Upregulation of heparin-binding epidermal growth factor-like growth factor and osteopontin in experimental hydronephrosis

This study examined the expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and osteopontin in unilateral ureteral obstruction (UUO) in the rat, a model of obstructive uropathy. HB-EGF mRNA was upregulated 5.5-fold at 4 h post-obstruction (P<0.05) and 4.5-fold after 12h (P<0.05). Immunohistochemical staining for HB-EGF demonstrated an increase in protein in the distended tubules. To determine what effects increased HB-EGF might have in the obstructed kidney, we attempted to determine whether HB-EGF upregulates osteopontin and α-smooth muscle actin (α-SMA) in the tubular line NRK-52E. Both of these molecules are increased in UUO. Osteopontin mRNA was upregulated in NRK-52E cells after 24, 48 and 72 h HB-EGF stimulation. In contrast, HB-EGF caused a downregulation of α-SMA protein by Western blot in NRK-52E cells. When a blocking mAb against secreted HB-EGF was administered, however, there was no effect on osteopontin mRNA levels or immunohistochemical staining for α-smooth muscle actin. These data suggest that the action of HB-EGF in UUO may be to increase osteopontin and reduce α-smooth muscle actin expression by tubular epithelial cells by an autocrine or intracrine mechanism. By reducing α-SMA expression, HB-EGF may also act to maintain epithelial cell morphology in this model.