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Gene Review

Slc34a1  -  solute carrier family 34 (sodium...

Mus musculus

Synonyms: Na(+)-dependent phosphate cotransporter 2A, Na(+)/Pi cotransporter 2A, Na/Pi cotransporter, NaPi-2a, NaPi-7, ...
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Disease relevance of Slc34a1

  • To determine the contribution of elevated serum 1,25(OH)2D levels to the development of hypercalciuria and nephrocalcinosis in Npt2-/- mice, we examined the effects of 1alphaOHase gene ablation and long-term Pi supplementation on urinary Ca excretion and renal calcification by microcomputed tomography [1].
  • The latter is associated with increased intestinal Ca absorption, hypercalcemia, hypercalciuria, and renal calcification in Npt2-/- mice [1].
  • Disruption of the Npt2a gene in mice elicits hypophosphatemia, renal Pi wasting, and an 80% decrease in renal BBM Na/Pi cotransport, and led to the demonstration that Npt2a is the target for hormonal and dietary regulation of renal Pi reabsorption [2].
  • We previously reported that a type II sodium phosphate (Na(+)-Pi) cotransporter (Npt2) protein is expressed in osteoclasts and that Pi limitation decreases osteoclast-mediated bone resorption in vitro [3].

High impact information on Slc34a1


Biological context of Slc34a1

  • The present data demonstrate that normalization of renal 24-hydroxylase gene expression in Pi-deprived Hyp mice by GH is not sufficient to correct the serum concentration of 1,25(OH)2D and is not associated with an alteration in renal Npt2 mRNA expression [8].
  • Interestingly, transcriptional activity of a reporter gene, containing Npt2a promoters 1 and 2, was renal cell-specifically increased by 1alpha, 25(OH)2D3 and its analogs [9].
  • The chromosomal structure analysis revealed that the Npt2a gene comprises of two promoters (promoters 1 and 2) and 14 exons, and spans approximately 17 kb [9].
  • Thus, Npt2a plays a major role in the maintenance of Pi homeostasis in both health and disease [2].
  • We have isolated a 4,740-bp fragment of the 5'-flanking sequence of the rat Npt2 gene, identified the transcription initiation site, and demonstrated that this 5'-flanking sequence drives luciferase-reporter gene expression, following transfection in the proximal tubule cell-derived opossum kidney (OK) cell line but not in unrelated cell lines [10].

Anatomical context of Slc34a1

  • Adenovirus-GFP-NHERF-1 infected NHERF-1 null proximal tubule cells but not cells infected with adenovirus-GFP demonstrated increased phosphate transport and Npt2a abundance in the plasma membrane when grown in low phosphate (0.1 mM) compared with high phosphate media (1.9 mM) [11].
  • Infection of NHERF-1 null cells with adenovirus-GFP-NHERF-1 increased phosphate transport and plasma membrane abundance of Npt2a [11].
  • These results indicate that the type II Na+/Pi co-transporter NaPi-7 mediated most Na+-dependent Pi transport in mouse kidney cortex [12].
  • Expression of the Npt2 gene, encoding the type II sodium-dependent phosphate cotransporter, is restricted to renal proximal tubule epithelium [10].
  • PiT-1 colocalizes with actin and is present on the basolateral membrane of the polarized osteoclast, similar to that previously reported for Npt2a [13].

Associations of Slc34a1 with chemical compounds

  • We show that the urinary Ca/creatinine ratio is significantly decreased in Npt2-/-/1alphaOHase-/- mice compared with Npt2-/- mice [1].
  • Finally, we show that PGE2 inhibited both phosphate and volume absorption in mouse proximal convoluted tubules perfused in vitro and reduced brush-border membrane vesicle NaPi-2a protein abundance from renal cortex incubated in vitro with PGE2 [14].
  • 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 [15].

Regulatory relationships of Slc34a1

  • These data suggested that two alternative promoters control the renal expression of Npt2a gene and both Npt2a variant transcripts are down regulated in Hyp mice [9].
  • Thus FGF23-induced changes in NaPi2a and 1alphaOHase expression are independent of the 1,25D/VDR system [16].

Other interactions of Slc34a1

  • Because growth hormone (GH) enhances renal Na+-Pi cotransport and permits the adaptive 1,25(OH)2D response in Pi-deprived hypophysectomized rats, we examined the effects of GH on vitamin D metabolism and renal Npt2 mRNA abundance in Hyp mice fed control and low Pi diets [8].
  • PTH inhibited phosphate transport and decreased Npt2a abundance in the plasma membrane of adenovirus-GFP-NHERF-1-infected NHERF-1 null proximal tubule cells but not cells infected with adenovirus-GFP [11].
  • We also demonstrate that GH did not normalize renal Npt2 mRNA expression, relative to beta-actin mRNA, in Hyp mice fed either control or low Pi diets [8].
  • In Npt2a(-/-) mice, serum FGF-23 concentrations were significantly lower than in WT mice, and these differences could be accounted for by the lower serum Pi levels in Npt2a(-/-) mice [17].
  • Reverse transcriptase polymerase chain reaction of MDCT cell RNA provided evidence for the expression of the Npt1 but not the Npt2 Na+-Pi cotransporter gene [18].

Analytical, diagnostic and therapeutic context of Slc34a1


  1. 1alpha-Hydroxylase gene ablation and Pi supplementation inhibit renal calcification in mice homozygous for the disrupted Npt2a gene. Tenenhouse, H.S., Gauthier, C., Chau, H., St-Arnaud, R. Am. J. Physiol. Renal Physiol. (2004) [Pubmed]
  2. Regulation of phosphorus homeostasis by the type iia na/phosphate cotransporter. Tenenhouse, H.S. Annu. Rev. Nutr. (2005) [Pubmed]
  3. Identification of the type II Na(+)-Pi cotransporter (Npt2) in the osteoclast and the skeletal phenotype of Npt2-/- mice. Gupta, A., Tenenhouse, H.S., Hoag, H.M., Wang, D., Khadeer, M.A., Namba, N., Feng, X., Hruska, K.A. Bone (2001) [Pubmed]
  4. Effects of Npt2 gene ablation and low-phosphate diet on renal Na(+)/phosphate cotransport and cotransporter gene expression. Hoag, H.M., Martel, J., Gauthier, C., Tenenhouse, H.S. J. Clin. Invest. (1999) [Pubmed]
  5. Signal transducer and activator of transcription (Stat) 5 controls the proliferation and differentiation of mammary alveolar epithelium. Miyoshi, K., Shillingford, J.M., Smith, G.H., Grimm, S.L., Wagner, K.U., Oka, T., Rosen, J.M., Robinson, G.W., Hennighausen, L. J. Cell Biol. (2001) [Pubmed]
  6. Targeted disruption of the mouse NHERF-1 gene promotes internalization of proximal tubule sodium-phosphate cotransporter type IIa and renal phosphate wasting. Shenolikar, S., Voltz, J.W., Minkoff, C.M., Wade, J.B., Weinman, E.J. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  7. The molecular defect in the renal sodium-phosphate transporter expression pathway of Gyro (Gy) mice is distinct from that of hypophosphatemic (Hyp) mice. Collins, J.F., Ghishan, F.K. FASEB J. (1996) [Pubmed]
  8. Growth hormone normalizes renal 1,25-dihydroxyvitamin D3-24-hydroxylase gene expression but not Na+-phosphate cotransporter (Npt2) mRNA in phosphate-deprived Hyp mice. Roy, S., Martel, J., Tenenhouse, H.S. J. Bone Miner. Res. (1997) [Pubmed]
  9. Alternative promoters and renal cell-specific regulation of the mouse type IIa sodium-dependent phosphate cotransporter gene. Yamamoto, H., Tani, Y., Kobayashi, K., Taketani, Y., Sato, T., Arai, H., Morita, K., Miyamoto, K., Pike, J.W., Kato, S., Takeda, E. Biochim. Biophys. Acta (2005) [Pubmed]
  10. Role of AP2 consensus sites in regulation of rat Npt2 (sodium-phosphate cotransporter) promoter. Shachaf, C., Skorecki, K.L., Tzukerman, M. Am. J. Physiol. Renal Physiol. (2000) [Pubmed]
  11. Adenoviral expression of NHERF-1 in NHERF-1 null mouse renal proximal tubule cells restores Npt2a regulation by low phosphate media and parathyroid hormone. Cunningham, R., Steplock, D., E, X., Biswas, R.S., Wang, F., Shenolikar, S., Weinman, E.J. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  12. Relative contributions of Na+-dependent phosphate co-transporters to phosphate transport in mouse kidney: RNase H-mediated hybrid depletion analysis. Miyamoto, K., Segawa, H., Morita, K., Nii, T., Tatsumi, S., Taketani, Y., Takeda, E. Biochem. J. (1997) [Pubmed]
  13. Na+-dependent phosphate transporters in the murine osteoclast: cellular distribution and protein interactions. Khadeer, M.A., Tang, Z., Tenenhouse, H.S., Eiden, M.V., Murer, H., Hernando, N., Weinman, E.J., Chellaiah, M.A., Gupta, A. Am. J. Physiol., Cell Physiol. (2003) [Pubmed]
  14. Fibroblast growth factor-23 increases mouse PGE2 production in vivo and in vitro. Syal, A., Schiavi, S., Chakravarty, S., Dwarakanath, V., Quigley, R., Baum, M. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  15. Na/P(i) cotransporter ( Npt2) gene disruption increases duodenal calcium absorption and expression of epithelial calcium channels 1 and 2. Tenenhouse, H.S., Gauthier, C., Martel, J., Hoenderop, J.G., Hartog, A., Meyer, M.H., Meyer, R.A., Bindels, R.J. Pflugers Arch. (2002) [Pubmed]
  16. Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism. Shimada, T., Yamazaki, Y., Takahashi, M., Hasegawa, H., Urakawa, I., Oshima, T., Ono, K., Kakitani, M., Tomizuka, K., Fujita, T., Fukumoto, S., Yamashita, T. Am. J. Physiol. Renal Physiol. (2005) [Pubmed]
  17. Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Perwad, F., Azam, N., Zhang, M.Y., Yamashita, T., Tenenhouse, H.S., Portale, A.A. Endocrinology (2005) [Pubmed]
  18. Na+ -phosphate cotransport in mouse distal convoluted tubule cells: evidence for Glvr-1 and Ram-1 gene expression. Tenenhouse, H.S., Gauthier, C., Martel, J., Gesek, F.A., Coutermarsh, B.A., Friedman, P.A. J. Bone Miner. Res. (1998) [Pubmed]
  19. Kidney cortex cells derived from SV40 transgenic mice retain intrinsic properties of polarized proximal tubule cells. Chalumeau, C., Lamblin, D., Bourgeois, S., Borensztein, P., Chambrey, R., Bruneval, P., Huyen, J.P., Froissart, M., Biber, J., Paillard, M., Kellermann, O., Poggioli, J. Kidney Int. (1999) [Pubmed]
  20. Assignment of renal-specific Na(+)-phosphate cotransporter gene Slc17a2 to mouse chromosome band 13B by in situ hybridization. Zhang, X.X., Tenenhouse, H.S., Hewson, A.S., Murer, H., Eydoux, P. Cytogenet. Cell Genet. (1997) [Pubmed]
  21. Odontoblast phosphate and calcium transport in dentinogenesis. Lundquist, P. Swedish dental journal. Supplement. (2002) [Pubmed]
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