FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1

Jyothsna Gattineni, Carlton Bates, Katherine Twombley, Vangipuram Dwarakanath, Michael L. Robinson, Regina Goetz, Moosa Mohammadi, Michel Baum

Research output: Contribution to journalArticle

217 Citations (Scopus)

Abstract

Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone that contributes to several hypophosphatemic disorders by reducing the expression of the type II sodium-phosphate cotransporters (NaPi-2a and NaPi-2c) in the kidney proximal tubule and by reducing serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels. The FGF receptor(s) mediating the hypophosphatemic action of FGF23 in vivo have remained elusive. In this study, we show that proximal tubules express FGFR1, -3, and -4 but not FGFR2 mRNA. To determine which of these three FGFRs mediates FGF23's hypophosphatemic actions, we characterized phosphate homeostasis in FGFR3-/- and FGFR4 -/- null mice, and in conditional FGFR1-/- mice, with targeted deletion of FGFR1 expression in the metanephric mesenchyme. Basal serum phosphorus levels and renal cortical brush-border membrane (BBM) NaPi-2a and NaPi-2c expression were comparable between FGFR1-/-, FGFR3 -/-, and FGFR4-/- mice and their wild-type counterparts. Administration of FGF23 to FGFR3-/- mice induced hypophosphatemia in these mice (8.0 ± 0.4 vs. 5.4 ± 0.3 mg/dl; p ≤ 0.001) and a decrease in renal BBM NaPi-2a and NaPi-2c protein expression. Similarly, in FGFR4-/- mice, administration of FGF23 caused a small but significant decrease in serum phosphorus levels (8.7 ± 0.3 vs. 7.6 ± 0.4 mg/dl; p ≤ 0.001) and in renal BBM NaPi-2a and NaPi-2c protein abundance. In contrast, injection of FGF23 into FGFR1-/- mice had no effects on serum phosphorus levels (5.6 ± 0.3 vs. 5.2 ± 0.5 mg/dl) or BBM NaPi-2a and NaPi-2c expression. These data show that FGFR1 is the predominant receptor for the hypophosphatemic action of FGF23 in vivo, with FGFR4 likely playing a minor role.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume297
Issue number2
DOIs
StatePublished - Aug 2009

Fingerprint

Hypophosphatemia
Fibroblast Growth Factor 1
Fibroblast Growth Factor Receptors
Microvilli
Kidney
Phosphorus
Membranes
Serum
Sodium-Phosphate Cotransporter Proteins
Proximal Kidney Tubule
Calcitriol
Mesoderm
fibroblast growth factor 23
Proteins
Homeostasis
Phosphates
Hormones
Messenger RNA
Injections

Keywords

  • Phosphaturia
  • Phosphorus
  • Proximal tubule

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. / Gattineni, Jyothsna; Bates, Carlton; Twombley, Katherine; Dwarakanath, Vangipuram; Robinson, Michael L.; Goetz, Regina; Mohammadi, Moosa; Baum, Michel.

In: American Journal of Physiology - Renal Physiology, Vol. 297, No. 2, 08.2009.

Research output: Contribution to journalArticle

Gattineni, Jyothsna ; Bates, Carlton ; Twombley, Katherine ; Dwarakanath, Vangipuram ; Robinson, Michael L. ; Goetz, Regina ; Mohammadi, Moosa ; Baum, Michel. / FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. In: American Journal of Physiology - Renal Physiology. 2009 ; Vol. 297, No. 2.
@article{ef5e9de50eb24ba1a101e36aa6c60de2,
title = "FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1",
abstract = "Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone that contributes to several hypophosphatemic disorders by reducing the expression of the type II sodium-phosphate cotransporters (NaPi-2a and NaPi-2c) in the kidney proximal tubule and by reducing serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels. The FGF receptor(s) mediating the hypophosphatemic action of FGF23 in vivo have remained elusive. In this study, we show that proximal tubules express FGFR1, -3, and -4 but not FGFR2 mRNA. To determine which of these three FGFRs mediates FGF23's hypophosphatemic actions, we characterized phosphate homeostasis in FGFR3-/- and FGFR4 -/- null mice, and in conditional FGFR1-/- mice, with targeted deletion of FGFR1 expression in the metanephric mesenchyme. Basal serum phosphorus levels and renal cortical brush-border membrane (BBM) NaPi-2a and NaPi-2c expression were comparable between FGFR1-/-, FGFR3 -/-, and FGFR4-/- mice and their wild-type counterparts. Administration of FGF23 to FGFR3-/- mice induced hypophosphatemia in these mice (8.0 ± 0.4 vs. 5.4 ± 0.3 mg/dl; p ≤ 0.001) and a decrease in renal BBM NaPi-2a and NaPi-2c protein expression. Similarly, in FGFR4-/- mice, administration of FGF23 caused a small but significant decrease in serum phosphorus levels (8.7 ± 0.3 vs. 7.6 ± 0.4 mg/dl; p ≤ 0.001) and in renal BBM NaPi-2a and NaPi-2c protein abundance. In contrast, injection of FGF23 into FGFR1-/- mice had no effects on serum phosphorus levels (5.6 ± 0.3 vs. 5.2 ± 0.5 mg/dl) or BBM NaPi-2a and NaPi-2c expression. These data show that FGFR1 is the predominant receptor for the hypophosphatemic action of FGF23 in vivo, with FGFR4 likely playing a minor role.",
keywords = "Phosphaturia, Phosphorus, Proximal tubule",
author = "Jyothsna Gattineni and Carlton Bates and Katherine Twombley and Vangipuram Dwarakanath and Robinson, {Michael L.} and Regina Goetz and Moosa Mohammadi and Michel Baum",
year = "2009",
month = "8",
doi = "10.1152/ajprenal.90742.2008",
language = "English (US)",
volume = "297",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "2",

}

TY - JOUR

T1 - FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1

AU - Gattineni, Jyothsna

AU - Bates, Carlton

AU - Twombley, Katherine

AU - Dwarakanath, Vangipuram

AU - Robinson, Michael L.

AU - Goetz, Regina

AU - Mohammadi, Moosa

AU - Baum, Michel

PY - 2009/8

Y1 - 2009/8

N2 - Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone that contributes to several hypophosphatemic disorders by reducing the expression of the type II sodium-phosphate cotransporters (NaPi-2a and NaPi-2c) in the kidney proximal tubule and by reducing serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels. The FGF receptor(s) mediating the hypophosphatemic action of FGF23 in vivo have remained elusive. In this study, we show that proximal tubules express FGFR1, -3, and -4 but not FGFR2 mRNA. To determine which of these three FGFRs mediates FGF23's hypophosphatemic actions, we characterized phosphate homeostasis in FGFR3-/- and FGFR4 -/- null mice, and in conditional FGFR1-/- mice, with targeted deletion of FGFR1 expression in the metanephric mesenchyme. Basal serum phosphorus levels and renal cortical brush-border membrane (BBM) NaPi-2a and NaPi-2c expression were comparable between FGFR1-/-, FGFR3 -/-, and FGFR4-/- mice and their wild-type counterparts. Administration of FGF23 to FGFR3-/- mice induced hypophosphatemia in these mice (8.0 ± 0.4 vs. 5.4 ± 0.3 mg/dl; p ≤ 0.001) and a decrease in renal BBM NaPi-2a and NaPi-2c protein expression. Similarly, in FGFR4-/- mice, administration of FGF23 caused a small but significant decrease in serum phosphorus levels (8.7 ± 0.3 vs. 7.6 ± 0.4 mg/dl; p ≤ 0.001) and in renal BBM NaPi-2a and NaPi-2c protein abundance. In contrast, injection of FGF23 into FGFR1-/- mice had no effects on serum phosphorus levels (5.6 ± 0.3 vs. 5.2 ± 0.5 mg/dl) or BBM NaPi-2a and NaPi-2c expression. These data show that FGFR1 is the predominant receptor for the hypophosphatemic action of FGF23 in vivo, with FGFR4 likely playing a minor role.

AB - Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone that contributes to several hypophosphatemic disorders by reducing the expression of the type II sodium-phosphate cotransporters (NaPi-2a and NaPi-2c) in the kidney proximal tubule and by reducing serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels. The FGF receptor(s) mediating the hypophosphatemic action of FGF23 in vivo have remained elusive. In this study, we show that proximal tubules express FGFR1, -3, and -4 but not FGFR2 mRNA. To determine which of these three FGFRs mediates FGF23's hypophosphatemic actions, we characterized phosphate homeostasis in FGFR3-/- and FGFR4 -/- null mice, and in conditional FGFR1-/- mice, with targeted deletion of FGFR1 expression in the metanephric mesenchyme. Basal serum phosphorus levels and renal cortical brush-border membrane (BBM) NaPi-2a and NaPi-2c expression were comparable between FGFR1-/-, FGFR3 -/-, and FGFR4-/- mice and their wild-type counterparts. Administration of FGF23 to FGFR3-/- mice induced hypophosphatemia in these mice (8.0 ± 0.4 vs. 5.4 ± 0.3 mg/dl; p ≤ 0.001) and a decrease in renal BBM NaPi-2a and NaPi-2c protein expression. Similarly, in FGFR4-/- mice, administration of FGF23 caused a small but significant decrease in serum phosphorus levels (8.7 ± 0.3 vs. 7.6 ± 0.4 mg/dl; p ≤ 0.001) and in renal BBM NaPi-2a and NaPi-2c protein abundance. In contrast, injection of FGF23 into FGFR1-/- mice had no effects on serum phosphorus levels (5.6 ± 0.3 vs. 5.2 ± 0.5 mg/dl) or BBM NaPi-2a and NaPi-2c expression. These data show that FGFR1 is the predominant receptor for the hypophosphatemic action of FGF23 in vivo, with FGFR4 likely playing a minor role.

KW - Phosphaturia

KW - Phosphorus

KW - Proximal tubule

UR - http://www.scopus.com/inward/record.url?scp=68049085792&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=68049085792&partnerID=8YFLogxK

U2 - 10.1152/ajprenal.90742.2008

DO - 10.1152/ajprenal.90742.2008

M3 - Article

VL - 297

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 2

ER -