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

On 17 May 2022, Martin Schepelmann, School of Biosciences, Cardiff University, United Kingdom, and his team published a paper titled “Impaired Mineral Ion Metabolism in a Mouse Model of Targeted Calcium-Sensing Receptor (CaSR) Deletion from Vascular Smooth Muscle Cells” in Journal of the American Society of Nephrology, which suggested that the VSMC-CaSR directly contributes to total body mineral ion homeostasis.

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Background: Impaired mineral ion metabolism is a hallmark of chronic kidney disease (CKD) -metabolic bone disorder. It can lead to pathological vascular calcification (VC) and is associated with an increased risk of cardiovascular mortality. Loss of calcium sensing receptor (CaSR) expression in vascular smooth muscle cells (VSMCs) exacerbates VC in vitro; conversely, VC can be reduced by CaSR allosteric activators, calcimimetics.  

Methods: To determine the role of the CaSR in VC, we characterized mice with targeted Casr gene knockout (KO) in VSMC (^SM22αCaSR^{∆flox/∆flox}).  

Results: VSMC cultured from KO mice calcified more readily than those from control (WT) mice in vitro. However, KO mice did not show ectopic calcifications in vivo but a profound mineral ion imbalance. Specifically, KO mice exhibited hypercalcemia, hypercalciuria, hyperphosphaturia, and osteopenia, with elevated circulating FGF23, calcitriol (1,25-D₃), and PTH levels. Renal tubular, but not vascular α-Klotho protein expression was increased in KO mice. The observed phenotype of the KO mice could not be accounted for by altered CaSR expression in the kidney or the parathyroid glands.  

Conclusions: These results suggest that the VSMC-CaSR directly contributes to total body  mineral ion homeostasis, in addition to the established role of the receptor in the parathyroid- kidney-bone axis.