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 6

Immunolocalization of CaSR in the rat kidney.

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Immunolocalization of CaSR in the rat kidney. (A) Immunolocalization of ...
(A) Immunolocalization of the CaSR protein in the renal cortex and outer medulla. Immunoperoxidase staining in rat kidney sections showed a cytoplasmic and basolateral labeling of tubular cells in the cortex (original magnification, ×200 and ×400) and the inner and outer stripes of the outer medulla (×100). The stained tubules were present in the medullary rays (arrows) and in the juxtaglomerular apparatus (asterisk). Proximal tubules and glomeruli showed no detectable CaSR staining (×1,000). (B) CaSR is expressed in the rat TAL. Shown is double staining with Abs directed against CaSR (red) and Tamm-Horsfall protein (Thp), specifically expressed in the TAL (green). When comparing with tubular segments that stained for Tamm-Horsfall protein, CaSR staining was basolateral (original magnification, ×2,000). (C) CaSR is not detectable in the rat distal convoluted tubule (DCT). Sections of rat kidney double stained for CaSR and the thiazide-sensitive NaCl cotransporter (Ncc) localized in the DCT. Basolateral CaSR staining was interrupted when the tubule showed apical staining for Ncc, thus representing the distal limit for CaSR staining (original magnification, ×1,500). (D) CaSR is not detectable in the rat CCD. Sections of rat kidney double stained for CaSR and aquaporin-2 (Aqp2). In the merged image, tubular segments that stained for aquaporin-2 did not show CaSR staining and vice versa (original magnification, ×1,000).