Adrenomedullin decreases extracellular signal-regulated kinase activity through an increase in protein phosphatase-2A activity in mesangial cells

Adrenomedullin is a recently identified peptide hormone that has receptors in a number of different systems including renal mesangial cells. We report ed recently that adrenomedullin can cause a decrease in extracellular signa l-regulated kinase (ERK) activity and increase jun amino-terminal kinase (J NK) and P38 mitogen-activated protein kinase (P38 MAPK) acitivities in rat mesangial cells. Associated with these responses we also reported that adre nomedullin can decrease proliferation and increase apoptosis in mesangial c ells. The major aim of the present study was to examine the mechanism of de crease in ERK activity by adrenomedullin and to identify the role of protei n phosphatase 2A (PP2A) in the decrease in ERK activity, using okadaic acid [9,10-Deepithio-9,10-didehydroacanthifolicin], a selective inhibitor of PP 2A at low nanomolar concentrations. The adrenomedullin-induced decrease in [H-3]-thymidine incorporation and increase in apoptosis were reversed by ok adaic acid at the concentration that selectively inhibits PP2A. Okadaic aci d completely reversed the ERK inhibition caused by adrenomedullin, suggesti ng that PP2A may be involved in the adrenomedullin-mediated changes in prol iferation, apoptosis and ERK activity. PP2A activity in mesangial cells was increased over time following exposure to adrenomedullin. The tyrosine pho sphorylation of ERK did not change significantly following adrenomedullin t reatment although the ERK activity was decreased significantly. This sugges ts that the decrease in ERK activity is not mediated through a decrease in MEK (a dual phosphorylating kinase upstream of ERK) or by an increase in MK P-1/2 (a dual specificity phosphatase) activities. Thus we conclude that th e mechanism of adrenomedullin-induced decrease in ERK activity in rat mesan gial cells is at least in part mediated by an increase in PP2A activity. (C ) 2000 Elsevier Science B.V. All rights reserved.