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 (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 β-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.