title: 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.affiliation: INSERM UMRS 872, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Loupy
authors.forename: Suresh Krishna
authors.initials: SK
authors.lastname: Ramakrishnan
authors.forename: Bharath
authors.initials: B
authors.lastname: Wootla
authors.forename: Régine
authors.initials: R
authors.lastname: Chambrey
authors.forename: Renaud
authors.initials: R
authors.lastname: de la Faille
authors.forename: Soline
authors.initials: S
authors.lastname: Bourgeois
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.forename: Chantal
authors.initials: C
authors.lastname: Mandet
authors.forename: Erik Ilso
authors.initials: EI
authors.lastname: Christensen
authors.forename: Hélène
authors.initials: H
authors.lastname: Faure
authors.forename: Lydie
authors.initials: L
authors.lastname: Cheval
authors.forename: Kamel
authors.initials: K
authors.lastname: Laghmani
authors.forename: Corinne
authors.initials: C
authors.lastname: Collet
authors.forename: Dominique
authors.initials: D
authors.lastname: Eladari
authors.forename: Robert H
authors.initials: RH
authors.lastname: Dodd
authors.forename: Martial
authors.initials: M
authors.lastname: Ruat
authors.forename: Pascal
authors.initials: P
authors.lastname: Houillier
mesh_terms: D000596:Amino Acids / Q000652:urine; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology / Q000627:therapeutic use; D002118:Calcium / Q000097:blood* / Q000378:metabolism / Q000652:urine; D003404:Creatinine / Q000652:urine; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use; D007011:Hypoparathyroidism / Q000097:blood / Q000188:drug therapy; D008138:Loop of Henle / Q000378:metabolism; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use; D015675:Osteocalcin / Q000097:blood; D000077268:Pamidronate; D010281:Parathyroid Hormone / Q000378:metabolism*; D016105:Parathyroidectomy; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1
chemical_list: D000596:Amino Acids; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; C436740:N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine; D009281:Naphthalenes; D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; C578716:Slc12a1 protein, rat; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D015675:Osteocalcin; C036020:deoxypyridinoline; D003404:Creatinine; D000254:Sodium-Potassium-Exchanging ATPase; D000077268:Pamidronate; D002118:Calcium