Nephrol Dial Transplant (2003) 18: III79-III80
© 2003 European Renal Association-European Dialysis and Transplant Association
Original Article
Molecular targets of hyperphosphataemia in chronic renal failure
Ken-Ichi Miyamoto,
Mikiko Ito,
Hiriko Segawa and
Masashi Kuwahata
Nutritional Science, Department of Nutrition, School of Medicine, Tokushima University, Japan
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Abstract
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Dietary phosphate restriction can prevent or retard the progress
of chronic renal failure (CRF) and secondary hyperparathyroidism. The
klotho gene is involved in the development of a syndrome resembling
human ageing, and klotho mutant mice show abnormal calcium/vitamin
D metabolism, developing hyperphosphataemia and vascular calcification.
Phosphate retention rescues the phenotype of klotho mice. The
level of expression of klotho RNA was greatly reduced in the
kidneys of all CRF patients. Dietary P
i restriction induced
klotho expression, which enhances the beneficial effect of P
i restriction in patients with CRF and/or on haemodialysis.
Keywords: chronic renal failure; dietary phosphate; hyperphosphataemia; klotho; secondary hyperparathyroidism
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Introduction
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Phosphate (Pi) retention, or hyperphosphataemia, has been identified
as playing a major role in the progression of renal failure
and in the generation of secondary hyperparathyroidism and uraemic
bone disease [
1]. Hyperphosphataemia, independent of calcium
and calcitriol, enhances uraemia-induced hyperplasia of the
parathyroid glands, as well as parathyroid hormone (PTH) synthesis
and secretion [
2]. As shown in Figure 1
, there is now considerable
evidence that hyperphosphataemia regulates several signalling
pathways of cell functions [
1–
3]. Of great interest is
the recent identification of a novel Pi-regulating gene,
klotho [
4,
5], which in mice is involved in the development of a syndrome
resembling human ageing. The klotho mutant mice show abnormal
calcium/phosphate/vitamin D metabolism and develop hyperphosphataemia
and vascular calcification [
4,
5].
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Phenotypes of klotho mice
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The new mouse mutant known as klotho exhibits a syndrome resembling
human ageing, including a reduced life span, decreased activity,
infertility, osteoporosis, arteriosclerosis, atrophy of the
skin, etc. [
4]. All these phenotypes were caused by the disruption
of a single gene,
klotho [
4]. Klotho protein functions through
a signalling pathway involving a circulating humoral factor
[
4]. Ectopic calcification is evident in various organs of klotho
mice, as well as in arterial walls, including vessels in the
stomach, bronchial mucosa, alveolar cells, choroid plexuses,
skin, testes and cardiac muscle [
4]. It appears
4 weeks after
birth and progresses according to age. The distribution of ectopic
calcification in klotho mice resembles that in natural human
ageing [
4]. Plasma Pi and calcium concentrations are significantly
increased. The serum concentrations of calcitonin and PTH of
klotho mice (5 weeks) are normally up- and down-regulated, respectively,
in response to high concentrations of calcium. Despite the high
concentration of calcium, serum concentrations of 1,25-dihydroxyvitamin
D in klotho mice are significantly higher than those of wild-type
[
5].
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Phosphate retention rescues the phenotypes of klotho mice
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Reduction in
klotho expression causes accelerated senescence
in klotho mutant mice. Morishita
et al. demonstrated that a
low Pi diet (0.4%) modulated the phenotypes of klotho mice [
6].
Analysis of the structure of
klotho shows that the insertional
mutation in the klotho mice is not located in the gene, but
in the 5' flanking region
6 kb upstream from the transcription
start site. This may be the reason why
klotho is only slightly
transcribed in the mutants. A mutation in the promoter region
of
klotho made it hypersensitive to a low Pi diet compared with
normal mice, and dietary Pi restriction induced
klotho expression
in the kidney. We found a dietary Pi-responsive element in the
promoter region of
klotho that is also present in the promoter
of the type IIa Na/Pi co-transporter gene in the kidney, and
therefore explained why a phosphate-restricted diet rescues
the phenotypes of klotho mice [
7].
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Mechanisms of hyperphosphataemia in klotho mice
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Renal proximal tubular reabsorption of Pi is a key element in
overall Pi homeostasis, and type IIa Na/Pi co-transporters are
the key players [
8]. We analysed the concentrations of type
IIa protein in klotho mutant mice and found that it was significantly
increased in the brush border membrane of the proximal tubular
cells. Elevation of renal type IIa Na/Pi co-transporter activity
causes hyperphosphataemia in klotho mice; thus, reduction in
klotho expression increases the renal type IIa Na/Pi co-transporter.
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klotho expression in chronic renal failure (CRF) patients
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Patients with CRF develop multiple complications that are reminiscent
of the phenotypes observed in klotho mice. The
klotho gene is
expressed mainly in kidney and brain, and the evidence presented
here suggests that there might be involvement of klotho function
in the complications arising in CRF patients. Indeed, Kho
et al. demonstrated that the levels of
klotho RNA expression were
greatly reduced in the kidneys of all CRF patients [
9].
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Hyperphosphataemia represses the expression of klotho
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A reduction in klotho concentration causes up-regulation of
calcitriol synthesis and hyperphosphataemia. In renal failure
models, hyperphosphataemia promotes secondary hyperparathyroidism
whereas hypophosphataemia prevents the development of this condition
[
1]. Hyperphosphataemia also suppresses the expression of
klotho in the aorta, colon and thyroid gland of CRF models. Suppression
of
klotho may modulate the function of the type III Na/Pi co-transporter
in the aorta and then promote vascular calcification in haemodialysis
patients (H. Segawa
et al., personal communication).
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Conclusion
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There is substantial evidence from studies in experimental animals
and patients with CRF that dietary phosphate restriction can
prevent or retard the progression of this condition to secondary
hyperparathyroidism with associated vascular calcification.
A gene,
klotho, is involved in the development of a syndrome
resembling human ageing in mice. Klotho mice develop hyperphosphataemia
and vascular calcification, but dietary Pi restriction induces
expression of
klotho and rescues the phenotypes of the mice.
Up-regulation of
klotho may enhance the beneficial effect of
Pi restriction in CRF and haemodialysis patients.
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Acknowledgments
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Thanks to D. Nabeshima for providing klotho mice and
klotho cDNA, and to Dr Segawa for helpful discussion about the manuscript.
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Notes
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Correspondence and offprint requests to: Ken-Ichi Miyamoto PhD,
Nutritional Science, Department of Nutrition, School of Medicine,
Tokushima University, Kuramoto-cho 3, Tokushima City 770-8503,
Japan.
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References
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- Slatopolsky E, Brown A, Dusso A. Role of phosphorus in the pathogenesis of secondary hyperparathyroidism. Am J Kidney Dis 2002; 37:S54–S57
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- Kuro-oM, Matsumura Y, Aizawa H et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997; 390:45–51[CrossRef][Medline]
- Yoshida T, Fujimori T, Nabeshima Y. Mediation of unusually high concentrations of 1,25-dihydroxyvitamin D in homozygous klotho mutant mice by increased expression of renal 1 alpha-hydroxylase gene. Endocrinology 2002; 143:683–689[Abstract/Free Full Text]
- Shiraki-Iida T, Aizawa H, Matsumura Y et al. Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein. FEBS Lett 1998; 424:6–10[CrossRef][Web of Science][Medline]
- Kido S, Miyamoto K, Mizobuchi H et al. Identification of regulatory sequences and binding protein in the type II sodium/phosphate cotransporter NPT2 gene responsive to dietary phosphate. J Biol Chem 1999; 274:28256–28263[Abstract/Free Full Text]
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- Koh N, Fujimori T, Nishiguchi S et al. Severely reduced production of klotho in human chronic renal failure kidney. Biochem Biophys Res Commun 2001:1015–1020
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Introduction
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