title: Renal heparan sulfate proteoglycans modulate fibroblast growth factor 2 signaling in experimental chronic transplant dysfunction.
abstract: 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.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Kirankumar
authors.initials: K
authors.lastname: Katta
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Miriam
authors.initials: M
authors.lastname: Boersema
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Saritha
authors.initials: S
authors.lastname: Adepu
authors.affiliation: Immunology Section, Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Heleen
authors.initials: H
authors.lastname: Rienstra
authors.affiliation: Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Johanna W A M
authors.initials: JWAM
authors.lastname: Celie
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Rik
authors.initials: R
authors.lastname: Mencke
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Grietje
authors.initials: G
authors.lastname: Molema
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: van Goor
authors.affiliation: Department of Nephrology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Jo H M
authors.initials: JHM
authors.lastname: Berden
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Jan-Luuk
authors.initials: JL
authors.lastname: Hillebrands
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. Electronic address: j.van.den.born@umcg.nl.
authors.forename: Jacob
authors.initials: J
authors.lastname: van den Born
mesh_terms: D064591:Allografts / Q000378:metabolism / Q000473:pathology; D020816:Amino Acid Motifs; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002908:Chronic Disease; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects*; D050527:Mesangial Cells / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011509:Proteoglycans / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D016222:Fibroblast Growth Factor 2; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D011509:Proteoglycans; C071927:perlecan