Interaction of Adrenomedullin and Platelet-Derived Growth Factor on Rat Mesangial Cell Production of Endothelin

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Abstract
Abstract Adrenomedullin has recently been isolated from human pheochromocytoma. We designed the present study to examine the effect of adrenomedullin on the production of the vasoconstrictive and growth-promoting peptide endothelin-1 (ET-1) after stimulation with platelet-derived growth factor (PDGF) in cultured rat glomerular mesangial cells. PDGF stimulated ET-1 production in a concentration-dependent manner. Rat adrenomedullin inhibited this stimulated ET-1 production in a concentration-dependent manner between 10 −7 and 10 −8 mol/L. Rat adrenomedullin also increased the cellular level of cAMP in a concentration-dependent manner between 10 −7 and 10 −8 mol/L. Human adrenomedullin was less effective than rat adrenomedullin with respect to inhibiting ET-1 production and increasing cAMP levels. The addition of 8-bromo-cAMP (10 −3 and 10 −4 mol/L) reduced PDGF-induced ET-1 production. Furthermore, forskolin (10 −4 and 10 −5 mol/L), an activator of adenylate cyclase, reduced PDGF-induced ET-1 production. In contrast, the basal production of ET-1 was not significantly altered by rat and human adrenomedullin. These results indicate that adrenomedullin inhibits PDGF-induced ET-1 production in cultured rat mesangial cells, probably through a cAMP-dependent process.