TY - JOUR
T1 - Spleen contributes significantly to increased circulating levels of fibroblast growth factor 23 in response to lipopolysaccharide-induced inflammation
AU - Bansal, Shweta
AU - Friedrichs, William E.
AU - Velagapudi, Chakradhar
AU - Feliers, Denis
AU - Khazim, Khaled
AU - Horn, Diane
AU - Cornell, John E.
AU - Werner, Sherry L.
AU - Fanti, Paolo
N1 - Funding Information:
The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR001120 and by NIH-NIDDK U24DK07616 (sub-award 25732-14) to S.B. and in part by NIH-NCCAM AT004490 to P.F. This study was also supported in part by the NIH/NIA grant 5 R01 AG045040 to S.L.W.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - 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.
AB - 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.
KW - CKD spleen
KW - FGF23
KW - Inflammation
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U2 - 10.1093/ndt/gfw376
DO - 10.1093/ndt/gfw376
M3 - Article
C2 - 27836924
AN - SCOPUS:85032442724
VL - 32
SP - 960
EP - 968
JO - Nephrology Dialysis Transplantation
JF - Nephrology Dialysis Transplantation
SN - 0931-0509
IS - 6
ER -