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

Abstract 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 furt...

Full description

Bibliographic Details
Main Authors: Ganesh Pathare, Manuel Anderegg, Giuseppe Albano, Florian Lang, Daniel G. Fuster
Format: Article
Language:English
Published: Nature Publishing Group 2018-02-01
Series:Scientific Reports
Online Access:https://doi.org/10.1038/s41598-018-22041-1
id doaj-2295b5afddb84cd3af8e7164228d69f4
record_format Article
spelling doaj-2295b5afddb84cd3af8e7164228d69f42020-12-08T04:45:59ZengNature Publishing GroupScientific Reports2045-23222018-02-018111110.1038/s41598-018-22041-1Elevated FGF23 Levels in Mice Lacking the Thiazide-Sensitive NaCl cotransporter (NCC)Ganesh Pathare0Manuel Anderegg1Giuseppe Albano2Florian Lang3Daniel G. Fuster4Division of Nephrology and Hypertension, Bern University Hospital, University of BernDivision of Nephrology and Hypertension, Bern University Hospital, University of BernDivision of Nephrology and Hypertension, Bern University Hospital, University of BernDepartment of Cardiology, Vascular Medicine and Physiology, Eberhard-Karls-University of TübingenDivision of Nephrology and Hypertension, Bern University Hospital, University of BernAbstract 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.https://doi.org/10.1038/s41598-018-22041-1
collection DOAJ
language English
format Article
sources DOAJ
author Ganesh Pathare
Manuel Anderegg
Giuseppe Albano
Florian Lang
Daniel G. Fuster
spellingShingle Ganesh Pathare
Manuel Anderegg
Giuseppe Albano
Florian Lang
Daniel G. Fuster
Elevated FGF23 Levels in Mice Lacking the Thiazide-Sensitive NaCl cotransporter (NCC)
Scientific Reports
author_facet Ganesh Pathare
Manuel Anderegg
Giuseppe Albano
Florian Lang
Daniel G. Fuster
author_sort Ganesh Pathare
title Elevated FGF23 Levels in Mice Lacking the Thiazide-Sensitive NaCl cotransporter (NCC)
title_short Elevated FGF23 Levels in Mice Lacking the Thiazide-Sensitive NaCl cotransporter (NCC)
title_full Elevated FGF23 Levels in Mice Lacking the Thiazide-Sensitive NaCl cotransporter (NCC)
title_fullStr Elevated FGF23 Levels in Mice Lacking the Thiazide-Sensitive NaCl cotransporter (NCC)
title_full_unstemmed Elevated FGF23 Levels in Mice Lacking the Thiazide-Sensitive NaCl cotransporter (NCC)
title_sort elevated fgf23 levels in mice lacking the thiazide-sensitive nacl cotransporter (ncc)
publisher Nature Publishing Group
series Scientific Reports
issn 2045-2322
publishDate 2018-02-01
description Abstract 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.
url https://doi.org/10.1038/s41598-018-22041-1
work_keys_str_mv AT ganeshpathare elevatedfgf23levelsinmicelackingthethiazidesensitivenaclcotransporterncc
AT manuelanderegg elevatedfgf23levelsinmicelackingthethiazidesensitivenaclcotransporterncc
AT giuseppealbano elevatedfgf23levelsinmicelackingthethiazidesensitivenaclcotransporterncc
AT florianlang elevatedfgf23levelsinmicelackingthethiazidesensitivenaclcotransporterncc
AT danielgfuster elevatedfgf23levelsinmicelackingthethiazidesensitivenaclcotransporterncc
_version_ 1724391980779175936