title: Glucose-induced fibronectin and collagen type III expression in renal fibroblasts can occur independent of TGF-beta1.
abstract: BACKGROUND
  Various renal cell types have been shown to contribute to the excessive matrix deposition observed in diabetic nephropathy. The present study examined the effect of high ambient glucose and transforming growth factor-beta1 (TGF-beta1) on matrix production by human renal fibroblasts.
  
  
  METHODS
  Human renal fibroblasts (TK173) were used to examine the effects of high glucose and TGF-beta1 on fibronectin and collagen type III expression. Stable transfectants were generated of TK173 cells expressing a dominant negative TGF-beta type II receptor. Matrix components were measured in enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR).
  
  
  RESULTS
  Fibronectin secretion by renal fibroblasts was increased upon exposure to high glucose, but with delayed kinetics compared to TGF-beta1-induced fibronectin. Exposure to high glucose resulted in an increased secretion of latent TGF-beta1. However, treatment with neutralizing pan-specific anti-TGF-beta antibodies could not attenuate the effects of glucose. Furthermore, collagen type III was up-regulated by high glucose, but not by TGF-beta1. Importantly, fibroblasts expressing a dominant negative TGF-beta type II receptor were defective in TGF-beta1-induced fibronectin production, whereas glucose-induced fibronectin and collagen type III were unaffected.
  
  
  CONCLUSIONS
  These data show that in renal fibroblasts exposure to high glucose can increase matrix production independent of endogenous TGF-beta1. Although glucose activation is accompanied by an increased production of latent TGF-beta1, which can have an important role in vivo, the data suggest involvement of alternative growth factors in the mechanism by which hyperglycemic conditions can modulate matrix accumulation in diabetic nephropathy.
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lam
authors.forename: Nicole A M
authors.initials: NA
authors.lastname: Verhagen
authors.forename: Frank
authors.initials: F
authors.lastname: Strutz
authors.forename: Johan W
authors.initials: JW
authors.lastname: van der Pijl
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Daha
authors.forename: Cees
authors.initials: C
authors.lastname: van Kooten
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D002461:Cell Line, Transformed; D024061:Collagen Type III / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D005353:Fibronectins / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism / Q000503:physiopathology*; D007668:Kidney / Q000166:cytology*; D007700:Kinetics; D012333:RNA, Messenger / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000906:Antibodies; D024061:Collagen Type III; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D005947:Glucose