Skip to main content
SpringerLink
Log in

Secreted frizzled-related protein-4 reduces sodium–phosphate co-transporter abundance and activity in proximal tubule cells

  • Renal Function, Body Fluids
  • Published:
Pflügers Archiv Aims and scope Submit manuscript

Abstract

The phosphatonin, secreted frizzled-related protein-4 (sFRP-4), induces phosphaturia and inhibits 25-hydroxyvitamin D 1α-hydroxylase activity normally induced in response to hypophosphatemia. To determine the mechanism by which sFRP-4 alters renal phosphate (Pi) transport, we examined the effect of sFRP-4 on renal brush border membrane (BBMV) Na+-dependent Pi uptake, and the abundance and localization of the major Na+–Pi-IIa co-transporter in proximal tubules and opossum kidney (OK) cells. Infusion of sFRP-4 increased renal fractional excretion of Pi and decreased renal β-catenin concentrations. The increase in renal Pi excretion with sFRP-4 infusion was associated with a 21.9±3.4% decrease in BBMV Na+-dependent Pi uptake (P<0.001) compared with a 39.5±2.1% inhibition of Na+-dependent Pi transport in renal BBMV induced by PTH (P<0.001). sFRP-4 infusion was associated with a 30.7±4.8% decrease in Na+–Pi-IIa co-transporter protein abundance (P<0.01) assessed by immunoblotting methods compared to a 45.4±8.8% decrease induced by PTH (P<0.001). In OK cells, sFRP-4 reduced surface expression of a heterologous Na+–Pi-IIa co-transporter. We conclude that sFRP-4 increases renal Pi excretion by reducing Na+–Pi-IIa transporter abundance in the brush border of the proximal tubule through enhanced internalization of the protein.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23 (2000) Nat Genet 26:345–348

    Article  PubMed  Google Scholar 

  2. Bacic D, Capuano P, Baum M, Zhang J, Stange G, Biber J, Kaissling B, Moe OW, Wagner CA, Murer H (2005) Activation of dopamine D1-like receptors induces acute internalization of the renal Na+/phosphate cotransporter NaPi-IIa in mouse kidney and OK cells. Am J Physiol Ren Physiol 288:F740–F747

    Article  Google Scholar 

  3. Berndt T, Craig TA, Bowe AE, Vassiliadis J, Reczek D, Finnegan R, Jan De Beur SM, Schiavi SC, Kumar R (2003) Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. J Clin Invest 112:785–794

    Article  PubMed  Google Scholar 

  4. Berndt T, Knox FG (1992) Renal regulation of phosphate excretion. Raven Press, New York

    Google Scholar 

  5. Biber J, Murer H (1994) A molecular view of renal Na-dependent phosphate transport. Ren Physiol Biochem 17:212–215

    PubMed  Google Scholar 

  6. Biber J, Murer H (1993) Towards a molecular view of renal proximal tubular reabsorption of phosphate. Ren Physiol Biochem 16:37–47

    PubMed  Google Scholar 

  7. Biber J, Stieger B, Haase W, Murer H (1981) A high yield preparation for rat kidney brush border membranes. Different behaviour of lysosomal markers. Biochim Biophys Acta 647:169–176

    PubMed  Google Scholar 

  8. Bonjour JP, Preston C, Fleisch H (1977) Effect of 1,25-dihydroxyvitamin D3 on the renal handling of Pi in thyroparathyroidectomized rats. J Clin Invest 60:1419–1428

    PubMed  Google Scholar 

  9. Bowe AE, Finnegan R, Jan de Beur SM, Cho J, Levine MA, Kumar R, Schiavi SC (2001) FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. Biochem Biophys Res Commun 284:977–981

    Article  PubMed  Google Scholar 

  10. Cai Q, Hodgson SF, Kao PC, Lennon VA, Klee GG, Zinsmiester AR, Kumar R (1994) Brief report: inhibition of renal phosphate transport by a tumor product in a patient with oncogenic osteomalacia. N Engl J Med 330:1645–1649

    Article  PubMed  Google Scholar 

  11. Capuano P, Radanovic T, Wagner CA, Bacic D, Kato S, Uchiyama Y, St-Arnoud R, Murer H, Biber J (2005) Intestinal and renal adaptation to a low-Pi diet of type II NaPi cotransporters in vitamin D receptor- and 1alphaOHase-deficient mice. Am J Physiol Cell Physiol 288:C429–C434

    Article  PubMed  Google Scholar 

  12. Carpenter TO, Ellis BK, Insogna KL, Philbrick WM, Sterpka J, Shimkets R (2005) Fibroblast growth factor 7: an inhibitor of phosphate transport derived from oncogenic osteomalacia-causing tumors. J Clin Endocrinol Metab 90:1012–1020

    Article  PubMed  Google Scholar 

  13. Chen P, Toribara T, Warner H (1956) Microdetermination of phosphorus. Anal Chem 28:1756–1758

    Article  Google Scholar 

  14. Chen TC, Castillo L, Korycka-Dahl M, DeLuca HF (1974) Role of vitamin D metabolites in phosphate transport of rat intestine. J Nutr 104:1056–1060

    PubMed  Google Scholar 

  15. Custer M, Lotscher M, Biber J, Murer H, Kaissling B (1994) Expression of Na–P(i) cotransport in rat kidney: localization by RT-PCR and immunohistochemistry. Am J Physiol 266:F767–F774

    PubMed  Google Scholar 

  16. De Beur SM, Finnegan RB, Vassiliadis J, Cook B, Barberio D, Estes S, Manavalan P, Petroziello J, Madden SL, Cho JY, Kumar R, Levine MA, Schiavi SC (2002) Tumors associated with oncogenic osteomalacia express genes important in bone and mineral metabolism. J Bone Miner Res 17:1102–1110

    PubMed  Google Scholar 

  17. DeLuca HF (2004) Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr 80:1689S–1696S

    PubMed  Google Scholar 

  18. DeLuca HF (1980) Vitamin D: revisited 1980. Clin Endocrinol Metab 9:1–26

    Article  PubMed  Google Scholar 

  19. DeLuca HF, Schnoes HK (1983) Vitamin D: recent advances. Annu Rev Biochem 52:411–439

    Article  PubMed  Google Scholar 

  20. Econs MJ (1999) New insights into the pathogenesis of inherited phosphate wasting disorders. Bone 25:131–135

    Article  PubMed  Google Scholar 

  21. Econs MJ, Drezner MK (1994) Tumor-induced osteomalacia—unveiling a new hormone. N Engl J Med 330:1679–1681

    Article  PubMed  Google Scholar 

  22. Führ J, Kazmarczyk J, Krüttgen CD (1955) Eine einfache colorimetrische Methode zur Inulin-Bestimmung für Nieren-clearance-untersuchungen bei StoffwechselGesunden und Diabetikern. Klin Wochenschr 33:729–730

    Article  PubMed  Google Scholar 

  23. Fukumoto S, Yamashita T (2002) Fibroblast growth factor-23 is the phosphaturic factor in tumor-induced osteomalacia and may be phosphatonin. Curr Opin Nephrol Hypertens 11:385–389

    Article  PubMed  Google Scholar 

  24. Georgaki H, Puschett JB (1982) Acute effects of a “physiological” dose of 1,25-dihydroxy vitamin D3 on renal phosphate transport. Endocr Res Commun 9:135–143

    PubMed  Google Scholar 

  25. Hattenhauer O, Traebert M, Murer H, Biber J (1999) Regulation of small intestinal Na–P(i) type IIb cotransporter by dietary phosphate intake. Am J Physiol 277:G756–G762

    PubMed  Google Scholar 

  26. Helps C, Murer H, McGivan J (1995) 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 228:927–930

    Article  PubMed  Google Scholar 

  27. Hernando N, Forster IC, Biber J, Murer H (2000) Molecular characteristics of phosphate transporters and their regulation. Exp Nephrol 8:366–375

    Article  PubMed  Google Scholar 

  28. Hilfiker H, Hattenhauer O, Traebert M, Forster I, Murer H, Biber J (1998) Characterization of a murine type II sodium-phosphate cotransporter expressed in mammalian small intestine. Proc Natl Acad Sci USA 95:14564–14569

    Article  PubMed  Google Scholar 

  29. Johnson JA, Kumar R (1994) Vitamin D and renal calcium transport. Curr Opin Nephrol Hypertens 3:424–429

    PubMed  Google Scholar 

  30. Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y, Yamamoto T, Hampson G, Koshiyama H, Ljunggren O, Oba K, Yang IM, Miyauchi A, Econs MJ, Lavigne J, Juppner H (2003) Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med 348:1656–1663

    Article  PubMed  Google Scholar 

  31. Karim-Jimenez Z, Hernando N, Biber J, Murer H (2000) A dibasic motif involved in parathyroid hormone-induced down-regulation of the type IIa NaPi cotransporter. Proc Natl Acad Sci USA 97:12896–12901

    Article  PubMed  Google Scholar 

  32. Kaufmann M, Muff R, Stieger B, Biber J, Murer H, Fischer JA (1994) Apical and basolateral parathyroid hormone receptors in rat renal cortical membranes. Endocrinology 134:1173–1178

    Article  PubMed  Google Scholar 

  33. Kempson SA, Lotscher M, Kaissling B, Biber J, Murer H, Levi M (1995) Parathyroid hormone action on phosphate transporter mRNA and protein in rat renal proximal tubules. Am J Physiol 268:F784–F791

    PubMed  Google Scholar 

  34. Keusch I, Traebert M, Lotscher M, Kaissling B, Murer H, Biber J (1998) Parathyroid hormone and dietary phosphate provoke a lysosomal routing of the proximal tubular Na/Pi-cotransporter type II. Kidney Int 54:1224–1232

    Google Scholar 

  35. Kozak SL, Kabat D (1990) Ping-pong amplification of a retroviral vector achieves high-level gene expression: human growth hormone production. J Virol 64:3500–3508

    PubMed  Google Scholar 

  36. Kumar R (1980) The metabolism of 1,25-dihydroxyvitamin D3. Endocr Rev 1:258–267

    PubMed  Google Scholar 

  37. Kumar R (2002) New insights into phosphate homeostasis: fibroblast growth factor 23 and frizzled-related protein-4 are phosphaturic factors derived from tumors associated with osteomalacia. Curr Opin Nephrol Hypertens 11:547–553

    Article  PubMed  Google Scholar 

  38. Kumar R (1997) Phosphatonin—a new phosphaturetic hormone? (lessons from tumour-induced osteomalacia and X-linked hypophosphataemia). Nephrol Dial Transplant 12:11–13

    Article  PubMed  Google Scholar 

  39. Kumar R (2000) Tumor-induced osteomalacia and the regulation of phosphate homeostasis. Bone 27:333–338

    Article  PubMed  Google Scholar 

  40. Kumar R, Haugen JD, Wieben ED, Londowski JM, Cai Q (1995) Inhibitors of renal epithelial phosphate transport in tumor-induced osteomalacia and uremia. Proc Assoc Am Physicians 107:296–305

    PubMed  Google Scholar 

  41. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685

    PubMed  Google Scholar 

  42. Larsson T, Marsell R, Schipani E, Ohlsson C, Ljunggren O, Tenenhouse HS, Juppner H, Jonsson KB (2004) Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. Endocrinology 145:3087–3094

    Article  PubMed  Google Scholar 

  43. Levi M, Kempson SA, Lotscher M, Biber J, Murer H (1996) Molecular regulation of renal phosphate transport. J Membr Biol 154:1–9

    Article  PubMed  Google Scholar 

  44. Lotscher M, Kaissling B, Biber J, Murer H, Kempson SA, Levi M (1996) Regulation of rat renal Na/Pi-cotransporter by parathyroid hormone: immunohistochemistry. Kidney Int 49:1010–1011

    Google Scholar 

  45. Magagnin S, Werner A, Markovich D, Sorribas V, Stange G, Biber J, Murer H (1993) Expression cloning of human and rat renal cortex Na/Pi cotransport. Proc Natl Acad Sci USA 90:5979–5983

    PubMed  Google Scholar 

  46. Murer H (1992) Homer Smith award. Cellular mechanisms in proximal tubular Pi reabsorption: some answers and more questions. J Am Soc Nephrol 2:1649–1665

    PubMed  Google Scholar 

  47. Murer H, Biber J (1995) Molecular mechanisms in renal phosphate reabsorption. Nephrol Dial Transplant 10:1501–1504

    PubMed  Google Scholar 

  48. Murer H, Biber J (1994) Renal sodium-phosphate cotransport. Curr Opin Nephrol Hypertens 3:504–510

    PubMed  Google Scholar 

  49. Murer H, Biber J (1993) Structural identification of brush border membrane transport systems—towards an understanding of regulatory mechanisms. Clin Invest 71:852–854

    Google Scholar 

  50. Murer H, Evers C, Stoll R, Kinne R (1977) The effect of parathyroid hormone (PTH) and dietary phosphate on the sodium-dependent phosphate transport system located in the rat renal brush border membrane. Curr Probl Clin Biochem 8:455–462

    PubMed  Google Scholar 

  51. Murer H, Hernando N, Forster I, Biber J (2001) Molecular aspects in the regulation of renal inorganic phosphate reabsorption: the type IIa sodium/inorganic phosphate co-transporter as the key player. Curr Opin Nephrol Hypertens 10:555–561

    Article  PubMed  Google Scholar 

  52. Murer H, Hernando N, Forster L, Biber J (2001) Molecular mechanisms in proximal tubular and small intestinal phosphate reabsorption (plenary lecture). Mol Membr Biol 18:3–11

    Google Scholar 

  53. Murer H, Kohler K, Lambert G, Stange G, Biber J, Forster I (2002) The renal type IIa Na/Pi cotransporter: structure-function relationships. Cell Biochem Biophys 36:215–220

    Article  PubMed  Google Scholar 

  54. Murer H, Lotscher M, Kaissling B, Levi M, Kempson SA, Biber J (1996) Renal brush border membrane Na/Pi-cotransport: molecular aspects in PTH-dependent and dietary regulation. Kidney Int 49:1769–1773

    Google Scholar 

  55. Pfister MF, Hilfiker H, Forgo J, Lederer E, Biber J, Murer H (1998) Cellular mechanisms involved in the acute adaptation of OK cell Na/Pi-cotransport to high- or low-Pi medium. Pflugers Arch 435:713–719

    Article  PubMed  Google Scholar 

  56. Pfister MF, Ruf I, Stange G, Ziegler U, Lederer E, Biber J, Murer H (1998) Parathyroid hormone leads to the lysosomal degradation of the renal type II Na/Pi cotransporter. Proc Natl Acad Sci USA 95:1909–1914

    Article  PubMed  Google Scholar 

  57. Puschett JB, Fernandez PC, Boyle IT, Gray RW, Omdahl JL, DeLuca HF (1972) The acute renal tubular effects of 1,25-dihydroxycholecalciferol. Proc Soc Exp Biol Med 141:379–384

    PubMed  Google Scholar 

  58. Puschett JB, Kuhrman MS (1978) Renal tubular effects of 1,25-dihydroxy vitamin D3: interactions with vasopressin and parathyroid hormone in the vitamin D-depleted rat. J Lab Clin Med 92:895–903

    PubMed  Google Scholar 

  59. Radanovic T, Wagner CA, Murer H, Biber J (2005) Regulation of intestinal phosphate transport. I. Segmental expression and adaptation to low-P(i) diet of the type IIb Na(+)–P(i) cotransporter in mouse small intestine. Am J Physiol Gastrointest Liver Physiol 288:G496–G500

    Article  PubMed  Google Scholar 

  60. Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE, Waguespack S, Gupta A, Hannon T, Econs MJ, Bianco P, Gehron Robey P (2003) FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest 112:683–692

    Article  PubMed  Google Scholar 

  61. Rizzoli R, Fleisch H, Bonjour JP (1977) Role of 1,25-dihydroxyvitamin D3 on intestinal phosphate absorption in rats with a normal vitamin D supply. J Clin Invest 60:639–647

    PubMed  Google Scholar 

  62. Rowe PS, de Zoysa PA, Dong R, Wang HR, White KE, Econs MJ, Oudet CL (2000) MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia. Genomics 67:54–68

    Article  PubMed  Google Scholar 

  63. Rowe PS, Kumagai Y, Gutierrez G, Garrett IR, Blacher R, Rosen D, Cundy J, Navvab S, Chen D, Drezner MK, Quarles LD, Mundy GR (2004) MEPE has the properties of an osteoblastic phosphatonin and minhibin. Bone 34:303–319

    Article  PubMed  Google Scholar 

  64. Schiavi SC, Kumar R (2004) The phosphatonin pathway: new insights in phosphate homeostasis. Kidney Int 65:1–14

    Google Scholar 

  65. Segawa H, Kaneko I, Yamanaka S, Ito M, Kuwahata M, Inoue Y, Kato S, Miyamoto K (2004) Intestinal Na–P(i) cotransporter adaptation to dietary P(i) content in vitamin D receptor null mice. Am J Physiol Ren Physiol 287:F39–F47

    Article  Google Scholar 

  66. Shimada T, Urakawa I, Yamazaki Y, Hasegawa H, Hino R, Yoneya T, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T (2004) FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem Biophys Res Commun 314:409–414

    Article  PubMed  Google Scholar 

  67. Sitara D, Razzaque MS, Hesse M, Yoganathan S, Taguchi T, Erben RG, H JA-P, Lanske B (2004) Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol 23:421–432

    Article  PubMed  Google Scholar 

  68. Stauber A, Radanovic T, Stange G, Murer H, Wagner CA, Biber J (2005) Regulation of intestinal phosphate transport. II. Metabolic acidosis stimulates Na(+)-dependent phosphate absorption and expression of the Na(+)–P(i) cotransporter NaPi-IIb in small intestine. Am J Physiol Gastrointest Liver Physiol 288:G501–G506

    Article  PubMed  Google Scholar 

  69. Steele TH, Engle JE, Tanaka Y, Lorenc RS, Dudgeon KL, DeLuca HF (1975) Phosphatemic action of 1,25-dihydroxyvitamin D3. Am J Physiol 229:489–495

    PubMed  Google Scholar 

  70. Stoll R, Kinne R, Murer H (1979) Effect of dietary phosphate intake on phosphate transport by isolated rat renal brush-border vesicles. Biochem J 180:465–470

    PubMed  Google Scholar 

  71. Tanaka Y, Deluca HF (1973) The control of 25-hydroxyvitamin D metabolism by inorganic phosphorus. Arch Biochem Biophys 154:566–574

    Article  PubMed  Google Scholar 

  72. Towbin H, Staehelin T, Gordon J (1992) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications, 1979. Biotechnology 24:145–149

    PubMed  Google Scholar 

  73. Traebert M, Roth J, Biber J, Murer H, Kaissling B (2000) Internalization of proximal tubular type II Na–P(i) cotransporter by PTH: immunogold electron microscopy. Am J Physiol Ren Physiol 278:F148–F154

    Google Scholar 

  74. Verri T, Markovich D, Perego C, Norbis F, Stange G, Sorribas V, Biber J, Murer H (1995) Cloning of a rabbit renal Na–Pi cotransporter, which is regulated by dietary phosphate. Am J Physiol 268:F626–F633

    PubMed  Google Scholar 

  75. Werner A, Kempson SA, Biber J, Murer H (1994) Increase of Na/Pi-cotransport encoding mRNA in response to low Pi diet in rat kidney cortex. J Biol Chem 269:6637–6639

    PubMed  Google Scholar 

  76. Werner A, Moore ML, Mantei N, Biber J, Semenza G, Murer H (1991) Cloning and expression of cDNA for a Na/Pi cotransport system of kidney cortex. Proc Natl Acad Sci USA 88:9608–9612

    PubMed  Google Scholar 

  77. Werner A, Murer H, Kinne RK (1994) Cloning and expression of a renal Na–Pi cotransport system from flounder. Am J Physiol 267:F311–F317

    PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to thank Stacy Sommer for assistance in the animal experiments. These studies were supported by NIH grant DK 65830 to R. Kumar, the Swiss National Science Foundation (31-65397.01) to H. Murer, and the sixth European Frame Work EuReGene Project (005085) to C. A. Wagner and H. Murer. Theresa J. Berndt and Bernhard Bielesz contributed equally to this work.

Author information

Authors and Affiliations

  1. Division of Nephrology and Hypertension, Departments of Medicine and Biochemistry and Molecular Biology, Mayo Clinic Rochester, Mayo College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA

    Theresa J. Berndt, Theodore A. Craig, Peter J. Tebben & Rajiv Kumar

  2. Institute of Physiology and Center of Integrative Human Physiology, University of Zurich, Winterthurerstr 190, 8057, Zurich, Switzerland

    Bernhard Bielesz, Desa Bacic, Carsten A. Wagner, Jurg Biber & Heini Murer

  3. Receptor Ligand Therapeutics, Genzyme Corporation, One Mountain Road, Framingham, MA, 01701, USA

    Stephen O’Brien & Susan Schiavi

Authors
  1. Theresa J. Berndt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bernhard Bielesz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Theodore A. Craig
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter J. Tebben
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Desa Bacic
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carsten A. Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stephen O’Brien
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Susan Schiavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jurg Biber
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Heini Murer
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Rajiv Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rajiv Kumar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Berndt, T.J., Bielesz, B., Craig, T.A. et al. Secreted frizzled-related protein-4 reduces sodium–phosphate co-transporter abundance and activity in proximal tubule cells. Pflugers Arch - Eur J Physiol 451, 579–587 (2006). https://doi.org/10.1007/s00424-005-1495-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-005-1495-2

Keywords

Search

Navigation