Mazzocchi G, Rossi G P, Malendowicz L K, Champion H C, Nussdorfer G G
Department of Human Anatomy and Physiology, Section of Anatomy, School of Medicine, University of Padua, Italy.
FEBS Lett. 2000 Dec 29;487(2):194-8. doi: 10.1016/s0014-5793(00)02352-8.
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.
内皮素 -1（ET -1）[1 - 31]是一种新型的高血压肽，它模拟了经典的21个氨基酸肽ET -1[1 - 21]的许多血管效应。然而，与通过ETB受体作用增强培养的大鼠肾小球带（ZG）细胞醛固酮分泌的ET -1[1 - 21]不同，ET -1[1 - 31]并未引发这种效应。ET -1[1 - 21]和ET -1[1 - 31]均提高了培养的ZG细胞的增殖率，最大有效浓度为1×10⁻⁸ M。这种效应被ETA受体拮抗剂BQ - 123阻断，且不受ETB受体拮抗剂BQ - 788的影响。定量放射自显影显示，ET -1[1 - 21]在大鼠ZG和肾上腺髓质中均能取代与ETA受体结合的[¹²⁵I]PD - 151242以及与ETB受体结合的[¹²⁵I]BQ - 3020，而ET -1[1 - 31]仅能取代与[¹²⁵I]BQ - 3020的结合。酪氨酸激酶（TK）抑制剂曲磷胺 - 23和p42/p44丝裂原活化蛋白激酶（MAPK）抑制剂PD - 98059消除了ET -¹[1 - 31]的促增殖作用，而蛋白激酶 - C（PKC）抑制剂钙泊三醇 - C显著降低了该作用。ET -1[1 - 31]（1×10⁻⁸ M）刺激了分散的ZG细胞的TK和MAPK活性，这一效应被BQ - 123阻断。曲磷胺 - 23消除了ET -1[1 - 31]对TK活性的刺激作用，而钙泊三醇 - C降低了其对MAPK活性的刺激作用，曲磷胺 - 23和PD - 98059均可消除该作用。这些数据表明，ET -1[1 - 31]是ETA受体亚型的选择性激动剂，并通过PKC和TK依赖的p42/p44 MAPK级联激活增强培养的大鼠ZG细胞增殖。
