Thyroid hormones regulate phosphate homoeostasis through transcriptional control of the renal type IIa sodium-dependent phosphate co-transporter (Npt2a) gene

Biochem J. 2010 Mar 15;427(1):161-9. doi: 10.1042/BJ20090671.

Abstract

The type IIa renal sodium-dependent phosphate (Na/Pi) co-transporter Npt2a is implicated in the control of serum phosphate levels. It has been demonstrated previously that renal Npt2a protein and its mRNA expression are both up-regulated by the thyroid hormone T3 (3,3',5-tri-iodothyronine) in rats. However, it has never been established whether the induction was mediated by a direct effect of thyroid hormones on the Npt2a promoter. To address the role of Npt2a in T3-dependent regulation of phosphate homoeostasis and to identify the molecular mechanisms by which thyroid hormones modulate Npt2a gene expression, mice were rendered pharmacologically hypo- and hyper-thyroid. Hypothyroid mice showed low levels of serum phosphate and a marked decrease in renal Npt2a protein abundance. Importantly, we also showed that Npt2a-deficient mice had impaired serum phosphate responsiveness to T3 compared with wild-type mice. Promoter analysis with a luciferase assay revealed that the transcriptional activity of a reporter gene containing the Npt2a promoter and intron 1 was dependent upon TRs (thyroid hormone receptors) and specifically increased by T3 in renal cells. Deletion analysis and EMSAs (electrophoretic mobility-shift assays) determined that there were unique TREs (thyroid-hormone-responsive elements) within intron 1 of the Npt2a gene. These results suggest that Npt2a plays a critical role as a T3-target gene, to control phosphate homoeostasis, and that T3 transcriptionally activates the Npt2a gene via TRs in a renal cell-specific manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Dogs
  • Electrophoretic Mobility Shift Assay
  • Female
  • Gene Expression Regulation*
  • HeLa Cells
  • Homeostasis
  • Humans
  • Kidney / cytology
  • Kidney / metabolism*
  • Luciferases / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Phosphates / metabolism*
  • Promoter Regions, Genetic
  • Rats
  • Receptors, Thyroid Hormone / metabolism
  • Response Elements
  • Sodium-Phosphate Cotransporter Proteins, Type IIa / physiology*
  • Transcription, Genetic / drug effects*
  • Transcriptional Activation
  • Triiodothyronine / pharmacology*

Substances

  • Phosphates
  • Receptors, Thyroid Hormone
  • Slc34a1 protein, mouse
  • Sodium-Phosphate Cotransporter Proteins, Type IIa
  • Triiodothyronine
  • Luciferases