PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor
Alexandre Loupy, Suresh Krishna Ramakrishnan, Bharath Wootla, Régine Chambrey, Renaud de la Faille, Soline Bourgeois, Patrick Bruneval, Chantal Mandet, Erik Ilso Christensen, Hélène Faure, Lydie Cheval, Kamel Laghmani, Corinne Collet, Dominique Eladari, Robert H. Dodd, Martial Ruat, Pascal Houillier
Alexandre Loupy, Suresh Krishna Ramakrishnan, Bharath Wootla, Régine Chambrey, Renaud de la Faille, Soline Bourgeois, Patrick Bruneval, Chantal Mandet, Erik Ilso Christensen, Hélène Faure, Lydie Cheval, Kamel Laghmani, Corinne Collet, Dominique Eladari, Robert H. Dodd, Martial Ruat, Pascal Houillier
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Research Article Nephrology

PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor

Abstract

Tight regulation of calcium levels is required for many critical biological functions. The Ca2+-sensing receptor (CaSR) expressed by parathyroid cells controls blood calcium concentration by regulating parathyroid hormone (PTH) secretion. However, CaSR is also expressed in other organs, such as the kidney, but the importance of extraparathyroid CaSR in calcium metabolism remains unknown. Here, we investigated the role of extraparathyroid CaSR using thyroparathyroidectomized, PTH-supplemented rats. Chronic inhibition of CaSR selectively increased renal tubular calcium absorption and blood calcium concentration independent of PTH secretion change and without altering intestinal calcium absorption. CaSR inhibition increased blood calcium concentration in animals pretreated with a bisphosphonate, indicating that the increase did not result from release of bone calcium. Kidney CaSR was expressed primarily in the thick ascending limb of the loop of Henle (TAL). As measured by in vitro microperfusion of cortical TAL, CaSR inhibitors increased calcium reabsorption and paracellular pathway permeability but did not change NaCl reabsorption. We conclude that CaSR is a direct determinant of blood calcium concentration, independent of PTH, and modulates renal tubular calcium transport in the TAL via the permeability of the paracellular pathway. These findings suggest that CaSR inhibitors may provide a new specific treatment for disorders related to impaired PTH secretion, such as primary hypoparathyroidism.

Authors

Alexandre Loupy, Suresh Krishna Ramakrishnan, Bharath Wootla, Régine Chambrey, Renaud de la Faille, Soline Bourgeois, Patrick Bruneval, Chantal Mandet, Erik Ilso Christensen, Hélène Faure, Lydie Cheval, Kamel Laghmani, Corinne Collet, Dominique Eladari, Robert H. Dodd, Martial Ruat, Pascal Houillier

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Figure 7

Localization of CaSR in the rat kidney.

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Localization of CaSR in the rat kidney. (A) Quantification of Casr trans...
(A) Quantification of Casr transcripts along the rat nephron. RT-PCR analysis of mRNAs encoding CaSR was performed on microdissected renal tubules. Casr transcripts were detected at a significant level in the medullary TAL (mTAL) and cTAL. No significant transcript expression was detected in the PCT, PR, CCD, or OMCD. A non-significant level of Casr mRNAs was found in the CNT. *P < 0.001 between cTAL and mTAL Casr mRNA expression. (B) Western blotting for CaSR in rat microdissected CCD, using 1:1,000 anti-CaSR Ab (MA1-934). No signal was observed using anti-CaSR Ab. γ-ENaC (specific for CCD) was used as a positive control. (C) CaSR localization in the kidney by EM. CaSR immunocytochemistry of ultrathin cryosections from rat kidney with gold labeling for CaSR in the TAL showing basolateral gold labeling (arrow). No apical TAL labeling and no CCD labeling were noted (original magnification, ×100,000).