Impaired mineral ion metabolism in a mouse model of targeted Calcium-Sensing Receptor (CaSR) deletion from vascular smooth muscle cells

Schepelmann, Martin; Ranieri, Marianna; Lopez-Fernandez, Irene; Webberley, Thomas S.; Brennan, Sarah C.; Yarova, Polina L.; Graca, Joao; Hanif, Umar-Khetaab; Müller, Christian; Manhardt, Teresa; Salzmann, Martina; Quasnichka, Helen; Price, Sally A.; Ward, Donald T.; Gilbert, Thierry; Matchkov, Vladimir V.; Fenton, Robert A.; Herberger, Amanda; Hwong, Jenna; Santa Maria, Christian; Tu, Chia-Ling; Kallay, Enikö; Valenti, Giovanna; Chang, Wenhan; Riccardi, Daniela

Abstract

Background
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.

Methods
To determine the role of the CaSR in vascular calcification, we characterized mice with targeted Casr gene knockout in vascular smooth muscle cells (SM22αCaSRΔflox/Δflox).

Results
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.

Conclusions
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.

• Journal Article Type: Article
• Acceptance Date: Jul 3, 2022
• Online Publication Date: Jul 31, 2022
• Publication Date: Jul 31, 2022
• Deposit Date: Mar 11, 2025
• Journal: Journal of the American Society of Nephrology
• Print ISSN: 1046-6673
• Electronic ISSN: 1533-3450
• Publisher: American Society of Nephrology
• Peer Reviewed: Peer Reviewed
• Volume: 33
• Issue: 7
• Pages: 1323-1340
• DOI: https://doi.org/10.1681/asn.2021040585
• Public URL: https://uwe-repository.worktribe.com/output/13931544
• Additional Information: Received: 2021-04-30; Accepted: 2022-03-07