Interleukin-6 contributes to the increase in fibroblast growth factor 23 expression in acute and chronic kidney disease

Durlacher-Betzer, Karina; Hassan, Alia; Levi, Ronen; Axelrod, Jonathan H.; Silver, Justin; Naveh-Many, Tally

doi:10.1016/j.kint.2018.02.026

Cited by 126 publications

(101 citation statements)

References 52 publications

(54 reference statements)

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“…Such compensatory upregulation of VEGFR2 has been evoked as the explanation for why angiogenesis is not suppressed in mice deficient in the β3 integrin subunit (Reynolds et al, 2002), even though inhibitors of αVβ3 suppress angiogenesis in vivo Friedlander et al, 1995;West et al, 2012). While we did not study compensations in Il-6 -/or gp130 -/mice, others (Durlacher-Betzer et al, 2018;Kuhn et al, 2014) have. With respect to its requirement for cell viability and growth, most tellingly, one group studying astrocytes (Quintana et al, 2013;Quintana et al, 2008) found that while global IL-6R knockout (which leads to compensations) had a small effect, conditional knockout in astrocytes led to their apoptosis.…”

Section: Discussionmentioning

confidence: 79%

VEGFR2 survival and mitotic signaling depends on joint activation of associated C3ar1/C5ar1 and IL-6R–gp130

Hwang

Strainic

Pohlmann

et al. 2019

Journal of Cell Science

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Purified vascular endothelial cell (EC) growth factor receptor-2 (VEGFR2) auto-phosphorylates upon VEGF-A occupation in vitro, arguing that VEGR2 confers its mitotic and viability signaling in and of itself. Herein, we show that, in ECs, VEGFR2 function requires concurrent C3a/C5a receptor (C3ar1/C5ar1) and IL-6 receptor (IL-6R)-gp130 co-signaling. C3ar1/C5ar1 or IL-6R blockade totally abolished VEGFR2 auto-phosphorylation, downstream Src, ERK, AKT, mTOR and STAT3 activation, and EC cell cycle entry.

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Section: Discussionmentioning

confidence: 79%

VEGFR2 survival and mitotic signaling depends on joint activation of associated C3ar1/C5ar1 and IL-6R–gp130

Hwang

Strainic

Pohlmann

et al. 2019

Journal of Cell Science

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“…These results suggest that inflammation could be a trigger of FGF23 production. Indeed, proinflammatory cytokines including tumour necrosis factor α (TNFα), interleukin (IL)1β/6, and other inflammation‐associated molecules including bacterial lipopolysaccharides (LPS), other bacterial components or their toxins and advanced glycation end products (AGEs) upregulate Fgf23 gene expression directly and dose‐dependently (Fig. ).…”

Section: Homeostatic Regulation Of Fgf23mentioning

confidence: 99%

“…Chronic iron deficiency induces FGF23 in a way similar to chronic inflammation . IL‐6 also enhances Fgf23 promoter activity through signal transducer and activator of transcription 3 (STAT3) resulting in more Fgf23 gene expression .…”

Section: Homeostatic Regulation Of Fgf23mentioning

confidence: 99%

Regulation of fibroblast growth factor 23 (FGF23) in health and disease

et al. 2019

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Fibroblast growth factor 23 (FGF23) is mainly produced in the bone and, upon secretion, forms a complex with a FGF receptor and coreceptor αKlotho. FGF23 can exert several endocrine functions, such as inhibiting renal phosphate reabsorption and 1,25‐dihydroxyvitamin D3 production. Moreover, it has paracrine activities on several cell types, including neutrophils and hepatocytes. Klotho and Fgf23 deficiencies result in pathologies otherwise encountered in age‐associated diseases, mainly as a result of hyperphosphataemia‐dependent calcification. FGF23 levels are also perturbed in the plasma of patients with several disorders, including kidney or cardiovascular diseases. Here, we review mechanisms controlling FGF23 production and discuss how FGF23 regulation is perturbed in disease.

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“…The identification of molecular regulators of FGF23 production is of high interest and relevance. Known regulators include PTH [28], 1,25(OH) 2 D 3 [29], phosphate [30,31], inflammatory cytokines and factors such as TNFα [32], IL-1/6 [4,[33][34][35], or NFκB [33,36], TGFβ [37], AMP-dependent protein kinase (AMPK) [38] or insulin-dependent PI3 kinase signaling [39].…”

Section: Introductionmentioning

confidence: 99%

PKC regulates the production of fibroblast growth factor 23 (FGF23)

Bär

Hase

Föller

2019

Preprint

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Serine/threonine protein kinase C (PKC) is activated by diacylglycerol that is released from membrane lipids by phospholipase C in response to activation of G protein-coupled receptors or receptor tyrosine kinases. PKC isoforms are particularly relevant for proliferation and differentiation of cells including osteoblasts. Osteoblasts/osteocytes produce fibroblast growth factor 23 (FGF23), a hormone regulating renal phosphate and vitamin D handling. PKC activates NFκB, a transcription factor complex controlling FGF23 expression. Here, we analyzed the impact of PKC on FGF23 synthesis. Fgf23 expression was analyzed by qRT-PCR in UMR106 osteoblastlike cells and in IDG-SW3 osteocytes. Phorbol ester 12-O-tetradecanoylphorbol-13-acetate (PMA), a PKC activator, up-regulated Fgf23 expression. In contrast, PKC inhibitors calphostin C, Gö6976, sotrastaurin and ruboxistaurin supressed Fgf23 gene expression. NFκB inhibitor withaferin A abolished the stimulatory effect of PMA on Fgf23. PKC is a powerful regulator of FGF23 synthesis, an effect which is at least partly mediated by NFκB.

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Interleukin-6 contributes to the increase in fibroblast growth factor 23 expression in acute and chronic kidney disease

Cited by 126 publications

References 52 publications

VEGFR2 survival and mitotic signaling depends on joint activation of associated C3ar1/C5ar1 and IL-6R–gp130

VEGFR2 survival and mitotic signaling depends on joint activation of associated C3ar1/C5ar1 and IL-6R–gp130

Regulation of fibroblast growth factor 23 (FGF23) in health and disease

PKC regulates the production of fibroblast growth factor 23 (FGF23)

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