Impaired mineral ion metabolism is a hallmark of CKD–metabolic bone disorder. It can lead to pathologic vascular calcification and is associated with an increased risk of cardiovascular mortality. Loss of calcium-sensing receptor (CaSR) expression in vascular smooth muscle cells exacerbates vascular calcification in vitro. Conversely, vascular calcification can be reduced by calcimimetics, which function as allosteric activators of CaSR.

To determine the role of the CaSR in vascular calcification, we characterized mice with targeted Casr gene knockout in vascular smooth muscle cells (^SM22αCaSR^flox/flox).

Vascular smooth muscle cells cultured from the knockout (KO) mice calcified more readily than those from control (wild-type) mice in vitro. However, mice did not show ectopic calcifications in vivo but they did display a profound mineral ion imbalance. Specifically, KO mice exhibited hypercalcemia, hypercalciuria, hyperphosphaturia, and osteopenia, with elevated circulating fibroblast growth factor 23 (FGF23), calcitriol (1,25-D₃), and parathyroid hormone levels. Renal tubular α-Klotho protein expression was increased in KO mice but vascular α-Klotho protein expression was not. Altered CaSR expression in the kidney or the parathyroid glands could not account for the observed phenotype of the KO mice.

These results suggest that, in addition to CaSR’s established role in the parathyroid-kidney-bone axis, expression of CaSR in vascular smooth muscle cells directly contributes to total body mineral ion homeostasis.

矿物质离子代谢受损是 CKD 代谢性骨病的一个标志。它可导致病理性血管钙化，并与心血管死亡风险增加相关。血管平滑肌细胞中钙敏感受体（CaSR）表达的丧失会加剧体外血管钙化。相反，拟钙剂可减少血管钙化，拟钙剂可作为 CaSR 的变构激活剂。

为了确定 CaSR 在血管钙化中的作用，我们对血管平滑肌细胞 ( ^SM22α CaSR ^flox/flox )中靶向Casr基因敲除的小鼠进行了表征。

体外培养的基因敲除（KO）小鼠血管平滑肌细胞比对照（野生型）小鼠培养的血管平滑肌细胞更容易钙化。然而，小鼠体内并未表现出异位钙化，但它们确实表现出严重的矿物质离子失衡。具体而言，KO 小鼠表现出高钙血症、高钙尿症、高磷酸盐尿症和骨质减少，循环成纤维细胞生长因子 23 (FGF23)、骨化三醇 (1,25-D 3 ) 和甲状旁腺激素水平_升高。KO 小鼠肾小管α -Klotho 蛋白表达增加，但血管α -Klotho 蛋白表达没有增加。肾脏或甲状旁腺中 CaSR 表达的改变不能解释 KO 小鼠观察到的表型。

这些结果表明，除了 CaSR 在甲状旁腺-肾-骨轴中的既定作用之外，血管平滑肌细胞中 CaSR 的表达直接有助于全身矿物质离子稳态。