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Endothelin‐1[1–31], acting as an ETA‐receptor selective agonist, stimulates proliferation of cultured rat zona glomerulosa cells
Author(s) -
Mazzocchi Giuseppina,
Rossi Gian Paolo,
Malendowicz Ludwik K.,
Champion Hunter C.,
Nussdorfer Gastone G.
Publication year - 2000
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(00)02352-8
Subject(s) - zona glomerulosa , calphostin c , protein kinase c , endocrinology , medicine , receptor , endothelin 1 , endothelin receptor , angiotensin ii , mapk/erk pathway , tyrosine kinase , biology , calphostin , microbiology and biotechnology , chemistry , kinase , biochemistry
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.