Elevated FGF23 Levels in Mice Lacking the Thiazide-Sensitive NaCl cotransporter (NCC)

Sci Rep. 2018 Feb 26;8(1):3590. doi: 10.1038/s41598-018-22041-1.


Fibroblast growth factor 23 (FGF23) participates in the orchestration of mineral metabolism by inducing phosphaturia and decreasing the production of 1,25(OH)2D3. It is known that FGF23 release is stimulated by aldosterone and extracellular volume depletion. To characterize this effect further in a model of mild hypovolemia, we studied mice lacking the thiazide sensitive NaCl cotransporter (NCC). Our data indicate that NCC knockout mice (KO) have significantly higher FGF23, PTH and aldosterone concentrations than corresponding wild type (WT) mice. However, 1,25(OH)2D3, fractional phosphate excretion and renal brush border expression of the sodium/phosphate co-transporter 2a were not different between the two genotypes. In addition, renal expression of FGF23 receptor FGFR1 and the co-receptor Klotho were unaltered in NCC KO mice. FGF23 transcript was increased in the bone of NCC KO mice compared to WT mice, but treatment of primary murine osteoblasts with the NCC inhibitor hydrochlorothiazide did not elicit an increase of FGF23 transcription. In contrast, the mineralocorticoid receptor blocker eplerenone reversed excess FGF23 levels in KO mice but not in WT mice, indicating that FGF23 upregulation in NCC KO mice is primarily aldosterone-mediated. Together, our data reveal that lack of renal NCC causes an aldosterone-mediated upregulation of circulating FGF23.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldosterone / metabolism
  • Analysis of Variance
  • Animals
  • Calcium / metabolism
  • Disease Models, Animal
  • Eplerenone / pharmacology
  • Femur / metabolism
  • Fibroblast Growth Factor-23
  • Fibroblast Growth Factors / metabolism*
  • Gitelman Syndrome / metabolism
  • Glucuronidase / metabolism
  • Hydrochlorothiazide / pharmacology
  • Hypovolemia / metabolism
  • Klotho Proteins
  • Male
  • Mice
  • Mice, Knockout
  • Mineralocorticoid Receptor Antagonists / pharmacology
  • Parathyroid Hormone / metabolism
  • Phosphates / metabolism
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism
  • Receptors, Drug / antagonists & inhibitors
  • Receptors, Drug / genetics*
  • Receptors, Drug / metabolism*
  • Sodium Chloride Symporters / genetics*
  • Sodium Chloride Symporters / metabolism*
  • Thiazides / metabolism


  • Fgf23 protein, mouse
  • Mineralocorticoid Receptor Antagonists
  • Parathyroid Hormone
  • Phosphates
  • Receptors, Drug
  • Sodium Chloride Symporters
  • Thiazides
  • thiazide receptor
  • Hydrochlorothiazide
  • Aldosterone
  • Fibroblast Growth Factors
  • Eplerenone
  • Fibroblast Growth Factor-23
  • Fgfr1 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 1
  • Glucuronidase
  • Klotho Proteins
  • Calcium