Heparin-binding EGF-like growth factor contributes to reduced glomerular filtration rate during glomerulonephritis in rats

Heparin-binding epidermal growth factor-like growth factor (HE-EGF), a member of the epidermal growth factor (EGF) family, is expressed during inflammatory and pathological conditions. We have cloned the rat HB-EGF and followed the expression of HB-EGF in rat kidneys treated with anti,glomerular basement membrane (anti-GEM) antibody (Ab) to induce,glomerulonephritis (GN). We observed glomerular HE-EGF mRNA and protein within 30 minutes of Ab administration and showed by in situ hybridization that glomerular HB-EGF mRNA expression was predominantly in mesangial and epithelial cells. Expression of HE-EGF correlated with the onset of decreased renal function in this model. To test the direct effect of HB-EGF on renal function, we infused the renal cortex with active rHB-EGF, prepared from transfected Drosophila melanogaster cells. This treatment induced a significant decrease in single nephron GFR (SNGFR), single nephron plasma flow and glomerular ultrafiltration coefficient and an increase in the glomerular capillary hydrostatic pressure gradient. In addition, anti-HE-EGF Ab administered just before anti-GEM Ab blocked the fall in SNGFR and GFR at 90 minutes without any change in the glomerular histologic response. These studies suggest that HE-EGF expressed early in the anti-GEM Ab GN model contributes to the observed acute glomerular hemodynamic alterations.