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 Ca 2+ -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.

Claudin-14 Underlies Ca++-Sensing Receptor–Mediated Ca++ Metabolism via NFAT-microRNA–Based Mechanisms

“…Additional mechanisms, such as phosphorylation, palmitoylation, and trafficking, may also exist for claudin-14, -16, and -19 that explain more transient changes (within minutes) in paracellular Ca ++ transport during some in vitro recordings in perfused TALH tubules. 14,27 CaSR is the first identified G protein-coupled receptor to be activated by an extracellular ion-Ca ++ . 1 Its function has been shown to be crucial for many physiologic processes, including sperm generation, embryonic development, Ca ++ metabolism, neuronal excitability, etc., and underlie various diseases, such as hyper-and hypoparathyroidism, kidney stones, osteoporosis, Alzheimer disease, epilepsy, etc.…”

“…40 40 A direct support for the renal role of CaSR in defending hypercalcemia was provided by Toka et al 41 With a kidney-specific CaSR KO mouse model, Toka et al 41 have elegantly shown that the KO mice excrete significantly less Ca ++ in face of hypercalcemia, although their PTH secretion was intact. Loupy et al 14 have studied the renal role of CaSR in cases of hypercalcemia induced by the calcilytic compound NPS2143. In TPTX rats supplemented with a constant PTH level, NPS2143 administration elicited a significant decrease in urinary Ca ++ excretion without affecting net Ca ++ release from the bone or intestinal Ca ++ absorption.…”

“…13 NPS2143 is a novel CaSR antagonist (calcilytic) that has been previously shown to increase serum Ca ++ levels independent of PTH secretion, thus providing an effective treatment for restoring extracellular Ca ++ levels in primary hypoparathyroidism. 14 The kidney CaSR is predominantly expressed in the TALH, 14 colocalizing with claudin-14. To reveal how CaSR regulated claudin-14 in vivo in the kidney, we treated age-(8-10 weeks old) and sexmatched (male) mice (strain C57BL/6) with NPS2143 and cinacalcet over a range of doses and durations; then, we isolated kidneys at the end of each treatment and quantified claudin-14 mRNA and protein levels with real-time PCR and Western blot, respectively.…”

Claudins and the Kidney

“…Loupy et al showed that a CaSR antagonist increased Ca 2+ permeability in isolated perfused TALH, with no change in transepithelial voltage or Na flux. 80 This appears to be mediated by regulation of the expression of claudin-14. Activation of the CaSR causes robust upregulation of claudin-14, 81,82 which, through physical interaction, inhibits paracellular cation channels formed by claudin-16 and -19.…”

Thick Ascending Limb of the Loop of Henle

“…Both extracellular Ca 21 and PGE 2 activate the G i inhibitory G protein in TAL cells, opposing the stimulatory, G s -dependent effects of vasopressin on intracellular levels of cAMP (91). Extracellular Ca 21 exerts its effect through the CaSR, which is heavily expressed at the basolateral membrane of TAL cells (91,92); PGE 2 primarily signals through EP 3 PG receptors (76). The increases in intracellular Ca 21 due to the activation of the CaSR and other receptors directly inhibits cAMP generation by a Ca 21 -inhibitable adenylate cyclase that is expressed in the TAL, accompanied by an increase in phosphodiesterasedependent degradation of cAMP (91,93).…”