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

Endocrinology. 2001 Mar;142(3):1124-9. doi: 10.1210/endo.142.3.8029.


Several reports have suggested that the regulation of renal 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] 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)(2)D concentration. We undertook 1) to determine the mechanism for the increased circulating levels of 1,25-(OH)(2)D in Npt2(-/-) mice and 2) to establish whether renal 1alpha-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)(2)D concentration in Npt2(-/-) mice, relative 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 1alpha-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)(2)D concentration, renal 1 alpha-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)(2)D is responsible for the increased serum 1,25-(OH)(2)D concentration in Npt2(-/-) mice; and 2) renal 1alpha-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 1alpha-hydroxylase by Pi.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / genetics
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / metabolism*
  • Animals
  • Carrier Proteins / genetics*
  • Cytochrome P-450 Enzyme System / genetics
  • Diet
  • Female
  • Gene Expression / physiology*
  • Kidney / enzymology
  • Kidney / physiology*
  • Male
  • Mice
  • Mice, Knockout / genetics
  • Mitochondria / enzymology
  • Phosphates / administration & dosage
  • Phosphates / pharmacology*
  • RNA, Messenger / metabolism
  • Sodium-Phosphate Cotransporter Proteins
  • Sodium-Phosphate Cotransporter Proteins, Type I
  • Sodium-Phosphate Cotransporter Proteins, Type III
  • Steroid Hydroxylases / genetics
  • Symporters*
  • Vitamin D / analogs & derivatives*
  • Vitamin D / blood
  • Vitamin D3 24-Hydroxylase


  • Carrier Proteins
  • Phosphates
  • RNA, Messenger
  • Slc17a2 protein, mouse
  • Sodium-Phosphate Cotransporter Proteins
  • Sodium-Phosphate Cotransporter Proteins, Type I
  • Sodium-Phosphate Cotransporter Proteins, Type III
  • Symporters
  • Vitamin D
  • 1,25-dihydroxyvitamin D
  • Cytochrome P-450 Enzyme System
  • Steroid Hydroxylases
  • Vitamin D3 24-Hydroxylase
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase