title: Deficiency of the calcium-sensing receptor in the kidney causes parathyroid hormone-independent hypocalciuria.
abstract: Rare loss-of-function mutations in the calcium-sensing receptor (Casr) gene lead to decreased urinary calcium excretion in the context of parathyroid hormone (PTH)-dependent hypercalcemia, but the role of Casr in the kidney is unknown. Using animals expressing Cre recombinase driven by the Six2 promoter, we generated mice that appeared grossly normal but had undetectable levels of Casr mRNA and protein in the kidney. Baseline serum calcium, phosphorus, magnesium, and PTH levels were similar to control mice. When challenged with dietary calcium supplementation, however, these mice had significantly lower urinary calcium excretion than controls (urinary calcium to creatinine, 0.31±0.03 versus 0.63±0.14; P=0.001). Western blot analysis on whole-kidney lysates suggested an approximately four-fold increase in activated Na(+)-K(+)-2Cl(-) cotransporter (NKCC2). In addition, experimental animals exhibited significant downregulation of Claudin14, a negative regulator of paracellular cation permeability in the thick ascending limb, and small but significant upregulation of Claudin16, a positive regulator of paracellular cation permeability. Taken together, these data suggest that renal Casr regulates calcium reabsorption in the thick ascending limb, independent of any change in PTH, by increasing the lumen-positive driving force for paracellular Ca(2+) transport.
authors.affiliation: Division of Nephrology, Beth Israel Medical Center, 330 Brookline Avenue, Boston, MA 02115, USA.
authors.forename: Hakan R
authors.initials: HR
authors.lastname: Toka
authors.forename: Khaldoun
authors.initials: K
authors.lastname: Al-Romaih
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Koshy
authors.forename: Salvatore
authors.initials: S
authors.lastname: DiBartolo
authors.forename: Claudine H
authors.initials: CH
authors.lastname: Kos
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Quinn
authors.forename: Gary C
authors.initials: GC
authors.lastname: Curhan
authors.forename: David B
authors.initials: DB
authors.lastname: Mount
authors.forename: Edward M
authors.initials: EM
authors.lastname: Brown
authors.forename: Martin R
authors.initials: MR
authors.lastname: Pollak
mesh_terms: D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000652:urine*; D057167:Claudins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044169:Receptors, Calcium-Sensing / Q000172:deficiency* / Q000235:genetics; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1; D014157:Transcription Factors / Q000235:genetics
chemical_list: D057167:Claudins; D018398:Homeodomain Proteins; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D044169:Receptors, Calcium-Sensing; C497420:Six2 protein, mouse; C578715:Slc12a1 protein, mouse; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D014157:Transcription Factors; C502010:claudin 16; D002118:Calcium; C422064:claudin 14