Modulation of renal Ca2+ transport protein genes by dietary Ca2+ and 1,25-dihydroxyvitamin D3 in 25-hydroxyvitamin D3-1alpha-hydroxylase knockout mice.
Pseudovitamin D-deficiency rickets (PDDR) is an autosomal disease characterized by hyperparathyroidism, rickets, and undetectable levels of 1,25-dihydroxyvitaminD3 (1,25(OH)2D3). Mice in which the 25-hydroxyvitamin D3-1alpha-hydroxylase (1alpha-OHase) gene was inactivated presented the same clinical phenotype as patients with PDDR and were used to study renal expression of the epithelial Ca2+ channel (ECaC1), the calbindins, Na+/Ca2+ exchanger (NCX1), and Ca2+-ATPase (PMCA1b). Serum Ca2+ (1.20+/-0.05 mM) and mRNA/protein expression of ECaC1 (41+/-3%), calbindin-D28K (31+/-2%), calbindin-D9K (58+/-7%), NCX1 (10+/-2%), PMCA1b (96+/-4%) were decreased in 1alpha-OHase-/- mice compared with 1alpha-OHase+/- littermates. Feeding these mice a Ca2+-enriched diet normalized serum Ca2+ levels and expression of Ca2+ proteins except for calbindin-D9K expression. 1,25(OH)2D3 repletion resulted in increased expression of Ca2+ transport proteins and normalization of serum Ca2+ levels. Localization of Ca2+ transport proteins was clearly polarized in which ECaC1 was localized along the apical membrane, calbindin-D28K in the cytoplasm, and calbindin-D9K along the apical and basolateral membranes, resulting in a comprehensive mechanism facilitating renal transcellular Ca2+ transport. This study demonstrated that high dietary Ca2+ intake is an important regulator of the renal Ca2+ transport proteins in 1,25(OH)2D3-deficient status and thus contributes to the normalization of blood Ca2+ levels.
Department of Cell Physiology, University Medical Centre Nijmegen, 6500 HB Nijmegen, Netherlands.
Joost G J
JG
Hoenderop
Olivier
O
Dardenne
Monique
M
Van Abel
Annemiete W C M
AW
Van Der Kemp
Carel H
CH
Van Os
René
R
St -Arnaud
René J M
RJ
Bindels
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics*; D000284:Administration, Oral; D000818:Animals; D064092:Calbindin 1; D064026:Calbindins; D002117:Calcitriol / Q000008:administration & dosage / Q000494:pharmacology*; D002118:Calcium / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D015220:Calcium Channels / Q000032:analysis; D002135:Calcium-Binding Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D000252:Calcium-Transporting ATPases / Q000096:biosynthesis / Q000235:genetics; D027682:Cation Transport Proteins; D007668:Kidney / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D053499:Plasma Membrane Calcium-Transporting ATPases; D012333:RNA, Messenger / Q000096:biosynthesis; D012279:Rickets / Q000235:genetics / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000096:biosynthesis / Q000235:genetics; D019831:Sodium-Calcium Exchanger / Q000096:biosynthesis / Q000235:genetics; D050916:TRPV Cation Channels; D015854:Up-Regulation; D014808:Vitamin D Deficiency / Q000235:genetics / Q000378:metabolism
C576499:Calb1 protein, mouse; D064092:Calbindin 1; D064026:Calbindins; D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; D012333:RNA, Messenger; D064030:S100 Calcium Binding Protein G; C576507:S100g protein, mouse; D019831:Sodium-Calcium Exchanger; D050916:TRPV Cation Channels; C492240:Trpv5 protein, mouse; C110374:sodium-calcium exchanger 1; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D053499:Plasma Membrane Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002117:Calcitriol; D002118:Calcium