Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease

Abstract

Patients with chronic kidney disease (CKD) develop increased levels of the phosphate-regulating hormone, fibroblast growth factor (FGF) 23, that are associated with a higher risk of mortality. Increases in inflammatory markers are another common feature of CKD that predict poor clinical outcomes. Elevated FGF23 is associated with higher circulating levels of inflammatory cytokines in CKD, which can stimulate osteocyte production of FGF23. Here, we studied whether FGF23 can directly stimulate hepatic production of inflammatory cytokines in the absence of α-klotho, an FGF23 co-receptor in the kidney that is not expressed by hepatocytes. By activating FGF receptor isoform 4 (FGFR4), FGF23 stimulated calcineurin signaling in cultured hepatocytes, which increased the expression and secretion of inflammatory cytokines, including C-reactive protein. Elevating serum FGF23 levels increased hepatic and circulating levels of C-reactive protein in wild-type mice, but not in FGFR4 knockout mice. Administration of an isoform-specific FGFR4 blocking antibody reduced hepatic and circulating levels of C-reactive protein in the 5/6 nephrectomy rat model of CKD. Thus, FGF23 can directly stimulate hepatic secretion of inflammatory cytokines. Our findings indicate a novel mechanism of chronic inflammation in patients with CKD and suggest that FGFR4 blockade might have therapeutic anti-inflammatory effects in CKD.

Fibroblast growth factor 23: fueling the fire

“…1 In the current issue of the journal, Singh et al (2016) 2 implicates fibroblast growth factor 23 (FGF23) as an additional, novel factor contributing to uremic inflammation. Although higher FGF23 levels have been independently associated with higher levels of inflammatory markers in CKD patients, 3 in the current article, Singh et al 2 demonstrate through a series of elegant in vitro and in vivo experiments that FGF23 directly induces hepatic expression and secretion of inflammatory cytokines.…”

“…Lastly, in the 5/6 nephrectomy rat model, Singh et al 2 characterized the effects of pharmacologic blockade of FGF23-FGFR4 signaling. Compared with control animals, 5/6 nephrectomized rats had elevated FGF23 levels, increased hepatic CRP expression, and increased serum CRP.…”

“…Anti-FGFR4 inhibits FGF23-induced expression of hepatic inflammatory cytokines in cultured hepatocytes and decreases hepatic and serum CRP in rats with CKD. 2 Similarly, anti-FGFR4 reduces FGF23-induced hypertrophy of isolated cardiac myocytes and attenuates left ventricular hypertrophy in rats with CKD. 5 Certainly, it could be hypothesized that anti-FGFR4 treatment in CKD patients may result in less inflammation, less left ventricular hypertrophy, and improved cardiovascular outcomes.…”

Fibroblast Growth Factor-23: A Novel Biomarker for Cardiovascular Disease in Chronic Kidney Disease Patients

“…In addition, recent experimental data demonstrated that inflammation directly stimulates FGF-23 transcription and protein expression in osteocyte cell lines and increases circulating FGF-23 levels in animals with and without CKD in part through a hypoxia-inducible factor 1 a-depending mechanism. Conversely, elevated FGF-23 was found to induce hepatic production of IL-6 and CRP through an FGFR4-dependent but Klotho-independent mechanism [61,62]. Overall, the results of the above studies suggest the presence of a positive feedback loop between inflammation and elevated FGF-23 levels in CKD.…”

Associations of Fibroblast Growth Factor 23 with Markers of Inflammation and Leukocyte Transmigration in Chronic Kidney Disease

“…FGF23 acts through triggering genes, which encode cytokines such as interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α) [15,16] and associations of FGF23 levels with pro-inflammatory markers have been described in both CKD and non-CKD cohorts. This highlights the role of FGF23 as an inflammatory mediator, presumably acting through cytokine upregulation [9,[17][18][19][20][21]. Interestingly, a recent study described that FGF23 exposure inhibits neutrophil recruitment through interference of integrin expression, compromising host defense in CKD [22].…”