Page 84 - 2021_02-Haematologica-web

R. Agoro et al.
ABC
DE
and inflammation positively regulate each other, it is pos- sible that one condition may precede the other.
2
Figure 5. Effect of fibroblast growth factor 23 (FGF23) signaling disruption on inflammation and hepcidin secretion. C57BL/6J wild-type mice were treated with C-tail FGF23 (1 mg/kg, indicated as FGF23 BL) or vehicle (HEPES buffer) for 8 hours (h). Mice were then chal- lenged with LPS (intraperitoneal 50 mg/kg) or vehicle (0.9% NaCl) for 4 h. (A-D) Quantitative real-time RT-PCR for hepatic expression of (A) IL-6, (B) TNF-α, (C) IL-1β, and (D) hepcidin. Data are expressed as fold change (2-DDCt) relative to housekeeping gene Gapdh. (E) Serum concentration of hepcidin measured by ELISA. Samples were measured in duplicates (n=5-7 per group). Data are represented as mean+standard deviation. All data were ana- lyzed for normality with Shapiro-Wilk test and equivalence of variance using Levene’s test. Because the samples did not show normal dis- tribution, data were aligned in RANK transfor- mation, and confirmed for normality. As the samples showed normal distribution, two-way ANOVA was performed followed by Bonferroni’s multiple comparison test (A-E). Ctl: control (vehi- cle), ns: not significant, *P<0.05, **P<0.01, ***P<0.001.
increased hepcidin production, causing iron sequestration
FGF23 is a hormone primarily produced by osteocytes that affects many systems in the body. FGF23 is crucial for maintaining normal phosphate and vitamin D homeosta- sis. Its target organ for these actions is the kidney, where it inhibits phosphate reabsorption by downregulating the type II sodium-phosphate co-transporters (NaPi2a and NaPi2c), and reduces circulating calcitriol levels (1,25(OH)
cy, or directly by stimulating Hif1α transcription leading
vitamin D ) by decreasing renal expression of 1-α-hydrox- 3
upstream of the Fgf23 transcription start site was shown 60
ylase.17-20,47-50 FGF23 levels increase significantly in CKD and are associated with kidney disease progression, greater cardiovascular risk, left ventricular hypertrophy, and mor- tality.25,51 Phosphate, calcium, vitamin D, and parathyroid hormone (PTH) are known regulators of FGF23. However, in recent years, several other factors, such as inflamma- tion, iron status, and EPO have been identified to both regulate FGF23 and be regulated by it.13,29,52-58 Several mech- anisms have been proposed to explain the association between FGF23 and inflammation. It has been shown that inflammation stimulates FGF23 either indirectly through
to mediate inflammation-induced expression of Fgf23. FGF23 can directly target a number of different cell types and affect a variety of organs. Depending on the tar- get, the mechanisms of FGF23 actions can differ in their requirement for klotho and specific FGFR isoforms, there- by activating different signaling pathways and leading to cell type- and tissue-specific effects of FGF23.61 For exam- ple, FGF23 can directly stimulate secretion of proinflam- matory cytokines through activation of FGFR4 and PLC /calcineurin/NFAT signaling in the absence of klotho in the liver and bronchial epithelial cells in patients with CKD and chronic obstructive pulmonary disease (COPD),
in macrophages and subsequent functional iron deficien-
to increased HIF1α which together with HIF1β bind to
HIF response element on the Fgf23 promoter inducing its
transcription.12 More recently, IL6 was reported to induce
Fgf23 promoter activity through a STAT3 response ele-
ment on the Fgf23 promoter,59 and a distal enhancer
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haematologica | 2021; 106(2)