Inhibitory effect of epidermal growth factor and hepatocyte growth factor on endothelin-1 release by rabbit proximal tubule cells

Several studies have demonstrated an upregulation of endothelin-1 (ET-1) sy nthesis in acute and chronic renal failure. Epidermal growth factor (EGF) a nd hepatocyte growth factor (HGF) have been shown to stimulate renal tubula r cell proliferation and to accelerate renal regeneration after drug-induce d and ischemia-induced renal injury. This study aimed to investigate the ef fect of EGF and HGF on ET-1 release, and whether the effect of EGF and HGF is antagonized by the tyrosine kinase inhibitor lavendustin A. Rabbit proxi mal tubule cells were incubated for 48 h with EGF or HGF (0.1-10.0 nM), lav endustin A (0.1-10.0 muM) or co-incubated with EGF or HGF (1 nM) and lavend ustin A. ET-1 concentrations in the culture medium were measured with a spe cific enzyme-linked immunosorbent assay (ELISA). EGF and HGF exerted a sign ificant (p <0.001) dose-dependent inhibitory effect on ET-1 release. Lavend ustin A induced a dose-dependent stimulation of ET-1 release and antagonize d the inhibitory effect of EGF and HGF on ET-1 release. The inhibition of E GF and HGF receptor tyrosine kinase activity by lavendustin A was confirmed by Western blotting. These data suggest that EGF and HGF reduce ET-1 relea se via EGF and HGF receptor tyrosine kinase activity. The inhibitory action of EGF and HGF on ET-1 release might be involved in mediating the protecti ve effects of EGF and HGF in renal injury.