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Thromb Haemost 2010; 104(03): 464-470
DOI: 10.1160/TH09-12-0814
Theme Issue Article
Schattauer GmbH

Phosphate and vascular calcification: Emerging role of the sodium-dependent phosphate co-transporter PiT-1

Wei Ling Lau
1   Nephrology, University of Washington, Seattle, Washington, USA
,
Maria H. Festing
2   Bioengineering, University of Washington, Seattle, Washington, USA
,
Cecilia M. Giachelli
2   Bioengineering, University of Washington, Seattle, Washington, USA
› Author Affiliations Financial support:Dr. Giachelli’s research is supported by NIH grants HL62329, HL081785, and HL18645. W.L. Lau is funded by DK007467, and M.H. Festing is funded by NIH HL07828.
Further Information

Publication History

Received: 02 December 2009

Accepted after major revision: 01 July 2010

Publication Date:
23 November 2017 (online)

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Summary

Elevated serum phosphate is a risk factor for vascular calcification and cardiovascular events in kidney disease as well as in the general population. Elevated phosphate levels drive vascular calcification, in part, by regulating vascular smooth muscle cell (VSMC) gene expression, function, and fate. The type III sodium-dependent phosphate co-transporter, PiT-1, is necessary for phosphate-induced VSMC osteochondrogenic phenotype change and calcification, and has recently been shown to have unexpected functions in cell proliferation and embryonic development.

Keywords

Phosphate - vascular calcification - PiT-1 - kidney disease
 

  • References

  • 1 London G, Marchais S, Guérin A. et al. Arteriosclerosis, vascular calcifications and cardiovascular disease in uremia.. Curr Opin Nephrol Hypertens 2005; 14: 525-531.
    CrossrefPubMedGoogle Scholar
  • 2 Collins A, Li S, Gilbertson D. et al. Chronic kidney disease and cardiovascular disease in the Medicare population.. Kidney Int Suppl 2003; 87: S24-S31.
    PubMedGoogle Scholar
  • 3 USRDS.. United States Renal Data System Annual Data Report. 2009 http://www.usrds.org/adr.htm accessed on Oct 14, 2009.
    PubMedGoogle Scholar
  • 4 Braun J, Oldendorf M, Moshage W. et al. Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients.. Am J Kidney Dis 1996; 27: 394-401.
    CrossrefPubMedGoogle Scholar
  • 5 Ibels L, Alfrey A, Huffer W. et al. Arterial calcification and pathology in uremic patients undergoing dialysis.. Am J Med 1979; 66: 790-796.
    CrossrefPubMedGoogle Scholar
  • 6 Hruska K, Mathew S, Lund R. et al. Hyperphosphatemia of chronic kidney disease.. Kidney Int 2008; 74: 148-157.
    CrossrefPubMedGoogle Scholar
  • 7 Demer L, Tintut Y. Vascular calcification: pathobiology of a multifaceted disease.. Circulation 2008; 117: 2938-2948.
    CrossrefPubMedGoogle Scholar
  • 8 Shroff R, McNair R, Figg N. et al. Dialysis accelerates medial vascular calcification in part by triggering smooth muscle cell apoptosis.. Circulation 2008; 118: 1748-1757.
    CrossrefPubMedGoogle Scholar
  • 9 Blacher J, Safar M, Guerin A. et al. Aortic pulse wave velocity index and mortality in end-stage renal disease.. Kidney Int 2003; 63: 1852-1860.
    CrossrefPubMedGoogle Scholar
  • 10 Vanholder R, Massy Z, Argiles A. et al. Chronic kidney disease as cause of cardiovascular morbidity and mortality.. Nephrol Dial Transplant 2005; 20: 1048-1056.
    CrossrefPubMedGoogle Scholar
  • 11 Ahmed S, O’Neill K, Hood A. et al. Calciphylaxis is associated with hyperphosphatemia and increased osteopontin expression by vascular smooth muscle cells.. Am J Kidney Dis 2001; 37: 1267-1276.
    CrossrefPubMedGoogle Scholar
  • 12 Goldman L, Ausiello D. Cecil Medicine.. 23rd ed. Saunders Elsevier; 2007
    Google Scholar
  • 13 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: F691-F699.
    CrossrefPubMedGoogle Scholar
  • 14 Reichel H, Deibert B, Schmidt-Gayk H. et al. Calcium metabolism in early chronic renal failure: implications for the pathogenesis of hyperparathyroidism.. Nephrol Dial Transplant 1991; 6: 162-169.
    CrossrefPubMedGoogle Scholar
  • 15 Hattenhauer O, Traebert M, Murer H. et al. Regulation of small intestinal Na-P(i) type IIb cotransporter by dietary phosphate intake.. Am J Physiol 1999; 277: G756-G762.
    PubMedGoogle Scholar
  • 16 Shimada T, Hasegawa H, Yamazaki Y. et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.. J Bone Miner Res 2004; 19: 429-435.
    PubMedGoogle Scholar
  • 17 El-Abbadi M, Pai A, Leaf E. et al. Phosphate feeding induces arterial medial calcification in uremic mice: role of serum phosphorus, fibroblast growth factor-23, and osteopontin.. Kidney Int 2009; 75: 1297-1307.
    CrossrefPubMedGoogle Scholar
  • 18 Block G, Hulbert-Shearon T, Levin N. et al. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study.. Am J Kidney Dis 1998; 31: 607-617.
    CrossrefPubMedGoogle Scholar
  • 19 Young E, Albert J, Satayathum S. et al. Predictors and consequences of altered mineral metabolism: the Dialysis Outcomes and Practice Patterns Study.. Kidney Int 2005; 67: 1179-1187.
    CrossrefPubMedGoogle Scholar
  • 20 Dhingra R, Sullivan L, Fox C. et al. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community.. Arch Intern Med 2007; 167: 879-885.
    CrossrefPubMedGoogle Scholar
  • 21 Kestenbaum B, Sampson J, Rudser K. et al. Serum phosphate levels and mortality risk among people with chronic kidney disease.. J Am Soc Nephrol 2005; 16: 520-528.
    CrossrefPubMedGoogle Scholar
  • 22 Chertow G, Burke S, Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.. Kidney Int 2002; 62: 245-252.
    CrossrefPubMedGoogle Scholar
  • 23 Block G, Raggi P, Bellasi A. et al. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients.. Kidney Int 2007; 71: 438-441.
    CrossrefPubMedGoogle Scholar
  • 24 Suki W, Zabaneh R, Cangiano J. et al. Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients.. Kidney Int 2007; 72: 1130-1137.
    CrossrefPubMedGoogle Scholar
  • 25 St Peter W, Liu J, Weinhandl E. et al. A comparison of sevelamer and calcium-based phosphate binders on mortality, hospitalization, and morbidity in hemo-dialysis: a secondary analysis of the Dialysis Clinical Outcomes Revisited (DCOR) randomized trial using claims data.. Am J Kidney Dis 2008; 51: 445-454.
    CrossrefPubMedGoogle Scholar
  • 26 Jono S, McKee M, Murry C. et al. Phosphate regulation of vascular smooth muscle cell calcification.. Circ Res 2000; 87: E10-E17.
    CrossrefPubMedGoogle Scholar
  • 27 Cozzolino M, Staniforth M, Liapis H. et al. Sevelamer hydrochloride attenuates kidney and cardiovascular calcifications in long-term experimental uremia.. Kidney Int 2003; 64: 1653-1661.
    CrossrefPubMedGoogle Scholar
  • 28 Block G, Spiegel D, Ehrlich J. et al. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis.. Kidney Int 2005; 68: 1815-1824.
    CrossrefPubMedGoogle Scholar
  • 29 Steitz S, Speer M, Curinga G. et al. Smooth muscle cell phenotypic transition associated with calcification: upregulation of Cbfa1 and downregulation of smooth muscle lineage markers.. Circ Res 2001; 89: 1147-1154.
    CrossrefPubMedGoogle Scholar
  • 30 Wada T, McKee M, Steitz S. et al. Calcification of vascular smooth muscle cell cultures: inhibition by osteopontin.. Circ Res 1999; 84: 166-178.
    CrossrefPubMedGoogle Scholar
  • 31 Graciolli F, Neves K, dos Reis L. et al. Phosphorus overload and PTH induce aortic expression of Runx2 in experimental uraemia.. Nephrol Dial Transplant 2009; 24: 1416-1421.
    CrossrefPubMedGoogle Scholar
  • 32 Speer M, Yang H, Brabb T. et al. Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries.. Circ Res 2009; 104: 733-741.
    CrossrefPubMedGoogle Scholar
  • 33 Román-García P, Carrillo-López N, Fernández-Martín J. et al. High phosphorus diet induces vascular calcification, a related decrease in bone mass and changes in the aortic gene expression.. Bone 2010; 46: 121-128.
    CrossrefPubMedGoogle Scholar
  • 34 Reynolds J, Joannides A, Skepper J. et al. Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD.. J Am Soc Nephrol 2004; 15: 2857-2867.
    CrossrefPubMedGoogle Scholar
  • 35 Shroff R, McNair R, Skepper J. et al. Chronic mineral dysregulation promotes vascular smooth muscle cell adaptation and extracellular matrix calcification.. J Am Soc Nephrol 2010; 21: 103-112.
    CrossrefPubMedGoogle Scholar
  • 36 Son B, Kozaki K, Iijima K. et al. Gas6/Axl-PI3K/Akt pathway plays a central role in the effect of statins on inorganic phosphate-induced calcification of vascular smooth muscle cells.. Eur J Pharmacol 2007; 556: 1-8.
    CrossrefPubMedGoogle Scholar
  • 37 Son B, Kozaki K, Iijima K. et al. Statins protect human aortic smooth muscle cells from inorganic phosphate-induced calcification by restoring Gas6-Axl survival pathway.. Circ Res 2006; 98: 1024-1031.
    CrossrefPubMedGoogle Scholar
  • 38 Zhang S, Fantozzi I, Tigno D. et al. Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells.. Am J Physiol Lung Cell Mol Physiol 2003; 285: L740-L754.
    CrossrefPubMedGoogle Scholar
  • 39 Murshed M, Harmey D, Millán J. et al. Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone.. Genes Dev 2005; 19: 1093-1104.
    CrossrefPubMedGoogle Scholar
  • 40 Lomashvili K, Cobbs S, Hennigar R. et al. Phosphate-induced vascular calcification: role of pyrophosphate and osteopontin.. J Am Soc Nephrol 2004; 15: 1392-1401.
    CrossrefPubMedGoogle Scholar
  • 41 Lomashvili K, Garg P, Narisawa S. et al. Upregulation of alkaline phosphatase and pyrophosphate hydrolysis: potential mechanism for uremic vascular calcification.. Kidney Int 2008; 73: 1024-1030.
    CrossrefPubMedGoogle Scholar
  • 42 Rucker R. Calcium binding to elastin.. Adv Exp Med Biol 1974; 48: 185-209.
    PubMedGoogle Scholar
  • 43 Bouvet C, Moreau S, Blanchette J. et al. Sequential activation of matrix metalloproteinase 9 and transforming growth factor beta in arterial elastocalcinosis.. Arterioscler Thromb Vasc Biol 2008; 28: 856-862.
    CrossrefPubMedGoogle Scholar
  • 44 Hosaka N, Mizobuchi M, Ogata H. et al. Elastin Degradation Accelerates Phosphate-Induced Mineralization of Vascular Smooth Muscle Cells.. Calcif Tissue Int 2009; 85: 523-529.
    CrossrefPubMedGoogle Scholar
  • 45 Simionescu A, Philips K, Vyavahare N. Elastin-derived peptides and TGF-beta1 induce osteogenic responses in smooth muscle cells.. Biochem Biophys Res Commun 2005; 334: 524-532.
    CrossrefPubMedGoogle Scholar
  • 46 Heldin C, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins.. Nature 1997; 390: 465-471.
    CrossrefPubMedGoogle Scholar
  • 47 Lee K, Kim H, Li Q. et al. Runx2 is a common target of transforming growth factor beta1 and bone morphogenetic protein 2, and cooperation between Runx2 and Smad5 induces osteoblast-specific gene expression in the pluripotent mesenchymal precursor cell line C2C12.. Mol Cell Biol 2000; 20: 8783-8792.
    CrossrefPubMedGoogle Scholar
  • 48 Basalyga D, Simionescu D, Xiong W. et al. Elastin degradation and calcification in an abdominal aorta injury model: role of matrix metalloproteinases.. Circulation 2004; 110: 3480-3487.
    CrossrefPubMedGoogle Scholar
  • 49 Chung A, Yang H, Sigrist M. et al. Matrix metalloproteinase-2 and –9 exacerbate arterial stiffening and angiogenesis in diabetes and chronic kidney disease.. Cardiovasc Res 2009; 84: 494-504.
    CrossrefPubMedGoogle Scholar
  • 50 Takeda E, Taketani Y, Morita K. et al. Sodium-dependent phosphate co-transporters.. Int J Biochem Cell Biol 1999; 31: 377-381.
    CrossrefPubMedGoogle Scholar
  • 51 Werner A, Dehmelt L, Nalbant P. Na+-dependent phosphate cotransporters: the NaPi protein families.. J Exp Biol 1998; 201: 3135-3142.
    PubMedGoogle Scholar
  • 52 Villa-Bellosta R, Bogaert Y, Levi M. et al. Characterization of phosphate transport in rat vascular smooth muscle cells: implications for vascular calcification.. Arterioscler Thromb Vasc Biol 2007; 27: 1030-1036.
    CrossrefPubMedGoogle Scholar
  • 53 Li X, Yang H, Giachelli C. Role of the sodium-dependent phosphate cotrans-porter, Pit-1, in vascular smooth muscle cell calcification.. Circ Res 2006; 98: 905-912.
    CrossrefPubMedGoogle Scholar
  • 54 Villa-Bellosta R, Sorribas V. Phosphonoformic acid prevents vascular smooth muscle cell calcification by inhibiting calcium-phosphate deposition.. Arterioscler Thromb Vasc Biol 2009; 29: 761-766.
    CrossrefPubMedGoogle Scholar
  • 55 Ravera S, Virkki L, Murer H. et al. Deciphering PiT transport kinetics and substrate specificity using electrophysiology and flux measurements.. Am J Physiol Cell Physiol 2007; 293: C606-C620.
    CrossrefPubMedGoogle Scholar
  • 56 Li X, Yang H, Giachelli C. BMP-2 promotes phosphate uptake, phenotypic modulation, and calcification of human vascular smooth muscle cells.. Atherosclerosis 2008; 199: 271-277.
    CrossrefPubMedGoogle Scholar
  • 57 Suzuki A, Ghayor C, Guicheux J. et al. Enhanced expression of the inorganic phosphate transporter Pit-1 is involved in BMP-2-induced matrix mineralization in osteoblast-like cells.. J Bone Miner Res 2006; 21: 674-683.
    CrossrefPubMedGoogle Scholar
  • 58 Yang H, Curinga G, Giachelli C. Elevated extracellular calcium levels induce smooth muscle cell matrix mineralization in vitro.. Kidney Int 2004; 66: 2293-2299.
    CrossrefPubMedGoogle Scholar
  • 59 Villa-Bellosta R, Levi M, Sorribas V. Vascular smooth muscle cell calcification and SLC20 inorganic phosphate transporters: effects of PDGF, TNF-alpha, and Pi.. Pflugers Arch 2009; 458: 1151-1161.
    CrossrefPubMedGoogle Scholar
  • 60 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: 17-24.
    CrossrefPubMedGoogle Scholar
  • 61 Gallea S, Lallemand F, Atfi A. et al. Activation of mitogen-activated protein kinase cascades is involved in regulation of bone morphogenetic protein-2-induced osteoblast differentiation in pluripotent C2C12 cells.. Bone 2001; 28: 491-498.
    CrossrefPubMedGoogle Scholar
  • 62 Wang Z, Wang D, Hockemeyer D. et al. Myocardin and ternary complex factors compete for SRF to control smooth muscle gene expression.. Nature 2004; 428: 185-189.
    CrossrefPubMedGoogle Scholar
  • 63 Xiao G, Jiang D, Thomas P. et al. MAPK pathways activate and phosphorylate the osteoblast-specific transcription factor, Cbfa1.. J Biol Chem 2000; 275: 4453-4459.
    CrossrefPubMedGoogle Scholar
  • 64 Heldin C, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor.. Physiol Rev 1999; 79: 1283-1316.
    CrossrefPubMedGoogle Scholar
  • 65 Johann S, Gibbons J, O’Hara B. GLVR1, a receptor for gibbon ape leukemia virus, is homologous to a phosphate permease of Neurospora crassa and is expressed at high levels in the brain and thymus.. J Virol 1992; 66: 1635-1640.
    PubMedGoogle Scholar
  • 66 Miller D, Edwards R, Miller A. Cloning of the cellular receptor for amphotropic murine retroviruses reveals homology to that for gibbon ape leukemia virus.. Proc Natl Acad Sci USA 1994; 91: 78-82.
    CrossrefPubMedGoogle Scholar
  • 67 Kavanaugh M, Miller D, 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 USA 1994; 91: 7071-7075.
    CrossrefPubMedGoogle Scholar
  • 68 Olah Z, Lehel C, Anderson W. et al. The cellular receptor for gibbon ape leukemia virus is a novel high affinity sodium-dependent phosphate transporter.. J Biol Chem 1994; 269: 25426-25431.
    PubMedGoogle Scholar
  • 69 Collins J, Bai L, Ghishan F. The SLC20 family of proteins: dual functions as sodium-phosphate cotransporters and viral receptors.. Pflugers Arch 2004; 447: 647-652.
    CrossrefPubMedGoogle Scholar
  • 70 Palmer G, Zhao J, Bonjour J. et al. In vivo expression of transcripts encoding the Glvr-1 phosphate transporter/retrovirus receptor during bone development.. Bone 1999; 24: 1-7.
    CrossrefPubMedGoogle Scholar
  • 71 Beck L, Leroy C, Salaun C. et al. Identification of a novel function of PiT1 critical for cell proliferation and independent from its phosphate transport activity.. J Biol Chem 2009; 284: 31363-31374.
    CrossrefPubMedGoogle Scholar
  • 72 Segawa H, Onitsuka A, Furutani J. et al. Npt2a and Npt2c in mice play distinct and synergistic roles in inorganic phosphate metabolism and skeletal development.. Am J Physiol Renal Physiol 2009; 297: F671-F678.
    CrossrefPubMedGoogle Scholar
  • 73 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.. Biochemical and Biophysical Research Communications 2009; 381: 482-486.
    CrossrefPubMedGoogle Scholar
  • 74 Festing M, Speer M, Yang H. et al. Generation of mouse conditional and null alleles of the type III sodium-dependent phosphate cotransporter PiT-1.. Genesis 2009; 47: 858-863.
    PubMedGoogle Scholar
  • 75 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: e9148.
    CrossrefPubMedGoogle Scholar
  • 76 Walsh M, Manns B, Klarenbach S. et al. The effects of nocturnal compared with conventional hemodialysis on mineral metabolism: A randomized-controlled trial.. Hemodial Int 2010; 14: 174-181.
    CrossrefPubMedGoogle Scholar
  • 77 Davenport A, Gardner C, Delaney M. The effect of dialysis modality on phosphate control : haemodialysis compared to haemodiafiltration. The Pan Thames Renal Audit.. Nephrol Dial Transplant 2010; 25: 897-901.
    CrossrefPubMedGoogle Scholar
  • 78 Kuhlmann M. Phosphate elimination in modalities of hemodialysis and peritoneal dialysis.. Blood Purif 2010; 29: 137-144.
    CrossrefPubMedGoogle Scholar
  • 79 Ahlenstiel T, Pape L, Ehrich J. et al. Self-adjustment of phosphate binder dose to meal phosphorus content improves management of hyperphosphataemia in children with chronic kidney disease.. Nephrol Dial Transplant. 2010 epub ahead of print.
    PubMedGoogle Scholar
  • 80 Kalantar-Zadeh K, Gutekunst L, Mehrotra R. et al. Understanding sources of dietary phosphorus in the treatment of patients with chronic kidney disease.. Clin J Am Soc Nephrol 2010; 5: 519-530.
    CrossrefPubMedGoogle Scholar
  • 81 Navaneethan S, Palmer S, Craig J. et al. Benefits and harms of phosphate binders in CKD: a systematic review of randomized controlled trials.. Am J Kidney Dis 2009; 54: 619-637.
    CrossrefPubMedGoogle Scholar