HEPARIN-BINDING EPIDERMAL GROWTH FACTOR-LIKE GROWTH-FACTOR IN EXPERIMENTAL-MODELS OF MEMBRANOUS AND MINIMAL CHANGE NEPHROPATHY

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a recently described member of the epidermal growth factor (EGF) fami ly. It binds to heparan sulfate proteoglycans via a cationic domain an d is a potent mitogen for epithelial cells, fibroblasts and vascular s mooth muscle cells. In the present study we have attempted to identify changes in quantity and distribution of HB-EGF in two models of acute glomerular epithelial cell injury, using Western blotting, immunohist ochemistry and in situ hybridization. Prior to disease induction, West ern blots showed some expression of HB-EGF protein within glomeruli. W ithin the first three days in the acute puromycin aminonucleoside (PAN ) and passive heymann nephritis (PHN) models, immunohistochemistry and in situ hybridization demonstrated an up-regulation of HB-EGF mRNA an d protein in glomerular epithelial cells (GEC). In both cases, increas ed protein and mRNA was found prior to the onset of proteinuria and co ntinued until day 21 post-induction, the last time point studied. Earl y in the course of the models, HB-EGF was localized to the cytoplasm o f glomerular epithelial cells. At day 21 however, HB-EGF protein was d istributed in a nodular pattern within GEC and along the glomerular ba sement membrane (GBM) in both models, suggesting that the secreted for m might bind to the membrane. The increase in HB-EGF protein within gl omeruli was confirmed by Western blots of glomerular membrane protein which. however, demonstrated a single 29 kDa species, consistent with the transmembrane form. These data are not consistent with binding of the secreted form of HB-EGF to the GBM. The transmembrane form of HB-E GF is able to signal in a juxtracrine fashion, so increased expression of HB-EGF mRNA and protein by GEC might contribute to the genesis of proteinuria through the initiation of abortive GEC mitogenesis.