HIGH GLUCOSE-CONCENTRATION INDUCES THE OVEREXPRESSION OF TRANSFORMINGGROWTH-FACTOR-BETA THROUGH THE ACTIVATION OF A PLATELET-DERIVED GROWTH-FACTOR LOOP IN HUMAN MESANGIAL CELLS

High glucose concentration has been shown to induce the overexpression of transforming growth factor (TGF)-beta 1 mRNA and protein in differ ent cell types, including murine mesangial cells, thus possibly accoun ting for the expansion of mesangial extracellular matrix observed in d iabetic glomerulopathy. In the present study, we evaluated platelet-de rived growth factor (PDGF) B-chain and PDGF-beta receptor gene express ion in human mesangial cells (HMCs) exposed to different concentration s of glucose and then sought a possible relationship between a PDGF lo op and the modulation of TGF-beta 1 expression. NMC [H-3]thymidine inc orporation was upregulated by 30 mmol/L glucose (HG) up to 24 hours, w hereas it was significantly inhibited at later time points. Neutralizi ng antibodies to PDGF BE abolished the biphasic response to HG, wherea s anti-TGF-beta antibodies reversed only the late inhibitory effect of hyperglycemic medium. HG induced an early and persistent increase of PDGF B-chain gene expression, as evaluated by reverse transcriptase po lymerase chain reaction, whereas PDGF-beta receptor mRNA increased by twofold after 6 hours, thereafter declining at levels 70% lower than i n controls after 24 hours. I-125-Labeled PDGF BE binding studies in HM Cs exposed to HG for 24 hours confirmed the decrease of PDGF-beta rece ptor expression. TGF-beta 1-specific transcripts showed 43 and 78% inc reases after 24 and 48 hours of incubation in HG, respectively, which was markedly diminished by anti-PDGF BE neutralizing antibodies or sur amin. We conclude that NG induces an early activation of a PDGF loop t hat, in turn, causes an increase of TGF-beta 1 gene expression, thus m odulating both HMC proliferation and mesangial matrix production.