Impaired Mineral Ion Metabolism in a Mouse Model of Targeted Calcium-Sensing Receptor (CaSR) Deletion from Vascular Smooth Muscle Cells.

Abstract

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 <i>in vitro.</i> 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 <i>Casr</i> gene knockout in vascular smooth muscle cells ( <i>^SM22α</i> CaSR <i>^{Δflox/Δflox}</i> ). Vascular smooth muscle cells cultured from the knockout (KO) mice calcified more readily than those from control (wild-type) mice <i>in vitro.</i> However, mice did not show ectopic calcifications <i>in vivo</i> 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 <i>α</i>-Klotho protein expression was increased in KO mice but vascular <i>α</i>-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.