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Disturbance in Phosphorus Metabolism by Cadmium Exposure

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

Abstract

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.

Keywords

Cadmium Fibroblast growth factor 23 Processing Phosphaturia Bone 

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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

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