Renal calcification in mice homozygous for the disrupted type IIa Na/Pi cotransporter gene Npt2.
Mice homozygous for the disrupted renal type IIa sodium/phosphate (Na/Pi) cotransporter gene (Npt2-/-) exhibit renal Pi wasting, hypophosphatemia, and an adaptive increase in the serum concentration of 1,25-dihydroxyvitamin D with associated hypercalcemia and hypercalciuria. Because hypercalciuria is a risk factor for nephrocalcinosis, we determined whether Npt2-/- mice form renal stones. Analysis of renal sections by von Kossa staining and intact kidneys by microcomputed tomography revealed renal calcification in adult Npt2-/- mice but not in Npt2+/+ littermates. Energy-dispersive spectroscopy and selected-area electron diffraction indicated that the calcifications are comprised of calcium and Pi with an apatitic mineral phase. To determine the age of onset of nephrocalcinosis, we examined renal sections of newborn and weanling mice. At both ages, mutant but not wild-type mice display renal calcification, which is associated with renal Pi wasting and hypercalciuria. Immunohistochemistry revealed that osteopontin co-localizes with the calcifications. Furthermore, renal osteopontin messenger RNA abundance is significantly elevated in Npt2-/- mice compared with Npt2+/+ mice. The onset of renal stones correlated developmentally with the absence of Npt2 expression and the expression of the genes responsible for the renal production (1alpha-hydroxylase) and catabolism (24-hydroxylase) of 1,25-dihydroxyvitamin D. In summary, we show that Npt2 gene ablation is associated with renal calcification and suggest that mutations in the NPT2 gene may contribute to nephrocalcinosis in a subset of patients with familial hypercalciuria.
Chau
Hien
H
Department of Biology, McGill University, Montreal, Quebec, Canada.
El-Maadawy
Sherif
S
McKee
Marc D
MD
Tenenhouse
Harriet S
HS
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000652:urine; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004247:DNA / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D006934:Hypercalcemia / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D007669:Kidney Calculi / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010710:Phosphates / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050608:Sodium-Phosphate Cotransporter Proteins; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D013250:Steroid Hydroxylases / Q000235:genetics; D027981:Symporters / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase
D010710:Phosphates; D012333:RNA, Messenger; C493548:SLC17A2 protein, human; C493554:SLC34A1 protein, human; C493549:Slc17a2 protein, mouse; C493555:Slc34a1 protein, mouse; D050608:Sodium-Phosphate Cotransporter Proteins; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D027981:Symporters; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002118:Calcium