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Impaired mineral ion metabolism in a mouse model of targeted calcium-sensing receptor (CaSR) deletion from vascular smooth muscle cells

Schepelmann, Martin ORCID: https://orcid.org/0000-0002-7017-5426, Ranieri, Marianna, Lopez-Fernandez, Irene, Webberley, Thomas S., Brennan, Sarah C. ORCID: https://orcid.org/0000-0002-8719-4367, 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 and Riccardi, Daniela ORCID: https://orcid.org/0000-0002-7322-3163 2022. Impaired mineral ion metabolism in a mouse model of targeted calcium-sensing receptor (CaSR) deletion from vascular smooth muscle cells. Journal of the American Society of Nephrology 33 (7) , pp. 1323-1340. 10.1681/ASN.2021040585

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: American Society of Nephrology
ISSN: 1046-6673
Date of First Compliant Deposit: 30 May 2022
Date of Acceptance: 7 March 2022
Last Modified: 23 May 2024 19:01
URI: https://orca.cardiff.ac.uk/id/eprint/150114

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