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

Joseph G. Borer, John M. Park, Anthony Atala, Hiep T. Nguyen, Rosalyn M. Adam, Alan B. Retik, Michael R. Freeman

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Heparin-binding epidermal growth factor-like growth factor (HB-EGF), an activating ligand for the epidermal growth factor receptor (ErbB1) tyrosine kinase and at least one isoform of the ErbB4 receptor tyrosine kinase, is synthesized by the smooth muscle of the human bladder wall. In this study we tested the hypothesis that HB-EGF plays a role in the bladder-wall thickening that occurs in response to obstructive syndromes affecting the lower urinary tract, possibly by acting as an autocrine smooth muscle cell (SMC) growth factor. HB-EGF was mitogenic for primary culture human bladder SMC, and cell growth in serum-containing medium was inhibited more than 70% by [Glu52]- 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 primary 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 bladder wall. Reverse transcription-polymerase chain reaction analysis also demonstrated ErbB2 and ErbB3 expression in human bladder muscle tissue, suggesting the possibility of receptor cross-talk after ErbB1 activation. Urethral ligation in mice resulted in an increase in steady-state HB-EGF mRNA expression 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-EGF mRNA levels. Dissection of bladder tissue into muscle and mucosal layers demonstrated that the increase in HB-EGF mRNA occurred predominantly in the muscle layer, with peak levels (13-fold higher than sham controls) occurring 12 hours after obstruction. These data support a physiologic role for HB-EGF as a mediator of hypertrophic bladder tissue growth.

Original languageEnglish
Pages (from-to)1335-1345
Number of pages11
JournalLaboratory Investigation
Volume79
Issue number11
StatePublished - Nov 1 1999
Externally publishedYes

Fingerprint

Urinary Tract
Epidermal Growth Factor
Smooth Muscle
Heparin
Urinary Bladder
Intercellular Signaling Peptides and Proteins
Smooth Muscle Myocytes
Growth Factor Receptors
Messenger RNA
Muscles
Heparin-binding EGF-like Growth Factor
Receptor Cross-Talk
Diphtheria Toxin
Growth Inhibitors
Glyceraldehyde-3-Phosphate Dehydrogenases
Receptor Protein-Tyrosine Kinases
Growth
Mitogens
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Borer, J. G., Park, J. M., Atala, A., Nguyen, H. T., Adam, R. M., Retik, A. B., & Freeman, M. R. (1999). Heparin-binding EGF-like growth factor expression increases selectively in bladder smooth muscle in response to lower urinary tract obstruction. Laboratory Investigation, 79(11), 1335-1345.

Heparin-binding EGF-like growth factor expression increases selectively in bladder smooth muscle in response to lower urinary tract obstruction. / Borer, Joseph G.; Park, John M.; Atala, Anthony; Nguyen, Hiep T.; Adam, Rosalyn M.; Retik, Alan B.; Freeman, Michael R.

In: Laboratory Investigation, Vol. 79, No. 11, 01.11.1999, p. 1335-1345.

Research output: Contribution to journalArticle

Borer, JG, Park, JM, Atala, A, Nguyen, HT, Adam, RM, Retik, AB & Freeman, MR 1999, 'Heparin-binding EGF-like growth factor expression increases selectively in bladder smooth muscle in response to lower urinary tract obstruction', Laboratory Investigation, vol. 79, no. 11, pp. 1335-1345.
Borer, Joseph G. ; Park, John M. ; Atala, Anthony ; Nguyen, Hiep T. ; Adam, Rosalyn M. ; Retik, Alan B. ; Freeman, Michael R. / Heparin-binding EGF-like growth factor expression increases selectively in bladder smooth muscle in response to lower urinary tract obstruction. In: Laboratory Investigation. 1999 ; Vol. 79, No. 11. pp. 1335-1345.
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