title: Hypervitaminosis D mediates compensatory Ca2+ hyperabsorption in TRPV5 knockout mice.
abstract: Vitamin D plays an important role in Ca(2+) homeostasis by controlling Ca(2+) (re)absorption in intestine, kidney, and bone. The epithelial Ca(2+) channel TRPV5 mediates the Ca(2+) entry step in active Ca(2+) reabsorption. TRPV5 knockout (TRPV5(-/-)) mice show impaired Ca(2+) reabsorption, hypercalciuria, hypervitaminosis D, and intestinal hyperabsorption of Ca(2+). Moreover, these mice demonstrate upregulation of intestinal TRPV6 and calbindin-D(9K) expression compared with wild-type mice. For addressing the role of the observed hypervitaminosis D in the maintenance of Ca(2+) homeostasis and the regulation of expression levels of the Ca(2+) transport proteins in kidney and intestine, TRPV5/25-hydroxyvitamin-D(3)-1alpha-hydroxylase double knockout (TRPV5(-/-)/1alpha-OHase(-/-)) mice, which show undetectable serum 1,25(OH)(2)D(3) levels, were generated. TRPV5(-/-)/1alpha-OHase(-/-) mice displayed a significant hypocalcemia compared with wild-type mice (1.10 +/- 0.02 and 2.54 +/- 0.01 mM, respectively; P < 0.05). mRNA levels of renal calbindin-D(28K) (7 +/- 2%), calbindin-D(9K) (32 +/- 4%), Na(+)/Ca(2+) exchanger (12 +/- 2%), and intestinal TRPV6 (40 +/- 8%) and calbindin-D(9K) (26 +/- 4%) expression levels were decreased compared with wild-type mice. Hyperparathyroidism and rickets were present in TRPV5(-/-)/1alpha-OHase(-/-) mice, more pronounced than observed in single TRPV5 or 1alpha-OHase knockout mice. It is interesting that a renal Ca(2+) leak, as demonstrated in TRPV5(-/-) mice, persisted in TRPV5(-/-)/1alpha-OHase(-/-) mice, but a compensatory upregulation of intestinal Ca(2+) transporters was abolished. In conclusion, the elevation of serum 1,25(OH)(2)D(3) levels in TRPV5(-/-) mice is responsible for the upregulation of intestinal Ca(2+) transporters and Ca(2+) hyperabsorption. Hypervitaminosis D, therefore, is of crucial importance to maintain normocalcemia in impaired Ca(2+) reabsorption in TRPV5(-/-) mice.
authors.affiliation: Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Kirsten Y
authors.initials: KY
authors.lastname: Renkema
authors.forename: Tom
authors.initials: T
authors.lastname: Nijenhuis
authors.forename: Bram C J
authors.initials: BC
authors.lastname: van der Eerden
authors.forename: Annemiete W C M
authors.initials: AW
authors.lastname: van der Kemp
authors.forename: Harrie
authors.initials: H
authors.lastname: Weinans
authors.forename: Johannes P T M
authors.initials: JP
authors.lastname: van Leeuwen
authors.forename: René J M
authors.initials: RJ
authors.lastname: Bindels
authors.forename: Joost G J
authors.initials: JG
authors.lastname: Hoenderop
mesh_terms: D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000097:blood / Q000378:metabolism* / Q000652:urine; D015220:Calcium Channels / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D003433:Crosses, Genetic; D005260:Female; D006706:Homeostasis; D007668:Kidney / Q000502:physiology; D008297:Male; D008659:Metabolic Diseases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D050916:TRPV Cation Channels / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D014807:Vitamin D / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D050916:TRPV Cation Channels; C492240:Trpv5 protein, mouse; D014807:Vitamin D; D002118:Calcium