Effect of hydrolysis-resistant FGF23-R179Q on dietary phosphate regulation of the renal type-II Na/Pi transporter.
Fibroblast growth factor 23 (FGF23), a phosphaturic factor, is involved in the regulation of renal inorganic phosphate (Pi) reabsorption. Proteolysis-resistant FGF23 mutants expressed in rodents reduce Pi uptake in both intestine and kidney, independent of parathyroid hormone action. In the present study, we investigated whether FGF23 affects dietary regulation of Na(+)-dependent Pi (Na/Pi) cotransport in the rat kidney using wild-type FGF23 and an R179Q mutant, which disrupts a consensus proteolytic cleavage motif. Rats injected with naked human FGF23 DNA (wild-type or R179Q mutant) expressed the human FGF23 transcript in the liver. In those animals, plasma calcium and parathyroid hormone levels were not affected by FGF23 (either wild-type or R179Q mutant). FGF23-R179Q did, however, significantly decrease plasma Pi and renal Na/Pi cotransport activity and also the level of type-IIc Na/Pi cotransporter protein in brush-border membrane vesicles (BBMVs) from normal rat kidney. Western blot and immunohistochemical analyses in rats fed a low-Pi diet showed the levels of types-IIa and -IIc Na/Pi cotransporters to be markedly increased. After injection of FGF23-R179Q DNA into the rats fed a low-Pi diet, the levels of the types-IIa and -IIc transporter proteins were decreased. The FGF23 mutant thus blunts the signalling of Pi deprivation to the renal type-II Na/Pi cotransporter, suggesting that the FGF23 pathway could be involved in the signalling of dietary Pi.
Segawa
Hiroko
H
Nutritional Science, Department of Nutrition, School of Medicine, Tokushima University, Kuramoto-cho 3, 770-8503 Tokushima City, Japan.
Kawakami
Eri
E
Kaneko
Ichiro
I
Kuwahata
Masashi
M
Ito
Mikiko
M
Kusano
Kenichiro
K
Saito
Hitoshi
H
Fukushima
Naoshi
N
Miyamoto
Ken-Ichi
K
D000818:Animals; D002118:Calcium / Q000097:blood; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D006868:Hydrolysis; D007150:Immunohistochemistry; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008297:Male; D016297:Mutagenesis, Site-Directed / Q000502:physiology; D010281:Parathyroid Hormone / Q000097:blood; D010710:Phosphates / Q000097:blood*; D016226:Phosphorus, Dietary / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D012964:Sodium / Q000378:metabolism; D050608:Sodium-Phosphate Cotransporter Proteins; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D027981:Symporters / Q000378:metabolism*; D014807:Vitamin D / Q000097:blood
C000717427:FGF23 protein, human; D010281:Parathyroid Hormone; D010710:Phosphates; D016226:Phosphorus, Dietary; D012333:RNA, Messenger; D050608:Sodium-Phosphate Cotransporter Proteins; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D027981:Symporters; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D012964:Sodium; D002118:Calcium