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Articles in PresS, published online ahead of print September 17, 2002
Am J Physiol Renal Physiol, 10.1152/ajprenal.00127.2002
Submitted on April 1, 2002
Accepted on September 15, 2002
1 Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
2 Department of Medicine, University of Toronto, Toronto, Ontario, Canada
* To whom correspondence should be addressed. E-mail: catharine.whiteside{at}utoronto.ca.
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 if ET-1 activation of glomerular mesangial cell ERK1/2 is mediated through epidermal growth factor 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 AG1478, a specific EGF receptor inhibitor, to 9 ± 1 fold. Moreover filipin III and ß-cyclodextrin, two cholesterol-depleting drugs known to disrupt caveolae, significantly reduced ET-1 induced phosphorylation of ERK1/2. In addition, pre-incubation 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 co-immunoprecipitation. Both activation of ERK1/2 and its interaction with caveolin-1 were reduced by AG1478, ß-cyclodextrin or inhibition of protein kinase C (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.
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