Correlation between hyperphosphatemia and type II Na-Pi cotransporter activity in klotho mice.
Recent studies have demonstrated that klotho protein plays a role in calcium/phosphate homeostasis. The goal of the present study was to investigate the regulation of Na-P(i) cotransporters in klotho mutant (kl/kl) mice. The kl/kl mice displayed hyperphosphatemia, high plasma 1,25(OH)(2)D(3) levels, increased activity of the renal and intestinal sodium-dependent P(i) cotransporters, and increased levels of the type IIa, type IIb, and type IIc transporter proteins compared with wild-type mice. Interestingly, transcript levels of the type IIa/type IIc transporter mRNA abundance, but not transcripts levels of type IIb transporter mRNA, were markedly decreased in kl/kl mice compared with wild-type mice. Furthermore, plasma fibroblast growth factor 23 (FGF23) levels were 150-fold higher in kl/kl mice than in wild-type mice. Feeding of a low-P(i) diet induced the expression of klotho protein and decreased plasma FGF23 levels in kl/kl mice, whereas colchicine treatment experiments revealed evidence of abnormal membrane trafficking of the type IIa transporter in kl/kl mice. Finally, feeding of a low-P(i) diet resulted in increased type IIa Na-P(i) cotransporter protein in the apical membrane in the wild-type mice, but not in kl/kl mice. These results indicate that hyperphosphatemia in klotho mice is due to dysregulation of expression and trafficking of the renal type IIa/IIc transporters rather than to intestinal P(i) uptake.
Segawa
Hiroko
H
Dept. of Molecular Nutrition, Institution of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan.
Yamanaka
Setsuko
S
Ohno
Yasue
Y
Onitsuka
Akemi
A
Shiozawa
Kazuyo
K
Aranami
Fumito
F
Furutani
Junya
J
Tomoe
Yuka
Y
Ito
Mikiko
M
Kuwahata
Masashi
M
Imura
Akihiro
A
Nabeshima
Yoichi
Y
Miyamoto
Ken-ichi
K
D000818:Animals; D002118:Calcium / Q000097:blood / Q000652:urine; D004032:Diet; D004705:Endocytosis / Q000502:physiology; D005089:Exocytosis / Q000502:physiology; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000096:biosynthesis; D005966:Glucuronidase / Q000096:biosynthesis; D007668:Kidney / Q000378:metabolism*; D000090265:Klotho Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D010710:Phosphates / Q000008:administration & dosage / Q000097:blood* / Q000652:urine; D015398:Signal Transduction; D050610:Sodium-Phosphate Cotransporter Proteins, Type II / Q000096:biosynthesis*
C000717428:Fgf23 protein, mouse; D010710:Phosphates; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins; D002118:Calcium