Home LiteratureArticle Details
PMID: 9560283 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 95 ·No. 9 ·1998-04-28 ·Pages 5372-7

Beck L, Karaplis AC, Amizuka N, Hewson AS, Ozawa H, Tenenhouse HS

Abstract

Npt2 encodes a renal-specific, brush-border membrane Na+-phosphate (Pi) cotransporter that is expressed in the proximal tubule where the bulk of filtered Pi is reabsorbed. Mice deficient in the Npt2 gene were generated by targeted mutagenesis to define the role of Npt2 in the overall maintenance of Pi homeostasis, determine its impact on skeletal development, and clarify its relationship to autosomal disorders of renal Pi reabsorption in humans. Homozygous mutants (Npt2(-/-)) exhibit increased urinary Pi excretion, hypophosphatemia, an appropriate elevation in the serum concentration of 1,25-dihydroxyvitamin D with attendant hypercalcemia, hypercalciuria and decreased serum parathyroid hormone levels, and increased serum alkaline phosphatase activity. These biochemical features are typical of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a Mendelian disorder of renal Pi reabsorption. However, unlike HHRH patients, Npt2(-/-) mice do not have rickets or osteomalacia. At weaning, Npt2(-/-) mice have poorly developed trabecular bone and retarded secondary ossification, but, with increasing age, there is a dramatic reversal and eventual overcompensation of the skeletal phenotype. Our findings demonstrate that Npt2 is a major regulator of Pi homeostasis and necessary for normal skeletal development.

MeSH Terms
Animals Biological Transport Body Weight Bone and Bones/abnormalities,pathology Calcitriol/metabolism Calcium/urine Carrier Proteins/physiology Female Gene Expression Heterozygote Kidney/metabolism Male Mice Mice, Knockout Microvilli/metabolism Phosphates/metabolism,urine RNA, Messenger/genetics Sodium/metabolism Sodium-Phosphate Cotransporter Proteins Sodium-Phosphate Cotransporter Proteins, Type I Sodium-Phosphate Cotransporter Proteins, Type III Symporters
Chemicals
Carrier Proteins Phosphates RNA, Messenger Slc17a2 protein, mouse Sodium-Phosphate Cotransporter Proteins Sodium-Phosphate Cotransporter Proteins, Type I Sodium-Phosphate Cotransporter Proteins, Type III Symporters Sodium Calcitriol Calcium
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Beck L
Departments of Pediatrics and Human Genetics, McGill University, Montreal Children's Hospital Research Institute, Montreal, PQ, Canada H3H 1P3.
Karaplis A C
Amizuka N
Hewson A S
Ozawa H
Tenenhouse H S
References (45)
45 references, click to expand
  1. Cleavage of structural proteins during the assembly of the head of bacteriophage T4.
    Nature. 1970 Aug 15;227(5259):680-5 PMID: 5432063
  2. Transcellular calcium transport in intestinal and renal epithelial cells.
    Biochim Biophys Acta. 1987 Jun 24;906(2):195-222 PMID: 2954588
  3. Hypophosphatemia: mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets.
    Proc Natl Acad Sci U S A. 1976 Dec;73(12):4667-71 PMID: 188049
  4. The defect in transcellular transport of phosphate in the nephron is located in brush-border membranes in X-linked hypophosphatemia (Hyp mouse model).
    Can J Biochem. 1978 Jun;56(6):640-6 PMID: 566613
  5. Dietary phosphate deprivation increases 1,25-dihyroxyvitamin D3 synthesis in rat kidney in vitro.
    J Biol Chem. 1983 Jan 25;258(2):1152-5 PMID: 6687381
  6. Hypercalciuric hypophosphatemic rickets, mineral balance, bone histomorphometry, and therapeutic implications of hypercalciuria.
    Pediatrics. 1989 Aug;84(2):276-80 PMID: 2787497
  7. Abnormal regulation of renal vitamin D catabolism by dietary phosphate in murine X-linked hypophosphatemic rickets.
    J Clin Invest. 1990 May;85(5):1450-5 PMID: 2332500
  8. Autosomal dominant hypophosphataemia with elevated serum 1,25 dihydroxyvitamin D and hypercalciuria.
    Pediatr Nephrol. 1987 Jul;1(3):479-84 PMID: 3153320
  9. Mechanism and regulation of intestinal phosphate absorption.
    Miner Electrolyte Metab. 1990;16(2-3):115-24 PMID: 2250617
  10. Osteomalacia in hereditary hypophosphatemic rickets with hypercalciuria: a correlative clinical-histomorphometric study.
    J Clin Endocrinol Metab. 1991 Jan;72(1):229-35 PMID: 1986023
  11. Cellular mechanisms in proximal tubular reabsorption of inorganic phosphate.
    Am J Physiol. 1991 May;260(5 Pt 1):C885-99 PMID: 2035618
  12. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene.
    Cell. 1991 Jun 28;65(7):1153-63 PMID: 2065352
  13. Cloning and expression of cDNA for a Na/Pi cotransport system of kidney cortex.
    Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9608-12 PMID: 1946375
  14. A new kindred with hereditary hypophosphatemic rickets with hypercalciuria: implications for correct diagnosis and treatment.
    Nephron. 1992;62(2):176-81 PMID: 1436310
  15. Expression cloning of human and rat renal cortex Na/Pi cotransport.
    Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5979-83 PMID: 8327470
  16. Localization of NaPi-1, a Na-Pi cotransporter, in rabbit kidney proximal tubules. I. mRNA localization by reverse transcription/polymerase chain reaction.
    Pflugers Arch. 1993 Aug;424(3-4):203-9 PMID: 8414907
  17. Localization of NaPi-1, a Na/Pi cotransporter, in rabbit kidney proximal tubules. II. Localization by immunohistochemistry.
    Pflugers Arch. 1993 Aug;424(3-4):210-5 PMID: 8414908
  18. Rat endopeptidase-24.18 alpha subunit is secreted into the culture medium as a zymogen when expressed by COS-1 cells.
    FEBS Lett. 1993 Dec 13;335(3):361-6 PMID: 8262184
  19. Molecular cloning of the cDNA encoding a human renal sodium phosphate transport protein and its assignment to chromosome 6p21.3-p23.
    Genomics. 1993 Nov;18(2):355-9 PMID: 8288239
  20. Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene.
    Genes Dev. 1994 Feb 1;8(3):277-89 PMID: 8314082
  21. Renal Na(+)-phosphate cotransport in murine X-linked hypophosphatemic rickets. Molecular characterization.
    J Clin Invest. 1994 Feb;93(2):671-6 PMID: 8113402
  22. Cloning of a Na/Pi cotransporter from opossum kidney cells.
    J Biol Chem. 1994 Mar 4;269(9):6615-21 PMID: 7509808
  23. Localization of a renal sodium-phosphate cotransporter gene to human chromosome 5q35.
    Genomics. 1994 Jan 1;19(1):176-7 PMID: 8188224
  24. Cell-surface receptors for gibbon ape leukemia virus and amphotropic murine retrovirus are inducible sodium-dependent phosphate symporters.
    Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7071-5 PMID: 8041748
  25. Molecular cloning, functional expression, tissue distribution, and in situ hybridization of the renal sodium phosphate (Na+/P(i)) transporter in the control and hypophosphatemic mouse.
    FASEB J. 1994 Aug;8(11):862-8 PMID: 8070635
  26. Cellular mechanisms of acute and chronic adaptation of rat renal P(i) transporter to alterations in dietary P(i).
    Am J Physiol. 1994 Nov;267(5 Pt 2):F900-8 PMID: 7977794
  27. Cloning of a rabbit renal Na-Pi cotransporter, which is regulated by dietary phosphate.
    Am J Physiol. 1995 Apr;268(4 Pt 2):F626-33 PMID: 7733319
  28. Parathyroid hormone action on phosphate transporter mRNA and protein in rat renal proximal tubules.
    Am J Physiol. 1995 Apr;268(4 Pt 2):F784-91 PMID: 7733336
  29. Cloning, genetic mapping, and expression analysis of a mouse renal sodium-dependent phosphate cotransporter.
    Am J Physiol. 1995 Jun;268(6 Pt 2):F1038-45 PMID: 7611445
  30. Effect of P(i) restriction on renal Na(+)-P(i) cotransporter mRNA and immunoreactive protein in X-linked Hyp mice.
    Am J Physiol. 1995 Jun;268(6 Pt 2):F1062-9 PMID: 7611447
  31. Transport characteristics of a murine renal Na/Pi-cotransporter.
    Pflugers Arch. 1995 Sep;430(5):830-6 PMID: 7478940
  32. Renal expression of Na+-phosphate cotransporter mRNA and protein: effect of the Gy mutation and low phosphate diet.
    Pflugers Arch. 1996 Apr;431(6):936-41 PMID: 8927512
  33. Structure of murine and human renal type II Na+-phosphate cotransporter genes (Npt2 and NPT2).
    Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7409-14 PMID: 8693007
  34. Pex/PEX tissue distribution and evidence for a deletion in the 3' region of the Pex gene in X-linked hypophosphatemic mice.
    J Clin Invest. 1997 Mar 15;99(6):1200-9 PMID: 9077527
  35. High resolution mapping of the renal sodium-phosphate cotransporter gene (NPT2) confirms its localization to human chromosome 5q35.
    Pediatr Res. 1997 May;41(5):632-4 PMID: 9128283
  36. Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning.
    Nat Genet. 1997 Aug;16(4):391-6 PMID: 9241280
  37. Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia.
    Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9831-5 PMID: 9275211
  38. Assignment of renal-specific Na(+)-phosphate cotransporter gene Slc17a2 to mouse chromosome band 13B by in situ hybridization.
    Cytogenet Cell Genet. 1997;77(3-4):304-5 PMID: 9284943
  39. Analysis of osteocalcin expression in transgenic mice reveals a species difference in vitamin D regulation of mouse and human osteocalcin genes.
    J Bone Miner Res. 1997 Oct;12(10):1570-6 PMID: 9333117
  40. Cloning, sequence analysis and expression of the cDNA encoding a sodium-dependent phosphate transporter from the bovine renal epithelial cell line NBL-1.
    Eur J Biochem. 1995 Mar 15;228(3):927-30 PMID: 7737195
  41. Hereditary hypophosphatemic rickets with hypercalciuria.
    N Engl J Med. 1985 Mar 7;312(10):611-7 PMID: 2983203
  42. Renal handling of phosphate.
    Physiol Rev. 1985 Apr;65(2):431-66 PMID: 3885273
  43. "Idiopathic" hypercalciuria and hereditary hypophosphatemic rickets. Two phenotypical expressions of a common genetic defect.
    N Engl J Med. 1987 Jan 15;316(3):125-9 PMID: 3796683
  44. Presence of multiple sodium-dependent phosphate transport processes in proximal brush-border membrane.
    Am J Physiol. 1987 Feb;252(2 Pt 2):F226-31 PMID: 3812737
  45. Stimulation of 25-hydroxyvitamin D3-1alpha-hydroxylase by phosphate depletion.
    J Biol Chem. 1976 May 25;251(10):3158-61 PMID: 1270442
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.95.9.5372
Published
1998-04-28
Pages
5372-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC20268
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.95.9.5372 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2