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 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.
Berndt
Theresa J
TJ
Division of Nephrology and Hypertension, Departments of Medicine and Biochemistry and Molecular Biology, Mayo Clinic Rochester, Mayo College of Medicine, MN, 55905, USA.
Bielesz
Bernhard
B
Craig
Theodore A
TA
Tebben
Peter J
PJ
Bacic
Desa
D
Wagner
Carsten A
CA
O'Brien
Stephen
S
Schiavi
Susan
S
Biber
Jurg
J
Murer
Heini
H
Kumar
Rajiv
R
D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D009893:Opossums; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000378:metabolism*; D000094742:Secreted Frizzled-Related Proteins
D011518:Proto-Oncogene Proteins; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; C118723:SFRP4 protein, human; D000094742:Secreted Frizzled-Related Proteins