Extracellular calcium-sensing receptor is functionally expressed in human artery

Abstract

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 microM; 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.

The Calcium-Sensing Receptor as a Regulator of Cellular Fate in Normal and Pathological Conditions

“…Recent reports clearly point to a role for the CaSR as a regulator of early development and as a guardian of the homeostatic balance between proliferation and differentiation in adults [19,68,70,71,73,75,89,92]. The identification of CaSR mutations that cause FHH and hypocalcemia [93][94][95][96][97][98], and the recent discoveries implicating the dysregulation of CaSR signaling in many other diseases [99,[113][114][115][119][120][121][122][123][124], position the CaSR as a broad therapeutic target. Adverse side-effects will likely be a challenging issue in the putative use of CaSR-modulating agents for the treatment of such a broad range of tissuespecific diseases; therefore, future studies should focus on the development of CaSR-modulating drugs with a higher selectivity for the CaSR and specificity for the tissue of interest.…”

“…Vascular calcification is an active, regulated process similar to that of osteogenesis in bone. During this process, loss of CaSR expression in vascular smooth muscle cells leads to the acquisition of an osteoblast-like phenotype and contributes to the generation of calcified nodules [119][120][121][122][123]. Koleganova and colleagues demonstrated, using an in vivo rat model for interstitial fibrosis and microvascular disease of the heart in uremia, that this transdifferentiation could be significantly delayed by administration of the calcimimetic R-568, suggesting the involvement of the CaSR in this process [124].…”

Vascular Calcification

“…Compared with normal individuals, the expression of this Ca 2ϩ -sensing receptor is downregulated in VSMCs from patients with CKD. 71 Thus, the extracellular Ca 2ϩ and Ca 2ϩ receptor axis may have a role in the progression of vascular calcification.…”

Vitamin D and calcium insufficiency-related chronic diseases: molecular and cellular pathophysiology

“…At present it is not known whether changes in dietary calcium affect blood pressure through the action of the CaR on endothelial and smooth vascular cells of human arteries (Molostvov et al, 2007). Alternatively, activation of the renal CaR leading to enhanced prostaglandin E 2 synthesis and natriuresis with subsequent reduction in plasma volume, may account for the blood pressure-lowering effect of elevated extracellular calcium (Wang et al, 2001).…”

“…Molostvov et al (2007) suggested that arterial calcification, which is a major cause of premature cardiovascular mortality, could be the result of CaR activation. Thus, one cannot exclude that calcium supplementation may cause adverse vascular events that compromise, at least in part, its beneficial action on cardiovascular risk.…”