Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review
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 et al.
In: Journal of the American Society of Nephrology : JASN, Vol. 33, No. 7, 07.2022, p. 1323-1340.Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review
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TY - JOUR
T1 - Impaired Mineral Ion Metabolism in a Mouse Model of Targeted Calcium-Sensing Receptor (CaSR) Deletion from Vascular Smooth Muscle Cells
AU - Schepelmann, Martin
AU - Ranieri, Marianna
AU - Lopez-Fernandez, Irene
AU - Webberley, Thomas S
AU - Brennan, Sarah C
AU - Yarova, Polina L
AU - Graca, Joao
AU - Hanif, Umar-Khetaab
AU - Müller, Christian
AU - Manhardt, Teresa
AU - Salzmann, Martina
AU - Quasnichka, Helen
AU - Price, Sally A
AU - Ward, Donald T
AU - Gilbert, Thierry
AU - Matchkov, Vladimir V
AU - Fenton, Robert A
AU - Herberger, Amanda
AU - Hwong, Jenna
AU - Santa Maria, Christian
AU - Tu, Chia-Ling
AU - Kallay, Enikö
AU - Valenti, Giovanna
AU - Chang, Wenhan
AU - Riccardi, Daniela
N1 - Copyright © 2022 by the American Society of Nephrology.
PY - 2022/7
Y1 - 2022/7
N2 - 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.
AB - 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.
KW - Animals
KW - Calcium/metabolism
KW - Disease Models, Animal
KW - Fibroblast Growth Factors/metabolism
KW - Klotho Proteins
KW - Mice
KW - Mice, Knockout
KW - Minerals/metabolism
KW - Muscle, Smooth, Vascular/metabolism
KW - Myocytes, Smooth Muscle/metabolism
KW - Receptors, Calcium-Sensing/genetics
KW - Vascular Calcification/etiology
U2 - 10.1681/ASN.2021040585
DO - 10.1681/ASN.2021040585
M3 - Journal article
C2 - 35581010
VL - 33
SP - 1323
EP - 1340
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
SN - 1046-6673
IS - 7
ER -