Prie_EU_Renal.qxp 9/7/07 10:36 am Page 27
Phosphorus Control
Control of Phosphate
a report by
Dominique Prié
Department of Clinical Investigation, Hôpital Necker Paris and Member, INSERM U845
Phosphate is one of the most abundant anions in the human body. The bind to sodium–hydrogen exchanger regulatory factor (NHERF)-1 and
majority of phosphate is found in bone – where it is linked with calcium NHERF2 proteins and that a disruption of NHERF1 gene in mice is
to form hydroxyapatite crystals – and in cells – where it is essential for associated with a specific decrease in NPT2a expression at the brush-
metabolism. Circulating phosphate represents only 1% of body border membrane of proximal tubule. NPT2a messenger RNA (mRNA) has
phosphate content. Phosphate is essential for life, and variations of also been detected in osteoclasts. Its role in bone mineralisation and the
plasma phosphate concentration are responsible for various disorders. possible regulation of its activity by hormones at this site is unknown.
Recently, several mechanisms controlling plasma phosphate
concentration have been identified. Plasma phosphate concentration is The properties of NPT2c are somewhat different from those of NPT2a. Its
maintained at relatively constant levels despite large variations of dietary activity does not generate current, indicating differences in the
intake throughout the day and from one day to the next. This is made stoichiometries of the proteins. Its expression seems growth-related, as
possible by the kidneys, which adapt urinary phosphate excretion relative suggested by a study performed on rats showing that NPT2c mRNA
to phosphate intake. Phosphate is freely filtered at the glomerulus before expression decreases after weaning. NPT2a and NPT2c can also differ in
it is almost entirely reabsorbed in the renal proximal tubule by active their hormonal regulation. Indeed, whereas all the data obtained in
sodium-dependent processes.
1
The amount of phosphate reclaimed by animals indicate that FGF23 markedly decreases NPT2c expression, the
the proximal tubule determines the value of plasma phosphate role of PTH is less certain. In NPT2a knock-out mice, NPT2c expression is
concentration. During the last 15 years our knowledge of phosphate normal and PTH infusion does not further decrease renal phosphate
homeostasis and the consequences of phosphate control disturbances in reabsorption, suggesting that NPT2c activity is not sensitive to PTH. A
humans with normal or altered renal function has been greatly improved recent study indicates that NPT2c – but not NPT2a – expression is
by the identification of several phosphate carriers and the discovery of upregulated by 1.25-(OH)
2
vitamin D. NPT2c also differs from NPT2a by
hormones that regulate these transporters. the absence of a PDZ-interacting domain at its carboxy terminal
extremity, suggesting differences of regulation.
Phosphate Carriers
Three families of sodium-phosphate transporters have been identified so These differences between NPT2a and NPT2c suggest that none of these
far.
2
Type 1 phosphate transporters are non-specific phosphate carriers – transporters can compensate for the defect of the other.
they transport phosphate and other anions such as chloride or organic
anion (para amino hippurate) with various affinities. The most well- The third member of the type 2 sodium phosphate transporter family is
characterised member of this family in mammals is sodium-phosphate NPT2b. This transporter is expressed in the intestine, lungs, kidneys and
transporter 1 (NPT)-1. It is mainly expressed in the kidneys and the liver. mammary and salivary glands. Its expression in the intestine is
Its precise role in phosphate homeostasis remains unclear, its gene has upregulated by 1.25-(OH)
2
vitamin D, but is not sensitive to PTH.
not been disrupted in animals and no mutations associated with a Intestinal NPT2b expression decreases following FGF23 infusion in
pathological state have been identified. animals. This is not a direct effect of FGF23 – it is mediated by the
diminution of 1.25-(OH)
2
vitamin D levels as shown by the lack of effect
The type 2 transporter family includes NPT2a, NPT2b and NPT2c.
1
NPT2a of FGF23 on NPT2b expression in the absence of vitamin D receptors or
and NPT2c are almost exclusively expressed in the apical domain of renal
proximal tubular cells. These two transporters are critical for renal
phosphate reabsorption. Their affinities for phosphate are similar and
Dominique Prié is a Nephrologist and Physiologist in the
Department of Clinical Investigation at Hôpital Necker, Paris
mutations in these genes in humans result in hypophosphataemia due to
and a member of the INSERM U845 research unit. He
inadequate renal phosphate reabsorption. However, they differ in some
studies the mechanisms of renal phosphate transport and its
regulation in normal and pathological conditions. Dr Prié has
of their properties.
published several papers in international peer-reviewed
journals on the defect of renal phosphate reabsorption and
NPT2a is an electrogenic transporter; it carries one divalent phosphate
the consequences on renal lithiasis formation, as well as
bone mineralisation, and is the author of chapters in books
anion together with three sodium cations, hence its activity generates a
on nephrology or physiology. He is a reviewer for several
current. Its expression at the brush-border membrane of proximal tubular
international journals and regularly gives international
cells is lowered by at least two hormones: the parathyroid hormone (PTH)
lectures. Dr Prié described and identified in patients the first
mutations in the gene SLC34A1 coding for one of the
and the fibroblast growth factor 23 (FGF23). The last three amino acids of sodium-phosphate transporters in the kidney.
NPT2a represent a sequence that can interact with PDZ (Psd-95/Dlg/ZO1)
E: prie@necker.fr
domains. In particular, it has been shown that in cultured cells NPT2a can
© TOUCH BRIEFINGS 2007 27
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