Renal expression of the sodium/phosphate cotransporter gene, Npt2, is not required for regulation of renal 1 alpha-hydroxylase by phosphate

Several reports have suggested that the regulation of renal 1,25-dihydroxyv itamin D [1,25-(OH)(2)D] synthesis by extracellular phosphate (Pi) is depen dent on normal transepithelial Pi transport by the renal tubule. Mice homoz ygous for the disrupted Na/Pi cotransporter gene Npt2 (Npt2(-/-)) exhibit r enal Pi wasting, an approximately 85% decrease in renal brush border membra ne Na/Pi cotransport, hypophosphatemia, and an increase in serum 1,25-(OH)( 2)D concentration. We undertook 1) to determine the mechanism for the incre ased circulating levels of 1,25-(OH)(2)D in Npt2(-/)- mice and 2) to establ ish whether renal 1 alpha -hydroxylase was appropriately regulated by dieta ry Pi in the absence of Npt2 gene expression. On a control diet, the 2.5-fo ld increase in the serum 1,25-(OH)(2)D concentration in Npt2(-/-) mice, rel ative to that in Npt2(+/+) littermates, is associated with a corresponding increase in renal mitochondrial 25-hydroxyvitamin D-1 alpha -hydroxylase (1 alpha -hydroxylase) activity and messenger RNA (mRNA) abundance. A low Pi diet elicits an increase in serum 1,25(OH)(2)D concentration, renal 1 alpha -hydroxylase activity, and mRNA abundance in Npt2(+/+) and Npt2 mice to si milar levels in both mouse strains. A high Pi diet has no effect on serum 1 ,25-(OH)(2)D concentration, renal la-hydroxylase activity, or mRNA abundanc e in Npt2(+/+) mice, but normalizes these parameters in Npt2(-/-) mice. In addition, renal 24-hydroxylase mRNA abundance is significantly reduced in N pt2(-/-) mice compared with that in Npt2(+/+) mice under all dietary condit ions. In summary, we demonstrate that 1) increased renal synthesis of 1,25- (OH)(2)D is responsible for the increased serum 1,25-(OH)(2)D concentration in Npt2(-/-) mice; and 2) renal Icu-hydroxylase gene expression is appropr iately regulated by dietary manipulation of serum Pi in both Npt2(+/+) and Npt2(-/-) mice. Thus, intact renal Na/Pi cotransport is not required for th e regulation of renal la-hydroxylase by Pi.