FGF23 fails to inhibit uremic parathyroid glands.
Fibroblast growth factor 23 (FGF23) modulates mineral metabolism by promoting phosphaturia and decreasing the production of 1,25-dihydroxyvitamin D(3). FGF23 decreases parathyroid hormone (PTH) mRNA and secretion, but despite a marked elevation in FGF23 in uremia, PTH production increases. Here, we investigated the effect of FGF23 on parathyroid function in normal and uremic hyperplastic parathyroid glands in rats. In normal parathyroid glands, FGF23 decreased PTH production, increased expression of both the parathyroid calcium-sensing receptor and the vitamin D receptor, and reduced cell proliferation. Furthermore, FGF23 induced phosphorylation of extracellular signal-regulated kinase 1/2, which mediates the action of FGF23. In contrast, in hyperplastic parathyroid glands, FGF23 did not reduce PTH production, did not affect expression of the calcium-sensing receptor or vitamin D receptor, and did not affect cell proliferation. In addition, FGF23 failed to activate the extracellular signal-regulated kinase 1/2-mitogen-activated protein kinase pathway in hyperplastic parathyroid glands. We observed very low expression of the FGF23 receptor 1 and the co-receptor Klotho in uremic hyperplastic parathyroid glands, which may explain the lack of response to FGF23 in this tissue. In conclusion, in hyperparathyroidism secondary to renal failure, the parathyroid cells resist the inhibitory effects of FGF23, perhaps as a result of the low expression of FGF23 receptor 1 and Klotho in this condition.
Canalejo
Rocío
R
Unidad de Investigacion, Servicio de Nefrologia, Departamento de Medicina, Red in ren, Instituto Maimó nides de Invstigación Biomédica de Córdoba, Hospital Universitario Reina Sofia, Cordoba, Spain.
Canalejo
Antonio
A
Martinez-Moreno
Julio Manuel
JM
Rodriguez-Ortiz
M Encarnacion
ME
Estepa
Jose C
JC
Mendoza
Francisco Javier
FJ
Munoz-Castaneda
Juan Rafael
JR
Shalhoub
Victoria
V
Almaden
Yolanda
Y
Rodriguez
Mariano
M
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D005966:Glucuronidase / Q000378:metabolism; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D000090265:Klotho Proteins; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010280:Parathyroid Glands / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010281:Parathyroid Hormone / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D044169:Receptors, Calcium-Sensing / Q000378:metabolism; D046509:Tissue Culture Techniques; D014511:Uremia / Q000378:metabolism* / Q000473:pathology
C505605:Fgf23 protein, rat; D010281:Parathyroid Hormone; D018167:Receptors, Calcitriol; D044169:Receptors, Calcium-Sensing; D005346:Fibroblast Growth Factors; C496350:Fgfr1 protein, rat; D051496:Receptor, Fibroblast Growth Factor, Type 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D005966:Glucuronidase; D000090265:Klotho Proteins