title: Coordinated control of renal Ca(2+) transport proteins by parathyroid hormone.
abstract: BACKGROUND
  The kidney is one of the affected organs involved in the clinical symptoms of parathyroid hormone (PTH)-related disorders, like primary hyperparathyroidism and familial hypocalciuric hypercalcemia. The molecular mechanism(s) underlying alterations in renal Ca(2+) handling in these disorders is poorly understood.
  
  
  METHODS
  Parathyroidectomized and PTH-supplemented rats and mice infused with the calcimimetic compound NPS R-467 were used to study the in vivo effect of PTH on the expression of renal transcellular Ca(2+) transport proteins, including the epithelial Ca(2+) channel transient receptor potential, vanilloid, member 5 (TRPV5), calbindins, and the Na(+)/Ca(2+)-exchanger (NCX1). In addition, the effect of PTH on transepithelial Ca(2+) transport in rabbit connecting tubule/cortical collecting duct (CNT/CCD) primary cultures was determined.
  
  
  RESULTS
  Decreased PTH levels in parathyroidectomized rats or NPS R-467-infused mice, resulted in reduced expression of these proteins, which is consistent with diminished Ca(2+) reabsorption, causing the development of the observed hypocalcemia. PTH supplementation of parathyroidectomized rats restored the expression of the renal Ca(2+) transport machinery and serum Ca(2+) levels, independent of serum 1,25-dihydroxyvitamin D(3) levels and renal vitamin D or Ca(2+)-sensing receptor mRNA abundance. Inhibition of the PTH-stimulated transepithelial Ca(2+) transport by the TRPV5-specific inhibitor ruthenium red reduced the PTH-stimulated expression of calbindin-D(28K) and NCX1 in rabbit CNT/CCD primary cultures.
  
  
  CONCLUSIONS
  PTH stimulates renal Ca(2+) reabsorption through the coordinated expression of renal transcellular Ca(2+) transport proteins. Moreover, the PTH-induced stimulation is enhanced by the magnitude of the Ca(2+) influx through the gatekeeper TRPV5, which in turn facilitates the expression of the downstream Ca(2+) transport proteins. Therefore, the renal transcellular Ca(2+) transport proteins, including TRPV5, could contribute to the pathogenesis of PTH-related disorders.
authors.affiliation: Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: van Abel
authors.forename: Joost G J
authors.initials: JG
authors.lastname: Hoenderop
authors.forename: Annemiete W C M
authors.initials: AW
authors.lastname: van der Kemp
authors.forename: Michael M
authors.initials: MM
authors.lastname: Friedlaender
authors.forename: Johannes P T M
authors.initials: JP
authors.lastname: van Leeuwen
authors.forename: René J M
authors.initials: RJ
authors.lastname: Bindels
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D064026:Calbindins; D002118:Calcium / Q000819:agonists / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D006996:Hypocalcemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007668:Kidney / Q000166:cytology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010281:Parathyroid Hormone / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D016105:Parathyroidectomy; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D044169:Receptors, Calcium-Sensing / Q000235:genetics / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000235:genetics / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D000814:Aniline Compounds; D064026:Calbindins; D015220:Calcium Channels; C111654:NPS R-467; D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D064030:S100 Calcium Binding Protein G; D019831:Sodium-Calcium Exchanger; D050916:TRPV Cation Channels; C492241:TRPV5 protein, rat; C110374:sodium-calcium exchanger 1; D002118:Calcium