Martin Schepelmann1,2, Marianna Ranieri3, Irene Lopez-Fernandez4, Thomas S Webberley4, Sarah C Brennan4,5, Polina L Yarova4,6, Joao Graca4,7, Umar-Khetaab Hanif4, Christian Müller2, Teresa Manhardt2, Martina Salzmann2, Helen Quasnichka4, Sally A Price7, Donald T Ward8, Thierry Gilbert9, Vladimir V Matchkov10, Robert A Fenton10, Amanda Herberger11, Jenna Hwong11, Christian Santa Maria11, Chia-Ling Tu11, Enikö Kallay2, Giovanna Valenti3, Wenhan Chang12, Daniela Riccardi1. 1. School of Biosciences, Cardiff University, Cardiff, United Kingdom wenhan.chang@ucsf.edu martin.schepelmann@meduniwien.ac.at. 2. Institute of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria. 3. Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy. 4. School of Biosciences, Cardiff University, Cardiff, United Kingdom. 5. Charles Perkins Centre, University of Sydney, Sydney, Australia. 6. Translational and Clinical Research Institute, Newcastle University Medical School, Newcastle upon Tyne, United Kingdom. 7. AstraZeneca, Macclesfield, United Kingdom. 8. Division of Diabetes, Endocrinology, and Gastroenterology, University of Manchester, Manchester, United Kingdom. 9. Centre for Developmental Biology, University Paul Sabatier, Toulouse, France. 10. Department of Biomedicine, Aarhus University, Aarhus, Denmark. 11. Department of Medicine, University of California, San Francisco, California. 12. Department of Medicine, University of California, San Francisco, California wenhan.chang@ucsf.edu martin.schepelmann@meduniwien.ac.at.
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 ( SM22α CaSR Δflox/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.
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 ( SM22α CaSR Δflox/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.
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