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Human Fibroblast Growth Factor-23 Mutants Suppress Na super(+)-dependent Phosphate Co-transport Activity and 1[alpha],25-Dihydroxyvitamin D sub(3) Production

Saito, H ; Kusano, K ; Kinosaki, M ; Ito, H ; Hirata, M ; Segawa, H ; Miyamoto, K ; Fukushima, N

The Journal of biological chemistry, 2003-01, Vol.278 (4), p.2206-2211 [Periódico revisado por pares]

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  • Título:
    Human Fibroblast Growth Factor-23 Mutants Suppress Na super(+)-dependent Phosphate Co-transport Activity and 1[alpha],25-Dihydroxyvitamin D sub(3) Production
  • Autor: Saito, H ; Kusano, K ; Kinosaki, M ; Ito, H ; Hirata, M ; Segawa, H ; Miyamoto, K ; Fukushima, N
  • É parte de: The Journal of biological chemistry, 2003-01, Vol.278 (4), p.2206-2211
  • Notas: ObjectType-Article-2
    SourceType-Scholarly Journals-1
    content type line 23
    ObjectType-Feature-1
  • Descrição: The human fibroblast growth factor 23 (hFGF23) and its autosomal dominant hypophosphatemic rickets (ADHR) mutant genes were incorporated into animals by naked DNA injection to investigate the action on phosphate homeostasis in vivo. The hFGF23 mutants (R176Q, R179Q, and R179W) markedly reduced serum phosphorus (6.2-6.9 mg/dl) compared with the plasmid MOCK (8.5 mg/dl). However, native hFGF23 did not affect serum phosphorus (8.6 mg/dl). Both hFGF23 and hFGF23R179Q mRNAs were expressed more than 100-fold in the liver 4 days after injection, however, the C-terminal portion of hFGF23 was detected only in the serum from hFGF23R179Q-injected animals (1109 pg/ml). hFGF23R179Q mutant was secreted as a 32-kDa protein, whereas, native hFGF23 was detected as a 20-kDa protein in the cell-conditioned media. These results suggest the hFGF23R179Q protein is resistant to intracellular proteolytic processing. The hFGF23R179Q suppressed Na/P sub(i) co-transport activities both in kidney and in small intestine by 45 and 30%, respectively, as well as serum 1[alpha],25-dihydroxyvitamin D sub(3) to less than 15 pg/ml. However, it had little effect on serum parathyroid hormone (PTH). Infusion of hFGF23R179Q protein normalized serum phosphorus in thyroparathyroidectomized rats without affecting serum calcium. Taken together, the FGF23 mutants reduce both phosphate uptake in intestine and phosphate reabsorption in kidney, independent of PTH action.
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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