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Renal Expression of the Sodium/Phosphate Cotransporter Gene, Npt2, Is Not Required for Regulation of Renal 1-Hydroxylase by Phosphate¹

Departments of Pediatrics and Human Genetics, McGill University-Montreal Children’s Hospital Research Institute (H.S.T., J.M., C.G.), Montréal, Québec, Canada H3H 1P3; and Department of Pediatrics, University of California (M.Y.H.Z., A.A.P.), San Francisco, California 94143

Address all correspondence and requests for reprints to: Harriet S. Tenenhouse, Ph.D., Montreal Children’s Hospital, 2300 Tupper Street, Montréal, Québec, Canada H3H 1P3. E-mail: mdht{at}www.debelle.mcgill.ca

Several reports have suggested that the regulation of renal 1,25-dihydroxyvitamin D [1,25-(OH)₂D] synthesis by extracellular phosphate (Pi) is dependent on normal transepithelial Pi transport by the renal tubule. Mice homozygous for the disrupted Na/Pi cotransporter gene Npt2 (Npt2^-/-) exhibit renal Pi wasting, an approximately 85% decrease in renal brush border membrane Na/Pi cotransport, hypophosphatemia, and an increase in serum 1,25-(OH)₂D concentration. We undertook 1) to determine the mechanism for the increased circulating levels of 1,25-(OH)₂D in Npt2^-/- mice and 2) to establish whether renal 1-hydroxylase was appropriately regulated by dietary Pi in the absence of Npt2 gene expression. On a control diet, the 2.5-fold increase in the serum 1,25-(OH)₂D concentration in Npt2^-/- mice, relative to that in Npt2^+/+ littermates, is associated with a corresponding increase in renal mitochondrial 25-hydroxyvitamin D-1-hydroxylase (1-hydroxylase) activity and messenger RNA (mRNA) abundance. A low Pi diet elicits an increase in serum 1,25-(OH)₂D concentration, renal 1-hydroxylase activity, and mRNA abundance in Npt2^+/+ and Npt2^-/- mice to similar levels in both mouse strains. A high Pi diet has no effect on serum 1,25-(OH)₂D concentration, renal 1-hydroxylase activity, or mRNA abundance in Npt2^+/+ mice, but normalizes these parameters in Npt2^-/- mice. In addition, renal 24-hydroxylase mRNA abundance is significantly reduced in Npt2^-/- mice compared with that in Npt2^+/+ mice under all dietary conditions. In summary, we demonstrate that 1) increased renal synthesis of 1,25-(OH)₂D is responsible for the increased serum 1,25-(OH)₂D concentration in Npt2^-/- mice; and 2) renal 1-hydroxylase gene expression is appropriately regulated by dietary manipulation of serum Pi in both Npt2^+/+ and Npt2^-/- mice. Thus, intact renal Na/Pi cotransport is not required for the regulation of renal 1-hydroxylase by Pi.

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