PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor
Alexandre Loupy, … , Martial Ruat, Pascal Houillier
Alexandre Loupy, … , Martial Ruat, Pascal Houillier
Published August 13, 2012
Citation Information: J Clin Invest. 2012;122(9):3355-3367. https://doi.org/10.1172/JCI57407.
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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 8

Effect of NPS2143 on transepithelial ion transport in the rat cTAL.

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Effect of NPS2143 on transepithelial ion transport in the rat cTAL. cTAL...
cTALs were dissected from rat kidney and perfused in vitro as explained in Methods. Peritubular addition of 1 μM NPS2143 elicited a significant and reversible increase in transepithelial Ca absorption (*P = 0.03), but did not change Vte (A) or transepithelial sodium or chloride absorption (B and C, respectively) (P = NS). n = 5. (D) 1 μM NPS2143 elicited a significant increase in the paracellular pathway permeability to Ca in rat cTAL microperfused in vitro (*P = 0.0027). n = 4. (E) As compared with the control period, PTH (300 pM in the peritubular fluid) elicited a significant increase in transepithelial Ca absorption (**P = 0.024); peritubular addition of 1 μM NPS2143, in the presence of PTH elicited a further increase in transepithelial Ca absorption (*P = 0.045 as compared with the PTH period) that was significantly lower than in the absence of peritubular PTH (n = 4). Vte was not changed throughout the experiment.