Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease

Although fibroblast growth factor 23 (FGF23) acting through its receptor Klotho-FGFR1c decreases parathyroid hormone expression, this hormone is increased in chronic kidney disease despite an elevated serum FGF23. We measured possible factors that might contribute to the resistance of parathyroid gl...

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Bibliographic Details
Published in:Kidney international 2010-02, Vol.77 (3), p.211-218
Main Authors: Galitzer, H., Ben-Dov, I.Z., Silver, Justin, Naveh-Many, Tally
Format: Article
Language:English
Subjects:
Adenine - toxicity
Animals
Biological and medical sciences
Chronic Disease
chronic renal failure
Down-Regulation - genetics
Endocrinopathies
Fibroblast Growth Factors - analysis
Fibroblast Growth Factors - physiology
gene expression
Glucuronidase - analysis
hyperparathyroidism
Hyperparathyroidism, Secondary - genetics
Kidney Diseases - chemically induced
Kidney Diseases - complications
Kidneys
Medical sciences
Nephrology. Urinary tract diseases
Non tumoral diseases. Target tissue resistance. Benign neoplasms
Parathyroid Glands - chemistry
parathyroid hormone
Parathyroid Hormone - analysis
Parathyroids. Parafollicular cells. Cholecalciferol. Phosphocalcic homeostasis (diseases)
Rats
Receptor, Fibroblast Growth Factor, Type 1 - analysis
RNA, Messenger - analysis
Urinary system involvement in other diseases. Miscellaneous
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Summary:Although fibroblast growth factor 23 (FGF23) acting through its receptor Klotho-FGFR1c decreases parathyroid hormone expression, this hormone is increased in chronic kidney disease despite an elevated serum FGF23. We measured possible factors that might contribute to the resistance of parathyroid glands to FGF23 in rats with the dietary adenine-induced model of chronic kidney disease. Quantitative immunohistochemical and reverse transcription–PCR analysis using laser capture microscopy showed that both Klotho and FGFR1 protein and mRNA levels were decreased in histological sections of the parathyroid glands. Recombinant FGF23 failed to decrease serum parathyroid hormone levels or activate the mitogen-activated protein kinase signaling pathway in the glands of rats with advanced experimental chronic kidney disease. In parathyroid gland organ culture, the addition of FGF23 decreased parathyroid hormone secretion and mRNA levels in control animals or rats with early but not advanced chronic kidney disease. Our results show that because of a downregulation of the Klotho–FGFR1c receptor complex, an increase of circulating FGF23 does not decrease parathyroid hormone levels in established chronic kidney disease. This in vivo resistance is sustained in parathyroid organ culture in vitro.
ISSN:0085-2538
1523-1755
DOI:10.1038/ki.2009.464