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
View: Text | PDF
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

×

Figure 2

Effects of 1-week daily administration of NPS2143 in TPTX, PTH-supplemented rats.

Options: View larger image (or click on image) Download as PowerPoint
Effects of 1-week daily administration of NPS2143 in TPTX, PTH-supplemen...
(A) Summary of the protocol. (B) Urinary Ca excretion (expressed as a ratio to urinary creatinine excretion) at baseline and during 1 week of daily administration of NPS2143 (or placebo). In NPS2143-treated rats (1.5 mg/d intraperitoneally), urinary Ca excretion significantly decreased and was lower than in control rats (P < 0.01) on the first day of NPS2143 administration. Subsequently, urinary Ca excretion increased back to baseline values. n = 9 per group. *P < 0.01, †P = 0.03 versus control group. (C) Blood ionized Ca concentration at baseline and on days 2, 4, and 7 of daily administration of NPS2143 (or placebo); in treated rats, blood ionized Ca concentration significantly increased by the second day of NPS2143 administration and remained higher than in control rats throughout the period. *P = 0.05, **P = 0.02, ***P = 0.01. (D–G) Twenty-four-hour urinary creatinine excretion and urinary phosphate, Na, and K excretion (expressed as a ratio to urinary creatinine excretion) at baseline and during 1 week of daily administration of NPS2143 (or placebo). No statistical difference between treated and control rats was seen for any variable. n = 9 per group.