open access

Vol 70, No 6 (2019)
Review paper
Published online: 2019-12-20
Submitted: 2019-02-13
Accepted: 2019-08-21
Get Citation

The role of sodium phosphate cotransporters in ectopic calcification

Sergio Gonzalo, Ricardo Villa-Bellosta
DOI: 10.5603/EP.a2019.0050
·
Pubmed: 31891412
·
Endokrynologia Polska 2019;70(6):496-503.

open access

Vol 70, No 6 (2019)
Review Article
Published online: 2019-12-20
Submitted: 2019-02-13
Accepted: 2019-08-21

Abstract

Phosphate plays a critical role in many vital cellular processes. Deviations from normal serum phosphate levels, including alterations in the extracellular phosphate/pyrophosphate ratio, can cause severe consequences, such as ectopic calcification. Cellular phosphate levels are tightly controlled by sodium phosphate cotransporters, underscoring their importance in cellular physiology. The role of sodium phosphate cotransporters in ectopic calcification requires further elucidation, taking into account their important role in the control of intracellular phosphate levels and the synthesis of ATP, the main source of extracellular pyrophosphate (a potent endogenous inhibitor of calcification). In this review, we discuss the roles of phosphate and pyrophosphate homeostasis in ectopic calcification, with a specific focus on phosphate transporters. We concentrate on the five known sodium-dependent phosphate transporters and review their localisation and regulation by external factors, and the effects observed in knockout studies and in naturally occurring mutations.

Abstract

Phosphate plays a critical role in many vital cellular processes. Deviations from normal serum phosphate levels, including alterations in the extracellular phosphate/pyrophosphate ratio, can cause severe consequences, such as ectopic calcification. Cellular phosphate levels are tightly controlled by sodium phosphate cotransporters, underscoring their importance in cellular physiology. The role of sodium phosphate cotransporters in ectopic calcification requires further elucidation, taking into account their important role in the control of intracellular phosphate levels and the synthesis of ATP, the main source of extracellular pyrophosphate (a potent endogenous inhibitor of calcification). In this review, we discuss the roles of phosphate and pyrophosphate homeostasis in ectopic calcification, with a specific focus on phosphate transporters. We concentrate on the five known sodium-dependent phosphate transporters and review their localisation and regulation by external factors, and the effects observed in knockout studies and in naturally occurring mutations.

Get Citation

Keywords

phosphate; ectopic calcification; pyrophosphate; transporters; ATP

About this article
Title

The role of sodium phosphate cotransporters in ectopic calcification

Journal

Endokrynologia Polska

Issue

Vol 70, No 6 (2019)

Article type

Review paper

Pages

496-503

Published online

2019-12-20

DOI

10.5603/EP.a2019.0050

Pubmed

31891412

Bibliographic record

Endokrynologia Polska 2019;70(6):496-503.

Keywords

phosphate
ectopic calcification
pyrophosphate
transporters
ATP

Authors

Sergio Gonzalo
Ricardo Villa-Bellosta

References (99)
  1. Hubbard SR, Till JH. Protein tyrosine kinase structure and function. Annu Rev Biochem. 2000; 69: 373–398.
  2. Berndt T, Kumar R. Novel mechanisms in the regulation of phosphorus homeostasis. Physiology (Bethesda). 2009; 24: 17–25.
  3. Villa-Bellosta R. Vascular Calcification Revisited: A New Perspective for Phosphate Transport. Curr Cardiol Rev. 2015; 11(4): 341–351.
  4. Murer H, Hernando N, Forster I, et al. Proximal tubular phosphate reabsorption: molecular mechanisms. Physiol Rev. 2000; 80(4): 1373–1409.
  5. Knochel JP. The pathophysiology and clinical characteristics of severe hypophosphatemia. Arch Intern Med. 1977; 137(2): 203–220.
  6. Knochel JP, Barcenas C, Cotton JR, et al. Hypophosphatemia and rhabdomyolysis. Trans Assoc Am Physicians. 1978; 91: 156–168.
  7. Shaikh A, Berndt T, Kumar R. Regulation of phosphate homeostasis by the phosphatonins and other novel mediators. Pediatr Nephrol. 2008; 23(8): 1203–1210.
  8. McIntyre CW. New developments in the management of hyperphosphatemia in chronic kidney disease. Semin Dial. 2007; 20(4): 337–341.
  9. Slatopolsky E, Bricker NS. The role of phosphorus restriction in the prevention of secondary hyperparathyroidism in chronic renal disease. Kidney Int. 1973; 4(2): 141–145.
  10. Calvo MS, Uribarri J. Public health impact of dietary phosphorus excess on bone and cardiovascular health in the general population. Am J Clin Nutr. 2013; 98(1): 6–15.
  11. Berndt TJ, Schiavi S, Kumar R. "Phosphatonins" and the regulation of phosphorus homeostasis. Am J Physiol Renal Physiol. 2005; 289(6): F1170–F1182.
  12. Bergwitz C, Jüppner H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med. 2010; 61: 91–104.
  13. Biber J, Hernando N, Forster I. Phosphate transporters and their function. Annu Rev Physiol. 2013; 75: 535–550.
  14. Breusegem SY, Takahashi H, Giral-Arnal H, et al. Differential regulation of the renal sodium-phosphate cotransporters NaPi-IIa, NaPi-IIc, and PiT-2 in dietary potassium deficiency. Am J Physiol Renal Physiol. 2009; 297(2): F350–F361.
  15. Murer H, Hernando N, Forster I, et al. Regulation of Na/Pi transporter in the proximal tubule. Annu Rev Physiol. 2003; 65: 531–542.
  16. Rutsch F, Nitschke Y, Terkeltaub R. Genetics in arterial calcification: pieces of a puzzle and cogs in a wheel. Circ Res. 2011; 109(5): 578–592.
  17. Shanahan CM, Crouthamel MH, Kapustin A, et al. Arterial calcification in chronic kidney disease: key roles for calcium and phosphate. Circ Res. 2011; 109(6): 697–711.
  18. Pradelli D, Faden G, Mureddu G, et al. Impact of aortic or mitral valve sclerosis and calcification on cardiovascular events and mortality: a meta-analysis. Int J Cardiol. 2013; 170(2): e51–e55.
  19. Dhingra R, Sullivan LM, Fox CS, et al. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med. 2007; 167(9): 879–885.
  20. Ishimura E, Taniwaki H, Tabata T, et al. Cross-sectional association of serum phosphate with carotid intima-medial thickness in hemodialysis patients. Am J Kidney Dis. 2005; 45(5): 859–865.
  21. Adeney KL, Siscovick DS, Ix JH, et al. Association of serum phosphate with vascular and valvular calcification in moderate CKD. J Am Soc Nephrol. 2009; 20(2): 381–387.
  22. Rocha-Singh KJ, Zeller T, Jaff MR. Peripheral arterial calcification: prevalence, mechanism, detection, and clinical implications. Catheter Cardiovasc Interv. 2014; 83(6): E212–E220.
  23. Urry DW. Neutral sites for calcium ion binding to elastin and collagen: a charge neutralization theory for calcification and its relationship to atherosclerosis. Proc Natl Acad Sci U S A. 1971; 68(4): 810–814.
  24. Jono S, McKee MD, Murry CE, et al. Phosphate regulation of vascular smooth muscle cell calcification. Circ Res. 2000; 87(7): E10–E17.
  25. Villa-Bellosta R, Egido J. Phosphate, pyrophosphate, and vascular calcification: a question of balance. Eur Heart J. 2017; 38(23): 1801–1804.
  26. Johnsson MS, Nancollas GH. The role of brushite and octacalcium phosphate in apatite formation. Crit Rev Oral Biol Med. 1992; 3(1–2): 61–82.
  27. Villa-Bellosta R, Sorribas V. Calcium phosphate deposition with normal phosphate concentration. Role of pyrophosphate. Circ J. 2011; 75(11): 2705–2710.
  28. Villa-Bellosta R, Millan A, Sorribas V. Role of calcium-phosphate deposition in vascular smooth muscle cell calcification. Am J Physiol Cell Physiol. 2011; 300(1): C210–C220.
  29. Schinke T, Karsenty G. Vascular calcification — a passive process in need of inhibitors. Nephrol Dial Transplant. 2000; 15(9): 1272–1274.
  30. Sage AP, Lu J, Tintut Y, et al. Hyperphosphatemia-induced nanocrystals upregulate the expression of bone morphogenetic protein-2 and osteopontin genes in mouse smooth muscle cells in vitro. Kidney Int. 2011; 79(4): 414–422.
  31. Villa-Bellosta R, Rivera-Torres J, Osorio FG, et al. Defective extracellular pyrophosphate metabolism promotes vascular calcification in a mouse model of Hutchinson-Gilford progeria syndrome that is ameliorated on pyrophosphate treatment. Circulation. 2013; 127(24): 2442–2451.
  32. Román-García P, Carrillo-López N, Fernández-Martín JL, et al. High phosphorus diet induces vascular calcification, a related decrease in bone mass and changes in the aortic gene expression. Bone. 2010; 46(1): 121–128.
  33. O'Neill WC, Lomashvili KA, Malluche HH, et al. Treatment with pyrophosphate inhibits uremic vascular calcification. Kidney Int. 2011; 79(5): 512–517.
  34. Riser BL, Barreto FC, Rezg R, et al. Daily peritoneal administration of sodium pyrophosphate in a dialysis solution prevents the development of vascular calcification in a mouse model of uraemia. Nephrol Dial Transplant. 2011; 26(10): 3349–3357.
  35. Villa-Bellosta R, Sorribas V. Phosphonoformic acid prevents vascular smooth muscle cell calcification by inhibiting calcium-phosphate deposition. Arterioscler Thromb Vasc Biol. 2009; 29(5): 761–766.
  36. Villa-Bellosta R, Wang X, Millán JL, et al. Extracellular pyrophosphate metabolism and calcification in vascular smooth muscle. Am J Physiol Heart Circ Physiol. 2011; 301(1): H61–H68.
  37. St Hilaire C, Ziegler SG, Markello TC, et al. NT5E mutations and arterial calcifications. N Engl J Med. 2011; 364(5): 432–442.
  38. Warraich S, Bone DBJ, Quinonez D, et al. Loss of equilibrative nucleoside transporter 1 in mice leads to progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis in humans. J Bone Miner Res. 2013; 28(5): 1135–1149.
  39. Reimer RJ, Edwards RH. Organic anion transport is the primary function of the SLC17/type I phosphate transporter family. Pflugers Arch. 2004; 447(5): 629–635.
  40. Wagner CA, Hernando N, Forster IC, et al. The SLC34 family of sodium-dependent phosphate transporters. Pflugers Arch. 2014; 466(1): 139–153.
  41. Collins JF, Bai L, Ghishan FK. The SLC20 family of proteins: dual functions as sodium-phosphate cotransporters and viral receptors. Pflugers Arch. 2004; 447(5): 647–652.
  42. Villa-Bellosta R, Sorribas V. Role of rat sodium/phosphate cotransporters in the cell membrane transport of arsenate. Toxicol Appl Pharmacol. 2008; 232(1): 125–134.
  43. Villa-Bellosta R, Sorribas V. Compensatory regulation of the sodium/phosphate cotransporters NaPi-IIc (SCL34A3) and Pit-2 (SLC20A2) during Pi deprivation and acidosis. Pflugers Arch. 2010; 459(3): 499–508.
  44. Forster IC, Hernando N, Biber J, et al. Phosphate transport kinetics and structure-function relationships of SLC34 and SLC20 proteins. Curr Top Membr. 2012; 70: 313–356.
  45. Werner A, Kinne RK. Evolution of the Na-P(i) cotransport systems. Am J Physiol Regul Integr Comp Physiol. 2001; 280(2): R301–R312.
  46. Fenollar-Ferrer C, Patti M, Knöpfel T, et al. Structural fold and binding sites of the human Na⁺-phosphate cotransporter NaPi-II. Biophys J. 2014; 106(6): 1268–1279.
  47. Villa-Bellosta R, Barac-Nieto M, Breusegem SY, et al. Interactions of the growth-related, type IIc renal sodium/phosphate cotransporter with PDZ proteins. Kidney Int. 2008; 73(4): 456–464.
  48. Biber J, Gisler SM, Hernando N, et al. Protein/protein interactions (PDZ) in proximal tubules. J Membr Biol. 2005; 203(3): 111–118.
  49. Forster IC, Loo DD, Eskandari S. Stoichiometry and Na+ binding cooperativity of rat and flounder renal type II Na+-Pi cotransporters. Am J Physiol. 1999; 276(4): F644–F649.
  50. Bacconi A, Virkki LV, Biber J, et al. Renouncing electroneutrality is not free of charge: switching on electrogenicity in a Na+-coupled phosphate cotransporter. Proc Natl Acad Sci U S A. 2005; 102(35): 12606–12611.
  51. Segawa H, Kaneko I, Takahashi A, et al. Growth-related renal type II Na/Pi cotransporter. J Biol Chem. 2002; 277(22): 19665–19672.
  52. Silverstein DM, Barac-Nieto M, Murer H, et al. A putative growth-related renal Na(+)-Pi cotransporter. Am J Physiol. 1997; 273(3 Pt 2): R928–R933.
  53. Dinour D, Davidovits M, Ganon L, et al. Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency. Pediatr Nephrol. 2016; 31(12): 2289–2297.
  54. Hisano S, Haga H, Li Z, et al. Immunohistochemical and RT-PCR detection of Na+-dependent inorganic phosphate cotransporter (NaPi-2) in rat brain. Brain Res. 1997; 772(1-2): 149–155.
  55. Mulroney SE, Woda CB, Halaihel N, et al. Central control of renal sodium-phosphate (NaPi-2) transporters. Am J Physiol Renal Physiol. 2004; 286(4): F647–F652.
  56. Albano G, Moor M, Dolder S, et al. Sodium-dependent phosphate transporters in osteoclast differentiation and function. PLoS One. 2015; 10(4): e0125104.
  57. Caverzasio J, Bonjour JP. Mechanism of rapid phosphate (Pi) transport adaptation to a single low Pi meal in rat renal brush border membrane. Pflugers Arch. 1985; 404(3): 227–231.
  58. Biber J, Hernando N, Forster I, et al. Regulation of phosphate transport in proximal tubules. Pflugers Arch. 2009; 458(1): 39–52.
  59. Lötscher M, Kaissling B, Biber J, et al. Role of microtubules in the rapid regulation of renal phosphate transport in response to acute alterations in dietary phosphate content. J Clin Invest. 1997; 99(6): 1302–1312.
  60. Traebert M, Roth J, Biber J, et al. Internalization of proximal tubular type II Na-P(i) cotransporter by PTH: immunogold electron microscopy. Am J Physiol Renal Physiol. 2000; 278(1): F148–F154.
  61. Beck L, Karaplis AC, Amizuka N, et al. Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc Natl Acad Sci U S A. 1998; 95(9): 5372–5377.
  62. Burris D, Webster R, Sheriff S, et al. Estrogen directly and specifically downregulates NaPi-IIa through the activation of both estrogen receptor isoforms (ERα and ERβ) in rat kidney proximal tubule. Am J Physiol Renal Physiol. 2015; 308(6): F522–F534.
  63. Shibasaki Y, Etoh N, Hayasaka M, et al. Targeted deletion of the tybe IIb Na(+)-dependent Pi-co-transporter, NaPi-IIb, results in early embryonic lethality. Biochem Biophys Res Commun. 2009; 381(4): 482–486.
  64. Corut A, Senyigit A, Ugur SA, et al. Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis. Am J Hum Genet. 2006; 79(4): 650–656.
  65. Izumi S, Miyazawa H, Ishii K, et al. Mutations in the SLC34A2 gene are associated with pulmonary alveolar microlithiasis. Am J Respir Crit Care Med. 2007; 175(3): 263–268.
  66. Hernando N, Myakala K, Simona F, et al. Intestinal Depletion of NaPi-IIb/Slc34a2 in Mice: Renal and Hormonal Adaptation. J Bone Miner Res. 2015; 30(10): 1925–1937.
  67. Bourgeois S, Capuano P, Stange G, et al. The phosphate transporter NaPi-IIa determines the rapid renal adaptation to dietary phosphate intake in mouse irrespective of persistently high FGF23 levels. Pflugers Arch. 2013; 465(11): 1557–1572.
  68. Picard N, Capuano P, Stange G, et al. Acute parathyroid hormone differentially regulates renal brush border membrane phosphate cotransporters. Pflugers Arch. 2010; 460(3): 677–687.
  69. Segawa H, Onitsuka A, Kuwahata M, et al. Type IIc sodium-dependent phosphate transporter regulates calcium metabolism. J Am Soc Nephrol. 2009; 20(1): 104–113.
  70. Myakala K, Motta S, Murer H, et al. Renal-specific and inducible depletion of NaPi-IIc/Slc34a3, the cotransporter mutated in HHRH, does not affect phosphate or calcium homeostasis in mice. Am J Physiol Renal Physiol. 2014; 306(8): F833–F843.
  71. Ewence AE, Bootman M, Roderick HL, et al. Calcium phosphate crystals induce cell death in human vascular smooth muscle cells: a potential mechanism in atherosclerotic plaque destabilization. Circ Res. 2008; 103(5): e28–e34.
  72. Grases F, Sanchis P, Perelló J, et al. Effect of crystallization inhibitors on vascular calcifications induced by vitamin D: a pilot study in Sprague-Dawley rats. Circ J. 2007; 71(7): 1152–1156.
  73. Villa-Bellosta R, Bogaert YE, Levi M, et al. Characterization of phosphate transport in rat vascular smooth muscle cells: implications for vascular calcification. Arterioscler Thromb Vasc Biol. 2007; 27(5): 1030–1036.
  74. Bøttger P, Hede SE, Grunnet M, et al. Characterization of transport mechanisms and determinants critical for Na+-dependent Pi symport of the PiT family paralogs human PiT1 and PiT2. Am J Physiol Cell Physiol. 2006; 291(6): C1377–C1387.
  75. Kakita A, Suzuki A, Nishiwaki K, et al. Stimulation of Na-dependent phosphate transport by platelet-derived growth factor in rat aortic smooth muscle cells. Atherosclerosis. 2004; 174(1): 17–24.
  76. Li X, Yang HY, Giachelli CM. Role of the sodium-dependent phosphate cotransporter, Pit-1, in vascular smooth muscle cell calcification. Circ Res. 2006; 98(7): 905–912.
  77. Ravera S, Virkki LV, Murer H, et al. Deciphering PiT transport kinetics and substrate specificity using electrophysiology and flux measurements. Am J Physiol Cell Physiol. 2007; 293(2): C606–C620.
  78. Farrell KB, Tusnady GE, Eiden MV. New structural arrangement of the extracellular regions of the phosphate transporter SLC20A1, the receptor for gibbon ape leukemia virus. J Biol Chem. 2009; 284(43): 29979–29987.
  79. Salaün C, Rodrigues P, Heard JM. Transmembrane topology of PiT-2, a phosphate transporter-retrovirus receptor. J Virol. 2001; 75(12): 5584–5592.
  80. Giachelli CM, Speer MY, Li X, et al. Regulation of vascular calcification: roles of phosphate and osteopontin. Circ Res. 2005; 96(7): 717–722.
  81. Li X, Giachelli CM. Sodium-dependent phosphate cotransporters and vascular calcification. Curr Opin Nephrol Hypertens. 2007; 16(4): 325–328.
  82. Yoshiko Y, Candeliere GA, Maeda N, et al. Osteoblast autonomous Pi regulation via Pit1 plays a role in bone mineralization. Mol Cell Biol. 2007; 27(12): 4465–4474.
  83. Nowik M, Picard N, Stange G, et al. Renal phosphaturia during metabolic acidosis revisited: molecular mechanisms for decreased renal phosphate reabsorption. Pflugers Arch. 2008; 457(2): 539–549.
  84. Chien ML, Foster JL, Douglas JL, et al. The amphotropic murine leukemia virus receptor gene encodes a 71-kilodalton protein that is induced by phosphate depletion. J Virol. 1997; 71(6): 4564–4570.
  85. Kavanaugh MP, Miller DG, Zhang W, et al. 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; 91(15): 7071–7075.
  86. Martinez FO, Sica A, Mantovani A, et al. Macrophage activation and polarization. Front Biosci. 2008; 13: 453–461.
  87. Willsky GR, Malamy MH. Characterization of two genetically separable inorganic phosphate transport systems in Escherichia coli. J Bacteriol. 1980; 144(1): 356–365.
  88. Fernandes I, Béliveau R, Friedlander G, et al. NaPO(4) cotransport type III (PiT1) expression in human embryonic kidney cells and regulation by PTH. Am J Physiol. 1999; 277(4): F543–F551.
  89. Villa-Bellosta R, Ravera S, Sorribas V, et al. The Na+-Pi cotransporter PiT-2 (SLC20A2) is expressed in the apical membrane of rat renal proximal tubules and regulated by dietary Pi. Am J Physiol Renal Physiol. 2009; 296(4): F691–F699.
  90. Beck L, Leroy C, Salaün C, et al. Identification of a novel function of PiT1 critical for cell proliferation and independent of its phosphate transport activity. J Biol Chem. 2009; 284(45): 31363–31374.
  91. Salaün C, Leroy C, Rousseau A, et al. Identification of a novel transport-independent function of PiT1/SLC20A1 in the regulation of TNF-induced apoptosis. J Biol Chem. 2010; 285(45): 34408–34418.
  92. Cecil DL, Rose DM, Terkeltaub R, et al. Role of interleukin-8 in PiT-1 expression and CXCR1-mediated inorganic phosphate uptake in chondrocytes. Arthritis Rheum. 2005; 52(1): 144–154.
  93. Mansfield K, Teixeira CC, Adams CS, et al. Phosphate ions mediate chondrocyte apoptosis through a plasma membrane transporter mechanism. Bone. 2001; 28(1): 1–8.
  94. Beck L, Leroy C, Beck-Cormier S, et al. The phosphate transporter PiT1 (Slc20a1) revealed as a new essential gene for mouse liver development. PLoS One. 2010; 5(2): e9148.
  95. Crouthamel MH, Lau WL, Leaf EM, et al. Sodium-dependent phosphate cotransporters and phosphate-induced calcification of vascular smooth muscle cells: redundant roles for PiT-1 and PiT-2. Arterioscler Thromb Vasc Biol. 2013; 33(11): 2625–2632.
  96. Wallingford MC, Gammill HS, Giachelli CM. Slc20a2 deficiency results in fetal growth restriction and placental calcification associated with thickened basement membranes and novel CD13 and lamininα1 expressing cells. Reprod Biol. 2016; 16(1): 13–26.
  97. Wang C, Li Y, Shi L, et al. Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. Nat Genet. 2012; 44(3): 254–256.
  98. Jensen N, Schrøder HD, Hejbøl EK, et al. Loss of function of Slc20a2 associated with familial idiopathic Basal Ganglia calcification in humans causes brain calcifications in mice. J Mol Neurosci. 2013; 51(3): 994–999.
  99. Hilfiker H, Hattenhauer O, Traebert M, et al. Characterization of a murine type II sodium-phosphate cotransporter expressed in mammalian small intestine. Proc Natl Acad Sci U S A. 1998; 95(24): 14564–14569.

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

Via MedicaWydawcą serwisu jest  "Via Medica sp. z o.o." sp.k., ul. Świętokrzyska 73, 80–180 Gdańsk

tel.:+48 58 320 94 94, faks:+48 58 320 94 60, e-mail:  viamedica@viamedica.pl