Adrenomedullin increases AP-1 expression in rat mesangial cells via activation of protein kinase-A and p38 MAPK.

Adrenomedullin (AM), a potent vasodilatory peptide, has anti-proliferative and pro-apoptotic effects in rat mesangial cells (RMCs). We have previously demonstrated that AM modulates activities of the members of MAPK family in RMCs. Because activation of MAPKs has been reported to induce AP-1 expression in other cell systems, the major aim of the present study was to examine the effects and mechanisms of AM on AP-1 member mRNA expression, in RMCs. AM produced a concentration- and time-dependent increase in c-fos and jun-B mRNA expression without observable effects on fos-B and c-jun. Associated with this change, AM increased the AP-1 DNA binding activity. RMCs transiently transfected with a luciferase fusion gene driven by an AP-1 cis-element demonstrate a concentration- and time-dependent increase in luciferase activity suggesting that AM increases AP-1-mediated gene transcription in these cultured cells. Both an AM-induced increase in AP-1 mRNA expression and AP-1 luciferase activities were inhibited by H89 (protein kinase-A inhibitor) and SB203580 (p38 MAPK inhibitor). These results indicate a likely role for the members of AP-1 family in AM-mediated biological responses in rat mesangial cells and a role for cAMP activation and subsequent activation of p38 MAPK in AM-induced AP-1 activity.