Endothelin-1[1–31], acting as an ETA-receptor selective agonist, stimulates proliferation of cultured rat zona glomerulosa cells

AbstractEndothelin-1 (ET-1)[1–31] is a novel hypertensive peptide that mimics many of the vascular effects of the classic 21 amino acid peptide ET-1[1–21]. However, at variance with ET-1[1–21] that enhances aldosterone secretion from cultured rat zona glomerulosa (ZG) cells by acting via ETB receptors, ET-1[1–31] did not elicit such effect. Both ET-1[1–21] and ET-1[1–31] raised the proliferation rate of cultured ZG cells, the maximal effective concentration being 10−8 M. This effect was blocked by the ETA-receptor antagonist BQ-123 and unaffected by the ETB-receptor antagonist BQ-788. Quantitative autoradiography showed that ET-1[1–21] displaced both [125I]PD-151242 binding to ETA receptors and [125I]BQ-3020 binding to ETB receptors in both rat ZG and adrenal medulla, while ET-1[1–31] displaced only [125I]BQ-3020 binding. The tyrosine kinase (TK) inhibitor tyrphostin-23 and the p42/p44 mitogen-activated protein kinase (MAPK) inhibitor PD-98059 abolished the proliferogenic effect of ET-1[1–31], while the protein kinase-C (PKC) inhibitor calphostin-C significantly reduced it. ET-1[1–31] (10−8 M) stimulated TK and MAPK activity of dispersed ZG cells, an effect that was blocked by BQ-123. The stimulatory action of ET-1[1–31] on TK activity was annulled by tyrphostin-23, while that on MAPK activity was reduced by calphostin-C and abolished by either tyrphostin-23 and PD-98059. These data suggest that ET-1[1–31] is a selective agonist of the ETA-receptor subtype, and enhances proliferation of cultured rat ZG cells through the PKC- and TK-dependent activation of p42/p44 MAPK cascade