Autocrine/paracrine role of adrenomedullin in cultured endothelial and mesangial cells

被引:85
作者
Michibata, H
Mukoyama, M
Tanaka, I
Suga, S
Nakagawa, M
Ishibashi, R
Goto, M
Akaji, K
Fujiwara, Y
Kiso, Y
Nakao, K
机构
[1] Kyoto Univ, Dept Med & Clin Sci, Grad Sch Med, Sakyo Ku, Kyoto 606, Japan
[2] Kyoto Pharmaceut Univ, Dept Med Chem, Kyoto 607, Japan
关键词
adrenomedullin; endothelium; mesangium; monoclonal antibody; proliferation;
D O I
10.1111/j.1523-1755.1998.00855.x
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Adrenomedullin (AM), a potent vasorelaxant and natriuretic peptide isolated from human pheochromocytoma, is present in the kidney and secreted from endothelial cells (EC) and vascular smooth muscle cells (VSMC), but the functional role of AM is still unclear. To clarify the significance of AM as a local regulator, we investigated its secretion and action in cultured cells, and examined the effects of neutralization using a specific monoclonal antibody against AM. The prepared antibody directed against the ring structure showed a high affinity for human and rat AM. Using radioimmunoassey with this antibody, we found significant secretion from cultured rat mesangial cells (MC) of a 6-kDa mature form of AM as seen from EC and VSMC. The addition of AM into cultured cells dose-dependently increased cAMP production and potently inhibited PDGF-stimulated thymidine incorporation. Pretreatment with the monoclonal antibody completely abolished cAMP increase induced by exogenous AM. Moreover, antibody neutralization of endogenously secreted AM in cultured EC, but not in MC or VSMC, markedly (by similar to 70%) reduced basal cAMP production and significantly (1.7-fold) enhanced DNA synthesis. These results indicate that AM, acting as an autocrine/paracrine regulator, exerts an antiproliferative action on EC and MC, and suggest its role as a local modulator of endothelial and mesangial function.
引用
收藏
页码:979 / 985
页数:7
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