Production of immunoreactive (ir-) endothelin-2 (ET-2) in renal adenocarcinoma cells, ACHN, was reduced by transforming growth factor-beta, basic fibroblast growth factor, transforming growth factor-alpha and, most strikingly, by epidermal growth factor (EGF). These growth factors did not show such inhibitory effects on the secretion of ir-ET-1 in ET-1-producing cells, indicating that the production of ET-2 and ET-1 is regulated differently by the growth factors. EGF specifically reduced the secretion of not only ir-ET-2 but also ir-big ET-2 with only a small decrease in total protein synthesis. Northern blot analysis indicated that EGF controls the ET-2-production at the transcription levels of ET-2 gene.