Secreted frizzled-related protein-4 reduces sodium-phosphate co-transporter abundance and activity in proximal tubule cells

The phosphatonin, secreted frizzled-related protein-4 (sFRP-4), induces phosphaturia and inhibits 25-hydroxyvitamin D 1alpha-hydroxylase activity normally induced in response to hypophosphatemia. To determine the mechanism by which sFRP-4 alters renal phosphate (P(i)) transport, we examined the effe...

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Bibliographic Details
Published in:Pflügers Archiv 2006-01, Vol.451 (4), p.579-587
Main Authors: Berndt, Theresa J, Bielesz, Bernhard, Craig, Theodore A, Tebben, Peter J, Bacic, Desa, Wagner, Carsten A, O'Brien, Stephen, Schiavi, Susan, Biber, Jurg, Murer, Heini, Kumar, Rajiv
Format: Article
Language:English
Subjects:
Animals
Cells, Cultured
Humans
Kidney Tubules, Proximal - cytology
Kidney Tubules, Proximal - drug effects
Kidney Tubules, Proximal - metabolism
Kidneys
Male
Opossums
Proto-Oncogene Proteins - pharmacology
Rats
Rats, Sprague-Dawley
Sodium-Phosphate Cotransporter Proteins, Type IIa - metabolism
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Summary:The phosphatonin, secreted frizzled-related protein-4 (sFRP-4), induces phosphaturia and inhibits 25-hydroxyvitamin D 1alpha-hydroxylase activity normally induced in response to hypophosphatemia. To determine the mechanism by which sFRP-4 alters renal phosphate (P(i)) transport, we examined the effect of sFRP-4 on renal brush border membrane (BBMV) Na(+)-dependent P(i) uptake, and the abundance and localization of the major Na(+)-P(i)-IIa co-transporter in proximal tubules and opossum kidney (OK) cells. Infusion of sFRP-4 increased renal fractional excretion of P(i) and decreased renal beta-catenin concentrations. The increase in renal P(i) excretion with sFRP-4 infusion was associated with a 21.9 +/- 3.4% decrease in BBMV Na(+)-dependent P(i) uptake (P < 0.001) compared with a 39.5 +/- 2.1% inhibition of Na(+)-dependent P(i) transport in renal BBMV induced by PTH (P < 0.001). sFRP-4 infusion was associated with a 30.7 +/- 4.8% decrease in Na(+)-P(i)-IIa co-transporter protein abundance (P < 0.01) assessed by immunoblotting methods compared to a 45.4 +/- 8.8% decrease induced by PTH (P < 0.001). In OK cells, sFRP-4 reduced surface expression of a heterologous Na(+)-P(i)-IIa co-transporter. We conclude that sFRP-4 increases renal P(i) excretion by reducing Na(+)-P(i)-IIa transporter abundance in the brush border of the proximal tubule through enhanced internalization of the protein.
ISSN:0031-6768
1432-2013
DOI:10.1007/s00424-005-1495-2