High glucose-induced TGF-beta 1 regulates mesangial production of heparan sulfate proteoglycan

V. Kolm, U. Sauer, B. Olgemooller and E. D. Schleicher Institute for Diabetes Research, Department of Biochemistry, Academic Hospital, University of Munich, Germany. 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.