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 1α-hydroxylase activity normally induced in response to hypophosphatemia. To determine the mechanism by which sFRP-4 alters renal phosphate (Pi) transport, we examined the effect of sFRP-4 on renal brush border membrane (BBMV) Na+-dependent Pi uptake, and the abundance and localization of the major Na+–Pi-IIa co-transporter in proximal tubules and opossum kidney (OK) cells. Infusion of sFRP-4 increased renal fractional excretion of Pi and decreased renal β-catenin concentrations. The increase in renal Pi excretion with sFRP-4 infusion was associated with a 21.9±3.4% decrease in BBMV Na+-dependent Pi uptake (P<0.001) compared with a 39.5±2.1% inhibition of Na+-dependent Pi transport in renal BBMV induced by PTH (P<0.001). sFRP-4 infusion was associated with a 30.7±4.8% decrease in Na+–Pi-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+–Pi-IIa co-transporter. We conclude that sFRP-4 increases renal Pi excretion by reducing Na+–Pi-IIa transporter abundance in the brush border of the proximal tubule through enhanced internalization of the protein.