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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/F946    most recent 00474.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (14) Citing Articles via Google Scholar Google Scholar Articles by Molostvov, G. Articles by Zehnder, D. Search for Related Content PubMed PubMed Citation Articles by Molostvov, G. Articles by Zehnder, D.

Extracellular calcium-sensing receptor is functionally expressed in human artery

¹Clinical Sciences Research Institute and ²BioMedical Research Institute, University of Warwick, and Departments of ³Pathology and ⁴Nephrology, University Hospital Coventry and Warwickshire, Coventry, United Kingdom

Submitted 30 November 2006 ; accepted in final form 29 May 2007

Accelerated medial calcification is a major cause of premature cardiovascular mortality in patients with chronic kidney disease (CKD). Evidence suggests that extracellular concentration of Ca²⁺ and vascular smooth muscle cells may play a pivotal role in the pathogenesis of vascular calcification. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor that is expressed in a range of tissues, but characterization of its expression and function in the cardiovascular system is limited. Here we report the expression of CaSR mRNA (RT-PCR) and protein (Western blotting and immunocytochemistry) in human aortic smooth muscle cells (HAoSMC). Treatment of HAoSMC with Ca²⁺ (0–5 mM; 0–30 min) or the CaSR agonists gentamycin and neomycin (0–300 µM; 0–30 min) resulted in a dose- and time-dependent phosphorylation of ERK1/2. Gentamycin- and neomycin-mediated ERK1/2 stimulation was inhibited by pretreatment with PD-98059, an ERK-activating kinase 1 (MEK1) inhibitor, confirming specificity of the observed effects. ERK1/2 activation was inhibited in HAoSMC, with CaSR expression knocked down by transfection with specific small-interference RNA, which confirmed that the observed neomycin/gentamycin-induced MEK1/ERK1/2 activation was mediated via the CaSR. CaSR mRNA and protein were also expressed in large and small arteries from normal subjects (kidney donors) and patients with end-stage renal disease (ESRD). The CaSR was detected in smooth muscle and endothelial cells. Expression was significantly lower in arteries from ESRD patients. In conclusion, these data not only demonstrate the presence of a functional CaSR in human artery but show a correlation between CaSR expression and progression of CKD.

vascular smooth muscle cell; calcification; chronic kidney disease

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