecan
  • Heparitin Sulfate