ANGIOTENSIN-II-INDUCED ALDOSTERONE SYNTHESIS IS POTENTIATED BY EPIDERMAL GROWTH-FACTOR

Epidermal growth factor (EGF) is a potent mitogen and has effects in several endocrine systems. We examined the effects of EGF on basal and angiotensin II (AII)-induced aldosterone synthesis in freshly isolated rat and cultured human adrenal glomerulosa cells. EGF alone caused a significant increase in basal aldosterone synthesis in both the rat and human cells. In addition, EGF caused a significant increase in AII-induced aldosterone secretion in both rat and cultured human cells during short and long term incubations. Further, we observed that the effect of EGF was highly specific to AII since it did not alter either potassium (8.7 mM) or ACTH (10(-10) M) mediated increases in aldosterone synthesis. We also investigated possible mechanisms of action of EGF. Since earlier studies showed that the lipoxygenase pathway of arachidonic acid plays a key role in mediating AII-induced aldosterone synthesis, we studied the effect of lipoxygenase inhibition in EGF action. We observed that the nonselective lipoxygenase blocker BW755c, which blocked AII-induced aldosterone synthesis, also inhibited EGF mediated increase in aldosterone synthesis. We also examined the effects of EGF on diacylglycerol (DG) formation since DG is an important second messenger in AII action. We found that EGF stimulated basal DG levels and also potentiated AII-induced DG formation, suggesting that EGF may potentiate AII-induced aldosterone synthesis via increases in DG. These results suggest that EGF may play an important role in aldosterone synthesis by acting as a specific positive modulator of AII action in the adrenal.