Na/P(i) cotransporter ( Npt2) gene disruption increases duodenal calcium absorption and expression of epithelial calcium channels 1 and 2.
Mice homozygous for the disrupted type-II Na/P(i) cotransporter gene ( Npt2(-/-)) exhibit hypophosphataemia, increased serum concentration of 1,25-dihydroxyvitamin D (1,25-(OH)(2)D) and calcium (Ca) and elevated urinary Ca excretion. To determine whether the hypercalcaemia and hypercalciuria are secondary to 1,25-(OH)(2)D-stimulated intestinal Ca absorption, we examined the effect of Npt2 gene disruption on serum Ca and urinary Ca excretion after an overnight fast, and on duodenal Ca absorption. We also compared the duodenal expression of the epithelial Ca channels, ECaC1 and ECaC2, and calbindinD(9K) mRNAs, relative to that of beta-actin mRNA, in Npt2(+/+) and Npt2(-/-) mice. Both serum Ca and urine Ca/creatinine were significantly decreased in Npt2(-/-) mice after an overnight fast and were no longer different from that in wild-type mice. Absorption of (45)Ca from isolated duodenal segments in vivo and (45)Ca appearing in the plasma were significantly increased in Npt2(-/-) compared with Npt2(+/+) mice. In addition, the duodenal abundance of ECaC1, ECaC2 and calbindinD(9K) mRNAs was significantly elevated in mutant mice relative to that in wild-type mice. In contrast, both duodenal Ca absorption and ECaC1 and ECaC2 mRNA abundance were lower in mice with X-linked hypophosphataemia ( Hyp) than in normal littermates. In summary, we provide evidence for increased duodenal Ca absorption in Npt2(-/-) mice and suggest a role for ECaC1, ECaC2 and calbindinD(9K) in mediating this response.
Tenenhouse
Harriet S
HS
Department of Pediatrics, McGill University-Montreal Children's Hospital Research Institute, 2300 Tupper Street, Montreal, Quebec H3H 1P3, Canada. mdht@debelle.mcgill.ca
Gauthier
Claude
C
Martel
Josée
J
Hoenderop
Joost G J
JG
Hartog
Anita
A
Meyer
Martha H
MH
Meyer
Ralph A
RA
Bindels
René J M
RJ
D000818:Animals; D064026:Calbindins; D002118:Calcium / Q000097:blood / Q000652:urine*; D015220:Calcium Channels / Q000235:genetics*; D004386:Duodenum / Q000378:metabolism*; D005215:Fasting / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000502:physiology; D017674:Hypophosphatemia / Q000235:genetics / Q000378:metabolism*; D007408:Intestinal Absorption / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016296:Mutagenesis; D009154:Mutation; D012333:RNA, Messenger / Q000032:analysis; D064030:S100 Calcium Binding Protein G / Q000235:genetics; D050608:Sodium-Phosphate Cotransporter Proteins; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D027981:Symporters / Q000235:genetics* / Q000378:metabolism*; D050916:TRPV Cation Channels
D064026:Calbindins; D015220:Calcium Channels; D012333:RNA, Messenger; D064030:S100 Calcium Binding Protein G; C493549:Slc17a2 protein, mouse; D050608:Sodium-Phosphate Cotransporter Proteins; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D027981:Symporters; D050916:TRPV Cation Channels; C492240:Trpv5 protein, mouse; C446923:Trpv6 protein, mouse; D002118:Calcium