INSULIN-LIKE GROWTH-FACTOR-I AND GROWTH-FACTOR-II STIMULATE EXTRACELLULAR-MATRIX PRODUCTION IN HUMAN GLOMERULAR MESANGIAL CELLS - COMPARISON WITH TRANSFORMING GROWTH-FACTOR-BETA

An enhanced paracrine/autocrine activity of the insulin-like growth fa ctor (IGF) system within the glomerulus has been implicated together w ith up-regulation of transforming growth factor-beta (TGF beta) in the pathogenesis of diabetic glomerular disease. This would imply their a bility to modulate extracellular matrix (ECM) and cell turnover at the mesangial level, but the direct effects of IGFs on ECM production hav e not been demonstrated to date. These experiments in cultured human m esangial cells were aimed at assessing the effects of IGF-I and IGF-II , compared with those of TGF beta, on 1) ECM medium accumulation and g ene expression, and 2) total protein synthesis and cell proliferation. Human mesangial cells were grown to subconfluence, growth arrested fo r 48 h, and then exposed for 4-24 h to serum-free medium containing IG F-I (10(-7)-10(-11) M), IGF-II (10(-7)-10(-11) M), TGF beta (10(-9)-10 (-11) M), or various combinations of two of these growth factors (10(- 9) M). All three growth factors dose dependently increased ECM protein and messenger RNA levels. The combination of either IGF-I or IGF-II w ith TGF beta, but not the two IGFs together, produced additive effects on matrix production. Total protein synthesis was also increased by I GF-I, IGF-II, and TGF beta, although to a lesser extent than ECM produ ction, whereas cell proliferation was enhanced by IGFs but not TGF bet a. These results demonstrate that IGF-I and IGF-II are effective, alth ough less potent than TGF beta, in stimulating the production of the E CM components that accumulate in the mesangial region during the cours e of diabetic glomerular disease.