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

Endothelin-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], Ho wever, at variance with ET-1[1-21] that enhances aldosterone secretion from cultured rat zone 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 th e proliferation rate of cultured ZG cells, the maximal effective concentrat ion 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 a utoradiography showed that ET-1[1-21] displaced both [I-125]PD-151242 bindi ng to ETA receptors and [I-125]BQ-3020 binding to ETB receptors in both rat ZG and adrenal medulla, while ET-1[1-31] displaced only [I-125]BQ-3020 bin ding. The tyrosine kinase (TK) inhibitor tyrphostin-23 and the p42/p44 mito gen-activated protein kinase (MAPK) inhibitor PD-98059 abolished the prolif erogenic effect of ET-1[1-31], while the protein kinase-C (PKC) inhibitor c alphostin-C significantly reduced it. ET-1[1-13] (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 tyrpho stin-23, while that on MAPK activity mas reduced by calphostin-C and abolis hed 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 prolifer ation of cultured rat ZG cells through the PKC- and TK-dependent activation of p42/p44 MAPK cascade. (C) 2000 Federation of European Biochemical Socie ties. Published by Elsevier Science B.V. All rights reserved.