title: High glucose-induced TGF-beta 1 regulates mesangial production of heparan sulfate proteoglycan.
abstract: Previous investigations have demonstrated that growing mesangial cells in high glucose concentration stimulates extracellular matrix synthesis and also increases the expression of transforming growth factor-beta (TGF-beta). We examined the effects of hyperglycemia on mesangial proliferation and heparan sulfate proteoglycan (HSPG) and fibronectin production. Prolonged exposure of mesangial cells to increasing glucose concentrations resulted in dose-dependent effects on growth inhibition and stimulation of matrix production. Treatment of mesangial cells with high glucose-conditioned medium or with TGF-beta 1 mimicked the effects of high-glucose incubation. Furthermore, TGF-beta 1 caused a dose-dependent increase in HSPG mRNA levels. The high-glucose effects on mesangial cells were preceded by an increase in total TGF-beta 1 protein. The presence of TGF-beta 1 antisense oligonucleotide attenuated the glucose-mediated effects on mesangial proliferation and matrix production. The data show that even moderately elevated glucose concentrations appear to affect the mesangial cells. The results indicate that 1) TGF-beta 1 protein production is necessary to obtain the high glucose-induced effects and 2) TGF-beta 1 stimulates mesangial HSPG expression and production. Because these effects may be attenuated by oligonucleotides antisense to TGF-beta 1, the results suggest a possible way for effective intervention in TGF-beta-mediated glomerulosclerosis.
authors.affiliation: Institute for Diabetes Research, Department of Biochemistry, Academic Hospital, University of Munich, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Kolm
authors.forename: U
authors.initials: U
authors.lastname: Sauer
authors.forename: B
authors.initials: B
authors.lastname: Olgemöller
authors.forename: E D
authors.initials: ED
authors.lastname: Schleicher
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005353:Fibronectins / Q000096:biosynthesis; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D009994:Osmolar Concentration; D011108:Polymers / Q000494:pharmacology; D011509:Proteoglycans / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013552:Swine; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*
chemical_list: D017077:Culture Media, Conditioned; D005353:Fibronectins; D005947:Glucose; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D016376:Oligonucleotides, Antisense; D011108:Polymers; D011509:Proteoglycans; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C024617:polyol