Vladimir Matchkov

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

  • Martin Schepelmann, Cardiff University, Medical University of Vienna
  • ,
  • Marianna Ranieri, University of Bari
  • ,
  • Irene Lopez-Fernandez, Cardiff University
  • ,
  • Thomas S Webberley, Cardiff University
  • ,
  • Sarah C Brennan, Cardiff University, University of Sydney
  • ,
  • Polina L Yarova, Cardiff University, Newcastle University Medical School
  • ,
  • Joao Graca, Cardiff University, AstraZeneca
  • ,
  • Umar-Khetaab Hanif, Cardiff University
  • ,
  • Christian Müller, Medical University of Vienna
  • ,
  • Teresa Manhardt, Medical University of Vienna
  • ,
  • Martina Salzmann, Medical University of Vienna
  • ,
  • Helen Quasnichka, Cardiff University
  • ,
  • Sally A Price, AstraZeneca
  • ,
  • Donald T Ward, University of Manchester
  • ,
  • Thierry Gilbert, Universite Toulouse III - Paul Sabatier
  • ,
  • Vladimir V Matchkov
  • Robert A Fenton
  • Amanda Herberger, University of California
  • ,
  • Jenna Hwong, University of California
  • ,
  • Christian Santa Maria, University of California
  • ,
  • Chia-Ling Tu, University of California
  • ,
  • Enikö Kallay, Medical University of Vienna
  • ,
  • Giovanna Valenti, University of Bari
  • ,
  • Wenhan Chang, University of California
  • ,
  • Daniela Riccardi, Cardiff University

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-D 3), 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.

Original languageEnglish
JournalJournal of the American Society of Nephrology : JASN
Volume33
Issue7
Pages (from-to)1323-1340
Number of pages18
ISSN1046-6673
DOIs
Publication statusPublished - Jul 2022

    Research areas

  • Animals, Calcium/metabolism, Disease Models, Animal, Fibroblast Growth Factors/metabolism, Klotho Proteins, Mice, Mice, Knockout, Minerals/metabolism, Muscle, Smooth, Vascular/metabolism, Myocytes, Smooth Muscle/metabolism, Receptors, Calcium-Sensing/genetics, Vascular Calcification/etiology

See relations at Aarhus University Citationformats

ID: 272523026