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]. 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 [(125)I]PD-151242 binding to ETA receptors and [(125)I]BQ-3020 binding to ETB receptors in both rat ZG and adrenal medulla, while ET-1[1-31] displaced only [(125)I]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.
Mazzocchi
G
G
Department of Human Anatomy and Physiology, Section of Anatomy, School of Medicine, University of Padua, Italy.
Rossi
G P
GP
Malendowicz
L K
LK
Champion
H C
HC
Nussdorfer
G G
GG
D000818:Animals; D001381:Azepines / Q000493:pharmacokinetics; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000031:analogs & derivatives; D016232:Endothelins / Q000493:pharmacokinetics / Q000494:pharmacology*; D007457:Iodine Radioisotopes; D007700:Kinetics; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000494:pharmacology; D010446:Peptide Fragments / Q000493:pharmacokinetics / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000819:agonists* / Q000502:physiology; D013937:Thymidine Kinase / Q000378:metabolism; D015384:Zona Glomerulosa / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*
D001381:Azepines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D007457:Iodine Radioisotopes; D009842:Oligopeptides; D010446:Peptide Fragments; D010880:Piperidines; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C419584:endothelin-1 (1-21); C114932:endothelin-1 (1-31); C075771:BQ 3020; C087850:PD 151242; C086539:BQ 788; D013937:Thymidine Kinase; D020928:Mitogen-Activated Protein Kinases