Abstract | BACKGROUND: METHODS: Activation of the CaSR was studied in mouse models and a ADH1 patient. In vitro CaSR activation was studied in HEK293 cells. FINDINGS: Cldn14 showed blood Ca2+ concentration-dependent regulation, which was absent in mice with kidney-specific Casr deletion, indicating Cldn14 is a suitable marker for chronic CaSR activation in the kidney. Mice with a gain-of-function mutation in the Casr (Nuf) were hypocalcemic with low plasma PTH levels. However, renal CaSRs were not activated at baseline but only after normalizing blood Ca2+ levels. Similarly, significant hypercalciuria was not observed in a ADH1 patient until blood Ca2+ was normalized. In vitro experiments indicate that increased CaSR expression in the parathyroid relative to the kidney could contribute to tissue-specific CaSR activation thresholds. INTERPRETATION: Our findings suggest that parathyroid CaSR overactivity can reduce plasma Ca2+ to levels insufficient to activate renal CaSRs, even when an activating mutation is present. These findings identify a conceptually new mechanism of CaSR-dependent Ca2+ balance regulation that aid in explaining the spectrum of hypercalciuria in ADH1 patients. FUNDING: Erasmus+ 2018/E+/4458087, the Canadian Institutes for Health research, the Novo Nordisk Foundation, the Beckett Foundation, the Carlsberg Foundation and Independent Research Fund Denmark.
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Authors | Wouter H van Megen, Rebecca Siu Ga Tan, R Todd Alexander, Henrik Dimke |
Journal | EBioMedicine
(EBioMedicine)
Vol. 78
Pg. 103947
(Apr 2022)
ISSN: 2352-3964 [Electronic] Netherlands |
PMID | 35313217
(Publication Type: Journal Article)
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Copyright | Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved. |
Chemical References |
- Parathyroid Hormone
- Receptors, Calcium-Sensing
- Calcium
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Topics |
- Animals
- Calcium
(metabolism)
- Canada
- HEK293 Cells
- Humans
- Hypercalciuria
(genetics)
- Hypocalcemia
(genetics)
- Hypoparathyroidism
(congenital)
- Kidney
(metabolism)
- Mice
- Parathyroid Hormone
- Receptors, Calcium-Sensing
(genetics, metabolism)
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