Growth factor stimulation of map kinase is inhibited by
prostaglandin e2 and forskolin in rat renal mesangial cells.
Li, Xiaomei, Fariba Zarinetchi, Robert W. Schrier, and Raphael A.
Nemenoff.
Division of Renal Diseases and Hypertension, Department of
Medicine, University of Colorado Health Sciences Center, Denver,
CO;
APStracts 2:0174C, 1995.
Activation of the mitogen-activated protein kinase (MAP kinase)
pathway is believed to play a critical role in normal and
pathophysiologic proliferation of mesangial cells. Recent studies
have shown that MAP Kinase activation by growth factors in other cell
types involves activation of the low molecular weight G-protein ras
and the protooncogene serine kinase c-raf-1. In this study, the role
of this pathway in rat renal mesangial cells was assessed. Platelet
-derived growth factor (PDGF), epidermal growth factor (EGF) as well
as phorbol esters (PMA) rapidly activated MAP kinase 3-4 fold in
these cells. PDGF and EGF, but not PMA were able to activate c-raf-1
and ras activity. Stimulation of mesangial cells with the
inflammatory mediator prostaglandin E2 (PGE2) or elevation of
intracellular cAMP by treatment with forskolin markedly blunted
activation of MAP kinase induced by PDGF and EGF, but not PMA.
Consistent with this observation, PGE2 abolished growth factor
-induced activation of c-raf-1. However, ras activation induced by
growth factors was not affected by PGE2 and forskolin. These results
suggest that MAP kinase activation can occur by at least two separate
pathways in mesangial cells. Tyrosine kinase receptors activate MAP
kinase through activation of ras and raf. This pathway can be blocked
by PGE2 and elevation of cAMP, presumably by interfering with the
ability of ras to activate raf. In addition, activation of protein
kinase C (PKC) by phorbol esters can activate MAP kinase in a
ras/raf-independent manner. This pathway is not sensitive to
inhibition by PGE2 or cAMP. It is likely that activation of each of
these pathways, while both resulting in a stimulated MAP kinase will
have different physiologic consequences in mesangial cells .
Received 24 August 1994; accepted in final form 10 April 1995.
APS Manuscript Number C502-4.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 25 April 1995.