In:
American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 284, No. 2 ( 2003-02-01), p. F303-F312
Abstract:
Endothelin-1 (ET-1) stimulates glomerular mesangial cell proliferation and extracellular matrix protein transcription through an ERK1/2-dependent pathway. In this study, we determined whether ET-1 activation of glomerular mesangial cell ERK1/2 is mediated through EGF receptor (EGF-R) transactivation and whether intact caveolae are required. We showed that ET-1 stimulated tyrosine phosphorylation of the EGF-R in primary cultured, growth-arrested rat mesangial cells. In response to ET-1, ERK1/2 phosphorylation was increased by 27 ± 1-fold and attenuated by AG-1478, a specific EGF-R inhibitor, to 9 ± 1-fold. Moreover, filipin III and β-cyclodextrin, two cholesterol-depleting drugs known to disrupt caveolae, significantly reduced ET-1-induced phosphorylation of ERK1/2. In addition, preincubation of mesangial cells with a myristoylated peptide that binds to the caveolin-1 scaffolding domain diminished ET-1 activation of ERK1/2. ET-1 caused interaction of caveolin-1 with phosphorylated ERK1/2 identified by coimmunoprecipitation. Activation of ERK1/2 and its interaction with caveolin-1 were reduced by AG-1478, β-cyclodextrin, or inhibition of PKC. Phosphorylated ERK1/2 localized at focal adhesion complexes along with phospho-caveolin-1, suggesting specific sites of compartmentalization of these signaling molecules. Hence, ET-1 activates mesangial cell ERK1/2 predominantly through a pathway involving EGF-R transactivation, leading to a mechanism involving attachment to caveolin-1, presumably in caveolae.
Type of Medium:
Online Resource
ISSN:
1931-857X
,
1522-1466
DOI:
10.1152/ajprenal.00127.2002
Language:
English
Publisher:
American Physiological Society
Publication Date:
2003
detail.hit.zdb_id:
1477287-5
