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1 Clinical Sciences, Warwick Medical School, Coventry, West Midlands, United Kingdom
2 Pathology, University Hospital Coventry and Warwickshire, Coventry, West Midlands, United Kingdom
3 Nephrology, University Hospital Coventry and Warwickshire, Coventry, West Midlands, United Kingdom
4 Biological Sciences, University of Warwick, Coventry, West Midlands, United Kingdom
* To whom correspondence should be addressed. E-mail: d.zehnder{at}warwick.ac.uk.
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 Ca-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 pre-treatment 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 (siRNA), which confirmed that the observed neomycin/gentamycin-induced MEK1/ERK1,2 activation was mediated via 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.
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