title: Inhibiting albumin glycation in vivo ameliorates glomerular overexpression of TGF-beta1.
abstract: BACKGROUND
  Glycated albumin has been causally linked to the pathobiology of diabetic renal disease through its ability to stimulate the expression of transforming growth factor-beta1 (TGF-beta1), activate protein kinase C (PKC) and extracellular signal-regulated kinase (ERK), and promote production of extracellular matrix proteins in cultured glomerular cells. Whether glycated albumin modulates glomerular TGF-beta1 expression in vivo is not known. To address this issue, we assessed glomerular TGF-beta1 expression and pathology in response to reducing the burden of glycated albumin in vivo.
  
  
  METHODS
  We measured serum glycated albumin, urine protein, glomerular TGF-beta1 expression and morphometry, and collagen IV and fibronectin mRNA in db/m and db/db controls and in db/db mice treated for eight weeks with a synthetic compound that inhibits the condensation of glucose with albumin.
  
  
  RESULTS
  In situ hybridization studies showed markedly increased glomerular TGF-beta1 mRNA in control db/db mice, which was significantly reduced in db/db mice treated for eight weeks with test compound. The treatment protocol, which normalized serum glycated albumin, concomitantly reduced the elevated protein excretion and the renal overexpression of mRNAs encoding fibronectin and collagen IV, and significantly decreased the mesangial matrix expansion, observed in db/db control animals.
  
  
  CONCLUSIONS
  These findings, to our knowledge, provide the first evidence that glomerular overexpression of TGF-beta1 in diabetes derives at least in part from elevated glycated albumin concentrations, and can be partially suppressed by inhibiting the formation of this glycated protein. The results further suggest that glycated albumin has an important nephropathogenic role in diabetes that is operative, and can be therapeutically addressed, independent of glycemic status.
authors.affiliation: Institute of Metabolic Research and Exocell, University City Science Center, Philadelphia, PA 19104, USA. drmpcohen@aol.com
authors.forename: Margo P
authors.initials: MP
authors.lastname: Cohen
authors.forename: Fuad N
authors.initials: FN
authors.lastname: Ziyadeh
authors.forename: Soon Won
authors.initials: SW
authors.lastname: Hong
authors.forename: Clyde W
authors.initials: CW
authors.lastname: Shearman
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hud
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Lautenslager
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Iglesias-de la Cruz
authors.forename: Sheldon
authors.initials: S
authors.lastname: Chen
mesh_terms: D000419:Albuminuria / Q000209:etiology; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000652:urine; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D017127:Glycation End Products, Advanced; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains / Q000235:genetics; D010648:Phenylacetates / Q000494:pharmacology*; D012709:Serum Albumin / Q000037:antagonists & inhibitors*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D000093423:Glycated Serum Albumin
chemical_list: C518289:2-(3-chlorophenylamino)phenylacetic acid; D000814:Aniline Compounds; D016326:Extracellular Matrix Proteins; D017127:Glycation End Products, Advanced; D010648:Phenylacetates; D012709:Serum Albumin; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D004008:Diclofenac; D000093423:Glycated Serum Albumin