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Expression of the calcium-sensing receptor in human vascular smooth muscle cells and its role in the regulation of cell proliferation and apoptosis
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Molostvov, Guerman, Omotoye, Samuel, Bennett, Jeanette, James, Sean G., Fletcher, Simon, Lehnert, Hendrik, Zehnder, Daniel and Bland, Rosemary (2007) Expression of the calcium-sensing receptor in human vascular smooth muscle cells and its role in the regulation of cell proliferation and apoptosis. In: 44th ERA-EDTA Congress, Barcelona, Spain, 22-24 Jun 2007. Published in: Nephrology Dialysis Transplantation, Volum 22 (Supplement 6). pp. 214-215. ISSN 0931-0509.
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Official URL: http://ndt.oxfordjournals.org/content/22/suppl_6.t...
Abstract
Introduction and Aims: Vascular smooth muscle cell (VSMC) proliferation,
differentiation and apoptosis are thought to contribute to the progressionSaturday, June 23, 2007 Novel therapies and insights in dialysis and transplantation vi215
of arteriosclerosis and medial calcification. Interactions between VSMC and
extracellular Ca2+ detected by the calcium-sensing receptor (CaSR) may
be pivotal. However, little is known about its expression and functional
significance in human VSMC. Here we report the expression of a functional
CaSR in human aortic SMC (HAoSMC) and human arteries. Additionally,
we demonstrate CaSR-mediated ERK1,2 activation and involvement of
CaSR with HAoSMC proliferation and apoptosis.
Methods: CaSR mRNA and protein were detected by RT-PCR, Western
blotting and immunohistochemistry. CaSR was stimulated by CaSR agonists
(Ca2+, neomycin, gentamycin). ERK1,2 phosphorylation was assessed by
Western blot analysis. Proliferation was analysed by the Biotrak ELISA
assay. Apoptosis was assessed by expression of cleaved caspase-3.
Results: CaSR mRNA and protein were expressed in HAoSMC, arteries
from normal subjects (kidney donors) and patients with end-stage renal disease
(ESRD). CaSR expression was considerably lower (p<0.05) in ESRD
than in kidney donors. Importantly, CaSR expression was reduced in regions
of calcium deposition. Treatment of HAoSMC with gentamycin/neomycin
(0-300μM) or Ca2+ (0-5mM) for 0-30 min significantly increased ERK1,2
phosphorylation. ERK1,2 activation was reduced (p<0.05) in the presence
of specific inhibitors of phospholipase C (PLC) (5μM U73122), protein kinase
C (PKC) (250nmol calphostin C) and ERK-activating kinase 1 (MEK1)
(10μM PD-98059), indicating that CaSR-mediated ERK1,2 phosphorylation
involves activation of PLC, PKC and MEK1. Incubation of HAoSMC
with neomycin/gentamycin (300μM) produced marked increase in cell
proliferation (2-3 fold, 24 hours, p<0.01). Pre-treatment with 5μM U73122
abolished neomycin/gentamycin-induced HAoSMC proliferation, consistent
with its effect on ERK1,2 phosphorylation. However, pre-incubation with
calphostin C and Ly-294002 did not significantly change CaSR agonistinduced
proliferation. Analysis of HAoSMC apoptosis was carried out in
parallel and demonstrated that pre-treatment with U73122 resulted in a
dramatic (>5 fold, p<0.01) up-regulation of apoptosis, suggesting a crucial
role of PLC signalling for VSMC survival.
Conclusions: Our data demonstrate that HAoSMC express a functional
CaSR, which when stimulated activates the MEK1/ERK1,2 signalling
pathway. CaSR-mediated signalling is closely involved in the regulation
of HAoSMC proliferation and apoptosis with MEK1/ERK1,2 and PLC
pathways playing central roles. In ESRD patients, loss of CaSR expression
in arterial SMC is associated with a progressive vascular calcification.
Item Type: | Conference Item (Paper) | ||||
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Subjects: | R Medicine > RD Surgery R Medicine > RC Internal medicine |
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Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Clinical Trials Unit Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Journal or Publication Title: | Nephrology Dialysis Transplantation | ||||
Publisher: | Oxford University Press | ||||
ISSN: | 0931-0509 | ||||
Official Date: | 2007 | ||||
Dates: |
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Volume: | Volum 22 | ||||
Number: | Supplement 6 | ||||
Number of Pages: | 2 | ||||
Page Range: | pp. 214-215 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Conference Paper Type: | Paper | ||||
Title of Event: | 44th ERA-EDTA Congress | ||||
Type of Event: | Other | ||||
Location of Event: | Barcelona, Spain | ||||
Date(s) of Event: | 22-24 Jun 2007 | ||||
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