INCREASED ACTIVITY OF THE INSULIN-LIKE GROWTH-FACTOR SYSTEM IN MESANGIAL CELLS CULTURED IN HIGH GLUCOSE CONDITIONS - RELATION TO GLUCOSE-ENHANCED EXTRACELLULAR-MATRIX PRODUCTION

Recent evidence suggests that several growth factors participate in di abetic glomerular disease by mediating increased extracellular matrix accumulation and altered cell growth and turnover leading to mesangial expansion. Transforming growth factor (TGF)-beta has been demonstrate d to be upregulated both in vivo and in vitro, whereas studies on the activity of the renal insulin-like growth factor (IGF) system in exper imental diabetes have provided conflicting results. We investigated th e effects of prolonged exposure (4 weeks) of cultured human and rat me sangial cells to high (30 mmol/l) glucose vs iso-osmolar mannitol or n ormal (5.5 mmol/l) glucose levels on: 1) the autocrine/paracrine activ ity of the IGF system (as assessed by measuring IGF-I and II, IGF-I an d II receptors, and IGF binding proteins); and, in parallel, on 2) TGF -beta 1 gene expression; 3) matrix production; and 4) cell proliferati on. High glucose levels progressively increased the medium content of IGF-I and the mRNA levels for IGF-I and IGF-II, increased IGF-I and IG F-II binding and IGF-I receptor gene expression, and reduced IGF bindi ng protein production. TGF-beta 1 transcripts and matrix accumulation and gene expression were increased in parallel, whereas cell prolifera tion was reduced. Iso-osmolar mannitol did not affect any of the above parameters. These experiments demonstrated that high glucose levels i nduce enhanced mesangial IGF activity, together with enhanced TGF-beta 1 gene expression, increased matrix production, and reduced cell prol iferation. It is possible that IGFs participate in mediating diabetes- induced changes in matrix turnover leading to mesangial expansion, by acting in a paracrine/autocrine fashion within the glomerulus.