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

SUMMARY 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 12 h (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.