Heparin alters epidermal growth factor metabolism in cultured rat glomerular epithelial cells

Extracellular matrix plays an important role in regulating cell growth. The authors have previously shown that heparin and heparan sulfate inhibit glomerular visceral epithelial cell (GEC) growth and that epidermal growth factor (EGF) can partially reverse the effect of heparin. The authors studied EGF processing by GEC in an attempt to clarify the mechanism by which heparin inhibits GEC growth. Control and heparin-treated GEC rapidly internalized 125I-EGF (within 15 minutes). In heparin-treated cells, 125I-EGF reappeared on the cell surface during the course of a 1-hour incubation and the percent internalized dropped significantly to 59.0% +/- 8.6%, suggesting recycling of 125I-EGF-occupied receptors. After incubation with 125I-EGF, heparin-treated cells also released significantly more cpm of 125I into EGF-free medium (2526 +/- 68 cpm-H; 903 +/- 32-C). Analysis of the released 125I by gel filtration chromatography showed more totally degraded 125I-EGF in media from heparin-treated cells (30.8% +/- 1.6% in heparin-treated versus 17.8% +/- 3.2 in control; P less than 0.05). Analysis of EGF-induced dimerization of receptors showed no effect of heparin on this ratio. These studies suggest that heparin decreases GEC response to EGF by accelerating its uptake and degradation. Matrix alterations in disease states may thus play a role in altering cell responsiveness to growth factors.