Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia

Agoro, Rafiou; Montagna, A.; Goetz, Regina; Aligbe, Onyedikachi; Singh, Govind; Coe, Lindsay M.; Mohammadi, Moosa; Rivella, Stefano; Sitara, Despina

doi:10.1096/fj.201700667r

Cited by 96 publications

(115 citation statements)

References 70 publications

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“…7A-C). We previously reported that treatment with the FGF23 C-tail blocking peptide significantly increases circulating Epo levels in mice (29). Here, we confirmed this effect in mice injected with LPS or saline (Fig.…”

Section: Inhibition Of Fgf23 Signaling Increases Renal and Extra-renasupporting

confidence: 87%

“…Here, we confirmed this effect in mice injected with LPS or saline (Fig. 7D) using a 10 times lower concentration of the FGF23 C-tail blocking peptide than the one we used in (29). However, we found that 4 hours of LPS treatment at the concentration of 50 µg/kg were not sufficient to alter circulating Epo levels (Fig.…”

Section: Inhibition Of Fgf23 Signaling Increases Renal and Extra-renasupporting

confidence: 69%

“…can inhibit FGF23 signaling and antagonize its phosphaturic activity in vivo by competing with the intact FGF23 for binding to the FGFR-Klotho complex (28). Moreover, we have previously successfully used the C-tail FGF23 in a CKD mouse model to rescue renal anemia and iron deficiency and attenuate chronic inflammation (29).…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that the 72-aa-long C-terminal tail of FGF23 (residues Ser180-Ile251), which corresponds to the C-terminal fragment of FGF23 generated by proteolytic cleavage at the RXXR motif, impairs FGF23 signaling and activity by acting as endogenous inhibitor of the full-length FGF23 for binding to the FGFR-Klotho complex (28). We previously reported that inhibition of FGF23 signaling using this FGF23 blocking peptide (BL) ameliorates iron deficiency in a mouse model of chronic kidney disease (29). Since Our data show that the increase in FGF23 in response to LPS was significantly reduced after inhibition of FGF23 signaling ( Fig.…”

Section: Inhibition Of Fgf23 Signaling Alleviates Hypoferremia Inducementioning

confidence: 99%

“…We recently reported that inhibition of FGF23 signaling rescues renal anemia in a mouse model of chronic kidney disease (29). Here, we investigated the effect of inhibition of FGF23 signaling in a mouse model of LPS-induced hypoferremia.…”

Section: Introductionmentioning

confidence: 99%

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C-FGF23 peptide alleviates hypoferremia during acute inflammation

Agoro¹,

Park²,

Hénaff³

et al. 2020

haematol

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Hypoferremia results as an acute phase response to infection and inflammation aiming to reduce iron availability to pathogens. Activation of toll-like receptors (TLRs), the key sensors of the innate immune system, induces hypoferremia mainly through the rise of the iron hormone hepcidin. Conversely, stimulation of erythropoiesis suppresses hepcidin expression via induction of the erythropoietin-responsive hormone erythroferrone. Iron deficiency stimulates transcription of the osteocyte-secreted protein FGF23. Here we hypothesized that induction of FGF23 in response to TLR4 activation is a potent contributor to hypoferremia and, thus, impairment of its activity may alleviate hypoferremia induced by lipopolysaccharide (LPS), a TLR 4 agonist. We used the C-terminal tail of FGF23 to impair endogenous full-length FGF23 signaling in wild-type mice, and investigated its impact on hypoferremia. Our data show that FGF23 is induced as early as pro-inflammatory cytokines in response to LPS, followed by upregulation of hepcidin and downregulation of erythropoietin (Epo) expression in addition to decreased serum iron and transferrin saturation. Further, LPS-induced hepatic and circulating hepcidin were significantly reduced by FGF23 signaling disruption. Accordingly, iron sequestration in liver and spleen caused by TLR4 activation was completely abrogated by FGF23 signaling inhibition, resulting in alleviation of serum iron and transferrin saturation deficit.Taken together, our studies highlight for the first time that inhibition of FGF23 signaling alleviates LPS-induced acute hypoferremia.

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Section: Inhibition Of Fgf23 Signaling Increases Renal and Extra-renasupporting

confidence: 87%

Section: Inhibition Of Fgf23 Signaling Increases Renal and Extra-renasupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Inhibition Of Fgf23 Signaling Alleviates Hypoferremia Inducementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

C-FGF23 peptide alleviates hypoferremia during acute inflammation

Agoro¹,

Park²,

Hénaff³

et al. 2020

haematol

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C-Terminal, but Not Intact, FGF23 and EPO Are Strongly Correlatively Elevated in Patients With Gain-of-Function Mutations in HIF2A: Clinical Evidence for EPO Regulating FGF23

Roszko

Brown

Pang

et al. 2020

Journal of Bone and Mineral Research

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Fibroblast growth factor 23 (FGF23) is a key phosphate-and vitamin D-regulating hormone. FGF23 circulates as an intact 251 amino acid protein or N-and C-terminal degradation products. Hormone activity resides in the intact molecule, but it has been suggested that high levels of the C-terminal protein can interfere with intact FGF23 (iFGF23) activity. New evidence points to involvement of the hypoxiainducible factor (HIF)/erythropoietin (EPO)/iron pathway as important in FGF23 physiology. Exactly how this pathway regulates FGF23 is not clear. Various in vitro, in vivo, and clinical studies involving perturbations in this pathway at various points have yielded conflicting results. Many of these studies are complicated by the confounding, independent effect of renal insufficiency on FGF23. To gain insight into FGF23 physiology, we studied 8 patients with a rare paraganglioma/somatostatinoma syndrome who had elevated blood EPO levels as a result of somatic gain-of-function mutations in HIF2A (EPAS1) that stimulate tumoral EPO production. All patients had normal renal function. EPO levels varied; most were very elevated and highly correlated with C-terminal FGF23 (cFGF23) levels that were also markedly elevated. Blood phosphate and intact FGF23 levels were normal. These data from patients with normal renal function in whom HIF activation was the inciting event suggest a direct role of the HIF/EPO pathway in FGF23 transcription and translation. They also demonstrate that posttranslational regulation was finely tuned to maintain normal blood phosphate levels. Additionally, normal phosphate and intact FGF23 levels in the setting of markedly increased C-terminal FGF23 levels suggest intact FGF23 action is not attenuated by C-terminal FGF23. Published 2020. This article is a U.S. Government work and is in the public domain in the USA. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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New developments in the biology of fibroblast growth factors

Ornitz

Itoh

2022

WIREs Mechanisms of Disease

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The fibroblast growth factor (FGF) family is composed of 18 secreted signaling proteins consisting of canonical FGFs and endocrine FGFs that activate four receptor tyrosine kinases (FGFRs 1-4) and four intracellular proteins (intracellular FGFs or iFGFs) that primarily function to regulate the activity of voltagegated sodium channels and other molecules. The canonical FGFs, endocrine FGFs, and iFGFs have been reviewed extensively by us and others. In this review, we briefly summarize past reviews and then focus on new developments in the FGF field since our last review in 2015. Some of the highlights in the past 6 years include the use of optogenetic tools, viral vectors, and inducible transgenes to experimentally modulate FGF signaling, the clinical use of small molecule FGFR inhibitors, an expanded understanding of endocrine FGF signaling, functions for FGF signaling in stem cell pluripotency and differentiation, roles for FGF signaling in tissue homeostasis and regeneration, a continuing elaboration of mechanisms of FGF signaling in development, and an expanding appreciation of roles for FGF signaling in neuropsychiatric diseases.

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Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia

Cited by 96 publications

References 70 publications

C-FGF23 peptide alleviates hypoferremia during acute inflammation

C-FGF23 peptide alleviates hypoferremia during acute inflammation

C-Terminal, but Not Intact, FGF23 and EPO Are Strongly Correlatively Elevated in Patients With Gain-of-Function Mutations in HIF2A: Clinical Evidence for EPO Regulating FGF23

New developments in the biology of fibroblast growth factors

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