Journal
KIDNEY INTERNATIONAL
Volume 96, Issue 4, Pages 890-905Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2019.04.009
Keywords
bone; chronic kidney disease (CKD); cytokine; fibroblast growth factor 23 (FGF23); inflammation; inflammatory bowel disease; tumor necrosis factor (TNF)
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Funding
- Swiss National Center for Competence in Research NCCR Kidney.CH
- Novartis Foundation for medical-biological research
- SNSF Early Postdoc. Mobility-Fellowship
- Deutsche Forschungsgemeinschaft [La 315-15]
- Integrative Kidney Physiology and Pathophysiology (IKPP Kidney. CH) under the European Union Seventh Framework Programme for Research, Technological Development and Demonstration [608847]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [205625/2014-2]
- SPUM grant from the Swiss National Center of Competence in Research [FN 33CM30-124087]
- AbbVie
- Swiss National Science Foundation (SNSF)
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Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis, and its early rise in patients with chronic kidney disease is independently associated with all-cause mortality. Since inflammation is characteristic of chronic kidney disease and associates with increased plasma FGF23 we examined whether inflammation directly stimulates FGF23. In a population-based cohort, plasma tumor necrosis factor (TNF) was the only inflammatory cytokine that independently and positively correlated with plasma FGF23. Mouse models of chronic kidney disease showed signs of renal inflammation, renal FGF23 expression and elevated systemic FGF23 levels. Renal FGF23 expression coincided with expression of the orphan nuclear receptor Nurr1 regulating FGF23 in other organs. Antibody-mediated neutralization of TNF normalized plasma FGF23 and suppressed ectopic renal Fgf23 expression. Conversely, TNF administration to control mice increased plasma FGF23 without altering plasma phosphate. Moreover, in Il10-deficient mice with inflammatory bowel disease and normal kidney function, plasma FGF23 was elevated and normalized upon TNF neutralization. Thus, the inflammatory cytokine TNF contributes to elevated systemic FGF23 levels and also triggers ectopic renal Fgf23 expression in animal models of chronic kidney disease.
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