Disturbance in Phosphorus Metabolism by Cadmium Exposure

  • Shinsuke KidoEmail author
  • Ichiro Kaneko
  • Ken-ichi Miyamoto
Part of the Current Topics in Environmental Health and Preventive Medicine book series (CTEHPM)


Itai-itai disease is an endemic disease characterized by osteomalacia accompanied with osteoporosis and multiple proximal tubular dysfunctions (Fanconi syndrome). Itai-itai disease is caused by environmental cadmium exposure, but the pathological mechanism of the disease remains unknown. Cadmium also yields irreversible bone and renal dysfunction; new validated biomarkers are needed for the detection of cadmium-induced nephropathy. We have focused on the role of fibroblast growth factor (FGF) 23, a protein that is essential for phosphate homeostasis in the bone-kidney axis, and have investigated the mechanism of cadmium-induced FGF23 production by bone cells. Cadmium injection in mice resulted in increased plasma FGF23 concentrations, but the level of FGF23 mRNA in the bone was not changed. Further studies indicated that increased plasma FGF23 levels in the cadmium-injected mice were caused by the posttranslational regulation of the FGF23 protein stability. FGF23 stability and secretion was altered by glycosylation of FGF23, which was in turn regulated by the activity of the GalNAc-T3 protein. We demonstrated that expression of the GalNAc-T3-encoding gene was significantly increased by cadmium exposure. Moreover, cadmium-dependent FGF23 accumulation was inhibited by an antagonist of the aryl hydrocarbon receptor (AhR), a transcription factor that can bind to the promoter of the GalNAc-T3 gene. Thus, cadmium stimulates transcription of the GalNAc-T3 gene via enhanced binding of AhR to the GalNAc-T3 promoter.

These findings suggest that the cadmium-induced increase in GalNAc-T3 expression suppresses proteolytic intracellular processing of FGF23, thereby yielding increased serum FGF23 concentrations, which in turn alter phosphate metabolism and dysfunction of the kidney and bone.


Cadmium Fibroblast growth factor 23 Processing Phosphaturia Bone 


  1. 1.
    Murer H, Silve C, Biber J. Phosphate metabolism renal handling of phosphate. In: Massry & glassock textbook of nephrology. 4th ed. Philadelphia: Lippincott Williams & Wilkins.Google Scholar
  2. 2.
    Murer H, Hernando N, Forster I, Biber J. Proximal tubular phosphate reabsorption: molecular mechanisms. Physiol Rev. 2000;80:1373–409.CrossRefGoogle Scholar
  3. 3.
    Tenenhouse HS. Regulation of phosphorus homeostasis by the type IIa Na/phosphate cotransporter. Annu Rev Nutr. 2005;25:197–214.CrossRefGoogle Scholar
  4. 4.
    Biber J, Hernando N, Forster I, Murer H. Regulation of phosphate transport in proximal tubules. Pflugers Arch. 2009;458:39–52.CrossRefGoogle Scholar
  5. 5.
    Segawa H, Kaneko I, Takahashi A, Kuwahata M, Ito M, Ohkido I, Tatsumi S, Miyamoto K. Growth-related renal type II Na/pi cotransporter. J Biol Chem. 2002;277:19665–72.CrossRefGoogle Scholar
  6. 6.
    Miyamoto K, Ito M, Tatsumi S, Kuwahata M, Segawa H. New aspect of renal phosphate reabsorption: the type II c sodium-dependent phosphate transporter. Am J Nephrol. 2007;27:503–15.CrossRefGoogle Scholar
  7. 7.
    Breusegem SY, Takahashi H, Girl-Arnal H, Wang X, Jiang T, Verlander JW, Wilson P, Miyazaki-Anzai S, Sutherland E, Caldas Y, Blaine JT, Segawa H, Miyamoto K, Barry NP, Levi M. 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:F350–61.CrossRefGoogle Scholar
  8. 8.
    Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, Yu X, Rauch F, Davis SI, Zhang S, Rios H, Drezner MK, Quarles LD, Bonewald LF, White KE. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet. 2006;38:1310–5.CrossRefGoogle Scholar
  9. 9.
    Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD. Pathogenic role of fgf23 in hyp mice. Am J Physiol Endocrinol Metab. 2006;291:E38–49.CrossRefGoogle Scholar
  10. 10.
    White KE, Evans WE, O’Riordan J, Speer MC, Econs MJ, Lorenz-Depiereux B, Grabowski M, Meitinger TTMS. Autosomal dominant hypophosphatemic rickets is associated with mutations in FGF23. Nat Genet. 2000;26:345–8.CrossRefGoogle Scholar
  11. 11.
    Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Fujita T, Fukumoto S, Yamashita T. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A. 2001;98:6500–5.CrossRefGoogle Scholar
  12. 12.
    Inoue Y, Segawa H, Kaneko I, Yamanaka S, Kusano K, Kawakami E, Furutani J, Ito M, Kuwahara M, Saito H, Fukushima N, Kato S, Kanayama HO, Miyamoto K. Role of the vitamin D receptor in FGF23 action on phosphate metabolism. Biochem J. 2005;390:325–31.CrossRefGoogle Scholar
  13. 13.
    Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, Kuro-o M. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem. 2006;281:6120–3.CrossRefGoogle Scholar
  14. 14.
    Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444:770–4.CrossRefGoogle Scholar
  15. 15.
    Murer H, Forster I, Biber J. The sodium phosphate cotransporter SLC34. Pflugers Arch. 2004;447:763–7.CrossRefGoogle Scholar
  16. 16.
    Tatsumi S, Miyagawa A, Kaneko I, Shiozaki Y, Sagawa H, Miyamoto K. Regulation of renal phosphate handling: inter-organ communication in health and disease. J Bone Miner Metab. 2016;34:1–10.CrossRefGoogle Scholar
  17. 17.
    Erben RG. Update on FGF23 and klotho signaling. Mol Cell Endocrinol. 2016;432:56–65.CrossRefGoogle Scholar
  18. 18.
    Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Yamashita T. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res. 2003;19:429–35.CrossRefGoogle Scholar
  19. 19.
    Guiterrez OM, Januzzi JL, Isakova T, Laliberte K, Smith K, Collerone G, Sarwar A, Hoffmann U, Coglianese E, Christensen R, Wang TJ, deFilippi C, Wolf M. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation. 2009;119:2545–52.CrossRefGoogle Scholar
  20. 20.
    Gutierrez OM, Mannsrtadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, Smith K, Lee H, Thadhani R, Juppner H, Wolf M. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008;359:584–92.CrossRefGoogle Scholar
  21. 21.
    Mirza MA, Larsson A, Melhus H, Ling L, Lasson TE. Serum intact FGF23 associate with left ventricular mass, hypertrophy and geometry in an elderly population. Atherosclerosis. 2009;207:546–51.CrossRefGoogle Scholar
  22. 22.
    Gutierrez O, Isakova T, Rhee E, Shah A, Holmes J, Collerone G, Juppner H, Wolf M. Fibroblast growth factor 23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol. 2005;16:2205–15.CrossRefGoogle Scholar
  23. 23.
    Wahl P, Wolf M. FGF23 in chronic kidney disease. Adv Exp Med Biol. 2012;728:107–25.CrossRefGoogle Scholar
  24. 24.
    Munoz Mendoza J, Isakova T, Ricardo AC, Xie H, Navaneethan SD, Anderson AH, Bezzano LA, Xie D, Kretzler M, Nessel L, Hamm LL, Negrea L, Leonard MB, Raj D, Wolf M, Chronic Renal Insufficiency Cohort. Fibroblast growth factor 23 and inflammation in CKD. Clin J Am Soc Nephrol. 2012;7:1155–62.CrossRefGoogle Scholar
  25. 25.
    Francis C, David V. Inflammations regulates fibroblast growth factor 23 production. Curr Opin Nephrol Hypertens. 2016;25:325–32.CrossRefGoogle Scholar
  26. 26.
    Adams RG, Harrison JF, Scott P. The development of cadmium-induced proteinuria, impaired renal function, and osteomalacia in alkaline battery workers. Q J Med. 1969;38:425–43.PubMedGoogle Scholar
  27. 27.
    Kazantzis G, Flynn FV, Spowage JS, Trott DG. Renal tubular malfunction and pulmonary emphysema in cadmium pigment workers. Q J Med. 1963;32:165–92.PubMedGoogle Scholar
  28. 28.
    Friberg L. Cadmium and the kidney. Environ Health Perspect. 1984;54:1–11.CrossRefGoogle Scholar
  29. 29.
    Friberg L, Piscator M, Nordberg GF, Kjellstrom T. Cadmium. Annu Rev Public Health. 1983;4:367–73.CrossRefGoogle Scholar
  30. 30.
    Klaassen CD, Liu J. Metallothionein transgenic and knock-out mouse models in the study of cadmium toxicity. J Toxicol Sci. 1998;23:97–102.CrossRefGoogle Scholar
  31. 31.
    Klaassen CD, Liu J, Diwan BA. Metallothionein protection of cadmium toxicity. Toxicol Appl Pharmacol. 2009;238:215–20.CrossRefGoogle Scholar
  32. 32.
    Gonick HC. Trace metals and the kidney. Miner Electrolyte Metab. 1978;1:107–20.Google Scholar
  33. 33.
    Cuypers A, Plusquin M, Remans T, Jozefczak M, Keunen E, Gielen H, Qpdenakker K, Nair AR, Munters E, Artois TJ, Nawrot T, Vangronsveld J, Smeets K. Cadmium stress: an oxidative challenge. Biometals. 2010;23:927–40.CrossRefGoogle Scholar
  34. 34.
    Wang B, Li Y, Shao C, Tan Y, Cai L. Cadmium and its epigenetic effects. Curr Med Chem. 2012;19:2611–20.CrossRefGoogle Scholar
  35. 35.
    Martinez-Zamudio R, Ha HC. Environmental epigenetic in metal exposure. Epigenetics. 2011;6:820–7.CrossRefGoogle Scholar
  36. 36.
    Vesey DA. Transport pathways for cadmium in the intestine and kidney proximal tubule: focus on the interaction with essential metals. Toxicol Lett. 2010;198:13–9.CrossRefGoogle Scholar
  37. 37.
    Almeida P, Stearns L. Political opportunities and local grassroots environmental movement: the case of Minamata. Soc Probl. 1998;45:37–60.CrossRefGoogle Scholar
  38. 38.
    Kaneta M, Hikichi H, Endo S, Sugiyama N. Chemical form of cadmium (and other heavy metals) in rice and wheat plants. Environ Health Persp. 1986;65:33–7.Google Scholar
  39. 39.
    Johri N, Jacquillet G, Unwin R. Heavy metals poisoning: the effects of cadmium on the kidney. Biometals. 2010;23:783–92.CrossRefGoogle Scholar
  40. 40.
    Kazantzis G. Cadmium, osteoporosis and calcium metabolism. Biometals. 2004;17:493–8.CrossRefGoogle Scholar
  41. 41.
    Iwata K, Saito H, Moriyama M, Nakano A. Renal tubular function after reduction of environmental cadmium exposure: a ten year follow up. Arch Environ Health. 1993;48:157–63.CrossRefGoogle Scholar
  42. 42.
    Lind Y, Engman J, Jorhem L, Glynn AW. Cadmium accumulation in liver and kidney of mice exposed to the same weekly cadmium dose continuously or once a week. Food Chem Toxicol. 1997;35:891–5.CrossRefGoogle Scholar
  43. 43.
    Aranami F, Segawa H, Furutani J, Kuwahara S, Tominaga R, Hanabusa E, Tatsumi S, Kido S, Ito M, Miyamoto K. Fibroblast growth factor 23 mediates the phosphaturic actions of cadmium. J Med Investig. 2010;57:95–108.CrossRefGoogle Scholar
  44. 44.
    Herak-Kramberger CM, Spindler B, Biber J, Murer H, Sabolic I. Renal type II Na/pi co-transporter is strongly impaired whereas the Na/sulphate-cotransporter and aquaporin I are unchanged in cadmium-treated rats. Pflugers Arch. 1996;432:336–44.CrossRefGoogle Scholar
  45. 45.
    Olauson H, Vervloet MG, Cozzolino M, Massey ZA, Urena Torres P, Larsson TE. New insights into the FGF23-Klotho axis. Semin Nephrol. 2014;34:586–97.CrossRefGoogle Scholar
  46. 46.
    Kido S, Fujihara M, Nomura K, Sasaki S, Mukai R, Ohnishi R, Kaneko I, Segawa H, Tatsumi S, Izumi H, Kohno K, Miyamoto K. Molecular mechanisms of cadmium-induced fibroblast growth factor 23 upregulation in osteoblast-like cells. Toxicol Sci. 2014;139:301–16.CrossRefGoogle Scholar
  47. 47.
    Frishberg Y, Ito N, Rinat C, Yamazaki Y, feinsteins S, Urakawa I, Navon-Elkan P, Becker-Cohen R, Yamashita T, Araya K, Igarashi T, Fujita T, Fukumoto S. Hyperostosis-hyperphosphatemia syndrome: a congenital disorder of O-glycosylation associated with augment processing of fibroblast growth factor 23. J Bone Miner Res. 2007;22:235–42.CrossRefGoogle Scholar
  48. 48.
    Kato K, Jeanneau C, Tarp MA, Benet-Pages A, Lorenz-Depiereux B, Bennett EP, Mandel U, Strom TM, Clausen H. Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J Biol Chem. 2006;281:18370–7.CrossRefGoogle Scholar
  49. 49.
    Ichikawa S, Lyles KW, Econs MJ. A novel GALNT3 mutation in a pseudoautosomal dominant form of tumoral calcinosis: evidence that the disorder is autosomal recessive. J Clin Endocrinol Metab. 2005;90:2420–3.CrossRefGoogle Scholar
  50. 50.
    Carlson DB, Perdew GH. A dynamic role for the Ah receptor in cell signaling? Insights from a diverse group of Ah receptor interacting proteins. J Biochem. 2002;16:317–25.Google Scholar
  51. 51.
    Elbekai RH, EI-Kadi AO. Modulation of aryl hydrocarbon receptor-regulated gene expression by arsenite, cadmium, and chromium. Toxicology. 2004;202:249–69.CrossRefGoogle Scholar
  52. 52.
    Elbekai RH, EI-Kadi AO. Transcriptional activation and posttranscriptional modification of cyp1a1 by arsenite, cadmium, and chromium. Toxicol Lett. 2007;172:106–19.CrossRefGoogle Scholar
  53. 53.
    Johnson MD, Kenny N, Stoica A, Hilakivi-Clarke L, Singh B, Chepko G, Clarke R, Sholler PF, Lirio AA, Foss C, Reiter R, Trock B, Paik S, Martin MB. Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland. Nat Med. 2003;9:1081–4.CrossRefGoogle Scholar
  54. 54.
    Martines-Campa C, Alonso-Gonzalez C, Mediavilla MD, Cos S, Gonzalez A, Ramos S, Sanchez-Barcelo EJ. Melatonin inhibits both ER alpha activation and breast cancer cell proliferation induced by a metalloestrogen, cadmium. J Pineal Res. 2006;40:291–6.CrossRefGoogle Scholar
  55. 55.
    Nomoto M, Izumi H, Ise T, Kato K, Takano H, Nagatani G, Shibao K, Ohta R, Imamura T, Kuwano M, Matsuo K, Yamada Y, Itoh H, Kohno K. Structural basis for the regulation of UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyl transferase-3 gene expression in adenocarcinoma cells. Cancer Res. 1999;59:6214–22.PubMedGoogle Scholar
  56. 56.
    Chefetz I, Kohno K, Izumi H, Uitto J, Richard G, Sprecher E. GALNT3, a gene associated with hyperphosphatemic familial tumoral calcinosis, is transcriptionally regulated by extracellular phosphate and modulates matrix metalloproteinase activity. Biochem Biophys Acta. 2009;1792:61–7.PubMedGoogle Scholar
  57. 57.
    Chefetz I, Sprecher E. Familial tumoral calcinosis and the role of O-glycosylation in the maintenance of phosphate homeostasis. Biochem Biophys Acta. 2009;1792:847–52.PubMedGoogle Scholar
  58. 58.
    Kido S, Kaneko I, Tatsumi S, Segawa H, Miyamoto K. Vitamin D and type II sodium-dependent phosphate cotransporters. Contrib Nephrol. 2013;180:86–97.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Shinsuke Kido
    • 1
    • 2
    Email author
  • Ichiro Kaneko
    • 3
  • Ken-ichi Miyamoto
    • 3
  1. 1.Laboratory of Clinical Nutrition, Department of Food Science and Nutrition, Faculty of AgricultureKindai UniversityNaraJapan
  2. 2.Agricultural Technology and Innovation Research Institute, Kindai UniversityNaraJapan
  3. 3.Department of Molecular NutritionInstitute of Biomedical Sciences, Tokushima University Graduate SchoolTokushimaJapan

Personalised recommendations