Tumor necrosis factor stimulates fibroblast growth factor 23 levels in chronic kidney disease and non-renal inflammation

Abstract

Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis, and its early rise in patients with chronic kidney disease (CKD) is independently associated with all-cause mortality. Since inflammation is characteristic of CKD 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 CKD 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 CKD.

Lifestyle, Inflammation, and Vascular Calcification in Kidney Transplant Recipients: Perspectives on Long-Term Outcomes

“…It has also been proposed that mediators of inflammation (e.g., interleukin 6 and tumor necrosis factor) contribute to fibroblast growth factor (FGF)-23 elevation and that, in turn, FGF-23 increases cytokine production, thus linking systemic inflammation with dysregulated phosphate metabolism in a vicious cycle [165,166]. It has been proposed that inflammatory mediators function as drug targets to decrease the burden of FGF23-associated injury in various tissues, thus offering a novel therapeutic opportunity to decrease the burden of cardiovascular diseases including vascular calcification in kidney disease patients [165,167]. Nevertheless, even in CKD patients within normal range of serum phosphate levels, vascular calcification is often observed.…”

The Role of Fibroblast Growth Factor 23 in Inflammation and Anemia

“…Additional mediators of the inflammatory milieu, such as tumor necrosis factor-α (TNF-α) and OSM, have also been shown to stimulate FGF23 synthesis and secretion. In cultured bone cells and following a recent study utilizing animal models of renal and extrarenal inflammation, Glosse et al showed that increasing concentrations of TNF-α elevates the production of FGF23 in a dose dependent-manner in UMR106 cells, while Egli-Spichtig et al revealed the contribution of TNF-α stimulation to the renal production of FGF23, respectively [181,182]. In addition to these reservoirs, Richter et al displayed that increasing concentrations of OSM coincided with increased FGF23 production in cardiac myocytes, thus exhibiting the heart as a novel source of FGF23 production [183].…”

FGF23 and inflammation—a vicious coalition in CKD

“…In the current issue, Egli-Spichtig and colleagues tackle this question experimentally by studying 3 animal models with renal and extrarenal inflammation, including a genetic mouse model for polycystic kidney disease (PKD). 6 These mice develop mild kidney injury at 12 weeks post induction of global PKD1 deletion, accompanied by renal inflammation and an elevation of serum intact FGF23, with associated decreases in renal NaPi2a expression and phosphate reabsorption. Although FGF23 is not produced by the healthy kidney, renal FGF23 expression is induced in PKD, as the authors found previously.…”

“…The present report further strengthens the ties between inflammatory cytokines and FGF23 as partners in crime driving CKD-associated injuries. Given that drugs that lower TNF appear to be safe in humans, the study of Egli-Spichtig et al 6 suggests a novel therapeutic opportunity to lower FGF23 levels in CKD, and potentially in other nonrenal inflammatory diseases associated with high FGF23. Furthermore, the inhibition of FGF23 production or actions might reduce the levels of inflammatory cytokines, including TNF, and thereby have beneficial antiinflammatory effects, as recently suggested by studies conducted in different animal models of CKD.…”