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 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.
Galitzer
H
H
Department of Nephrology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Ben-Dov
I Z
IZ
Silver
Justin
J
Naveh-Many
Tally
T
D000225:Adenine / Q000633:toxicity; D000818:Animals; D002908:Chronic Disease; D015536:Down-Regulation / Q000235:genetics; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000032:analysis / Q000502:physiology*; D005966:Glucuronidase / Q000032:analysis; D006962:Hyperparathyroidism, Secondary / Q000235:genetics*; D007674:Kidney Diseases / Q000139:chemically induced / Q000150:complications*; D000090265:Klotho Proteins; D010280:Parathyroid Glands / Q000737:chemistry*; D010281:Parathyroid Hormone / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000032:analysis
D010281:Parathyroid Hormone; D012333:RNA, Messenger; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C496350:Fgfr1 protein, rat; D051496:Receptor, Fibroblast Growth Factor, Type 1; D005966:Glucuronidase; D000090265:Klotho Proteins; D000225:Adenine