Heparin-binding EGF-like growth factor expression increases selectively inbladder smooth muscle in response to lower urinary tract obstruction

Heparin-binding epidermal growth factor-like growth factor (HB-EGF), an act ivating ligand for the epidermal growth factor receptor (ErbB1) tyrosine ki nase and at least one isoform of the ErbB4 receptor tyrosine kinase, is syn thesized by the smooth muscle of the human bladder wall. In this study we t ested the hypothesis that HB-EGF plays a role in the bladder-wall thickenin g that occurs in response to obstructive syndromes affecting the lower urin ary tract, possibly by acting as an autocrine smooth muscle cell (SMC) grow th factor. HB-EGF was mitogenic for primary culture human bladder SMC, and cell growth in serum-containing medium was inhibited more than 70% by [Glu5 2]-diphtheria toxin/CRM197, a specific HB-EGF inhibitor, consistent with a physiologic role for HB-EGF as an autocrine bladder SMC mitogen. Human and mouse bladder SMC in vivo and cultured human bladder SMC expressed the prim ary HB-EGF receptor, ErbB1, but not mRNA for the secondary HB-EGF receptor, ErbB4, thereby identifying ErbB1 as the cognate HB-EGF receptor in the bla dder wall. Reverse transcription-polymerase chain reaction analysis also de monstrated ErbB2 and ErbB3 expression in human bladder muscle tissue, sugge sting the possibility of receptor cross-talk after ErbB1 activation. Urethr al ligation in mice resulted in an increase in steady-state HB-EGF mRNA exp ression up to 24 hours in whole bladder tissue in comparison with ErbB1 and glyceraldehyde 3-phosphate dehydrogenase mRNA levels, which did not change in a demonstrable pattern. HB-EGF protein increased coordinately with HB-E GF mRNA levels. Dissection of bladder tissue into muscle and mucosal layers demonstrated that the increase in HB-EGF mRNA occurred predominantly in th e muscle layer, with peak levels (13-fold higher than sham controls) occurr ing 12 hours after obstruction. These data support a physiologic role for H B-EGF as a mediator of hypertrophic bladder tissue growth.