Spleen contributes significantly to increased circulating levels of fibroblast growth factor 23 in response to lipopolysaccharide-induced inflammation

Shweta Bansal, William E. Friedrichs, Chakradhar Velagapudi, Denis Feliers, Khaled Khazim, Diane Horn, John E. Cornell, Sherry L. Werner, Paolo Fanti

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Background: Circulating levels of fibroblast growth factor 23 (FGF23) increase progressively and correlate with systemic inflammation in chronic kidney disease (CKD). The aim of this study was to identify and characterize the causal relationship between FGF23 and inflammation in CKD. Methods: Circulating FGF23 and inflammatory cytokines were correlated in healthy subjects and patients with varying levels of CKD. In addition, FGF23 expression in blood and solid organs was measured in normal mice that were exposed acutely (one time) or chronically (2-week) to low-dose lipopolysaccharide (LPS); chronic exposure being either sustained (subcutaneous pellets), intermittent (daily injections) or combined sustained plus acute (subcutaneous pellets plus acute injection on the day of sacrifice). Blood was analyzed for both terminal (cFGF23) and intact (iFGF23) FGF23 levels. Solid tissues were investigated with immunohistochemistry, enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction. Results: FGF23 levels correlated significantly with neutrophil gelatinase-Associated lipocalin (r = 0.72, P < 0.001), C-reactive protein (r = 0.38, P < 0.001), tumor necrosis factor-A (r = 0.32, P = 0.001) and interleukin-6 (r = 0.48, P < 0.001). Acute LPS administration increased tissue FGF23 mRNA and plasma levels of cFGF23 but not iFGF23. Neither chronic sustained nor chronic pulsatile LPS increased the tissue or circulating levels of FGF23. However, acute on chronic LPS raised tissue FGF23 mRNA and both circulating cFG23 and iFGF23. Interestingly, the spleen was the major source of FGF23. Conclusion: Acute on chronic exposure to LPS stimulates FGF23 production in a normal mouse model of inflammation. We provide the first evidence that the spleen, under these conditions, contributes substantially to elevated circulating FGF23 levels.

Original languageEnglish (US)
Pages (from-to)960-968
Number of pages9
JournalNephrology Dialysis Transplantation
Volume32
Issue number6
DOIs
StatePublished - 2017

Keywords

  • CKD spleen
  • FGF23
  • Inflammation

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

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