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



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.



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-α ( 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.



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.
Division of Nephrology, Department of Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, TX 78229, USA.|Renal Section, South Texas Veterans Healthcare System, San Antonio, TX, USA.
Shweta
S
Bansal
Division of Nephrology, Department of Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, TX 78229, USA.
William E
WE
Friedrichs
Division of Nephrology, Department of Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, TX 78229, USA.|Renal Section, South Texas Veterans Healthcare System, San Antonio, TX, USA.
Chakradhar
C
Velagapudi
Division of Nephrology, Department of Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, TX 78229, USA.
Denis
D
Feliers
Faculty of Medicine, Galilee Medical Center, Bar-Ilan University, Safed, Israel.
Khaled
K
Khazim
Department of Pathology, University of Texas Health Sciences Center at San Antonio and South Texas Veterans Healthcare System, San Antonio, TX, USA.
Diane
D
Horn
Department of Epidemiology & Biostatistics, University of Texas Health Sciences Center at San Antonio, San Antonio, TX, USA.
John E
JE
Cornell
Department of Pathology, University of Texas Health Sciences Center at San Antonio and South Texas Veterans Healthcare System, San Antonio, TX, USA.
Sherry L
SL
Werner
Division of Nephrology, Department of Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, TX 78229, USA.
Paolo
P
Fanti
D000818:Animals; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000276:immunology; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000276:immunology; D000071068:Lipocalin-2 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D013154:Spleen / Q000378:metabolism*
D015415:Biomarkers; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; C508600:IL6 protein, human; D015850:Interleukin-6; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D008070:Lipopolysaccharides; D016328:NF-kappa B; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D002097:C-Reactive Protein
CKD spleen; FGF23; inflammation