Differential parathyroid and kidney Ca 2+ -sensing receptor activation in autosomal dominant hypocalcemia 1.

Background: Parathyroid Ca ²⁺ -sensing receptor (CaSR) activation inhibits parathyroid hormone (PTH) release, while activation of renal CaSRs attenuates Ca ²⁺ transport and increases expression of the pore-blocking claudin-14. Patients with autosomal dominant hypocalcemia 1 (ADH1), due to activating CASR mutations, exhibit hypocalcemia but not always hypercalciuria (elevated Ca ²⁺ in urine). The latter promotes nephrocalcinosis and renal insufficiency. Although CaSRs throughout the body including the kidney harbor activating CASR mutations, it is not understood why only some ADH1 patients display hypercalciuria.
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 Ca ²⁺ 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 Ca ²⁺ levels. Similarly, significant hypercalciuria was not observed in a ADH1 patient until blood Ca ²⁺ 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 Ca ²⁺ to levels insufficient to activate renal CaSRs, even when an activating mutation is present. These findings identify a conceptually new mechanism of CaSR-dependent Ca ²⁺ 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.
Competing Interests: Declaration of interests RTA has received consulting fees and a grant from Ardylex Inc to determine the mechanism of action of their drug Tenapanor, which is not related to this work. RTA has received honoraria for Ultragenyx for a lecture on FGF23 lowering therapies. WvM obtained an Erasmus+ grant for a graduate research stay in the lab of H. Dimke. The authors have declared that no conflict of interest exists.
(Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)