Expression of fgf23 and  klotho in developing embryonic tissues and adult kidney of the zebrafish, Danio rerio

Mangos, Steve; Amaral, Ansel P.; Faul, Christian; Jüppner, Harald; Reiser, Jochen; Wolf, Myles

doi:10.1093/ndt/gfs335

Cited by 31 publications

(17 citation statements)

References 31 publications

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“…In continued research, mainly driven by Faul and coworkers ( 21 , 56 , 59 – 61 ), several experimental settings were used to determine whether the FGF23 association with LVH was causative or purely associative. The authors concluded that FGF23 is within the causal pathway of CKD-associated LVH development.…”

Section: Specific Focus Upon Fgf23 As the Driving Force For Lvhmentioning

confidence: 99%

FGF23 in Cardiovascular Disease: Innocent Bystander or Active Mediator?

et al. 2018

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Fibroblast growth factor−23 (FGF23) is a mainly osteocytic hormone which increases renal phosphate excretion and reduces calcitriol synthesis. These renal actions are mediated via alpha-klotho as the obligate co-receptor. Beyond these canonical “mineral metabolism” actions, FGF23 has been identified as an independent marker for cardiovascular risk in various patient populations. Previous research has linked elevated FGF23 predominantly to left-ventricular dysfunction and consecutive morbidity and mortality. Moreover, some experimental data suggest FGF23 as a direct and causal stimulator for cardiac hypertrophy via specific myocardial FGF23-receptor activation, independent from alpha-klotho. This hypothesis offers fascinating prospects in terms of therapeutic interventions, specifically in patients with chronic kidney disease (CKD) in whom the FGF23 system is strongly stimulated and in whom left-ventricular dysfunction is a major disease burden. However, novel data challenges the previous stand-alone hypothesis about a one-way road which guides unidirectionally skeletal FGF23 toward cardiotoxic effects. In fact, recent data point toward local myocardial production and release of FGF23 in cases where (acute) myocardial damage occurs. The effects of this local production and the physiological meaning are under current examination. Moreover, epidemiologic studies suggest that high FGF-23 may follow, rather than induce, myocardial disease in certain conditions. In summary, while FGF23 is an interesting link between mineral metabolism and cardiac function underlining the meaning of the bone-heart axis, more research is needed before therapeutic interventions may be considered.

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Section: Specific Focus Upon Fgf23 As the Driving Force For Lvhmentioning

confidence: 99%

FGF23 in Cardiovascular Disease: Innocent Bystander or Active Mediator?

et al. 2018

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“…Furthermore, FGF23 might play important roles during embryonic development. In zebrafish embryos, FGF23 expression is confined to the cells of the corpuscles of Stannius which regulate mineral ion homeostasis in advanced bony fish, also called teleosts ( 295 ). During embryonic mouse development, FGF23 is predominantly expressed in somites, heart, and liver ( 296 ).…”

Section: Discussionmentioning

confidence: 99%

FGF23 Actions on Target Tissues—With and Without Klotho

2018

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Fibroblast growth factor (FGF) 23 is a phosphaturic hormone whose physiologic actions on target tissues are mediated by FGF receptors (FGFR) and klotho, which functions as a co-receptor that increases the binding affinity of FGF23 for FGFRs. By stimulating FGFR/klotho complexes in the kidney and parathyroid gland, FGF23 reduces renal phosphate uptake and secretion of parathyroid hormone, respectively, thereby acting as a key regulator of phosphate metabolism. Recently, it has been shown that FGF23 can also target cell types that lack klotho. This unconventional signaling event occurs in an FGFR-dependent manner, but involves other downstream signaling pathways than in “classic” klotho-expressing target organs. It appears that klotho-independent signaling mechanisms are only activated in the presence of high FGF23 concentrations and result in pathologic cellular changes. Therefore, it has been postulated that massive elevations in circulating levels of FGF23, as found in patients with chronic kidney disease, contribute to associated pathologies by targeting cells and tissues that lack klotho. This includes the induction of cardiac hypertrophy and fibrosis, the elevation of inflammatory cytokine expression in the liver, and the inhibition of neutrophil recruitment. Here, we describe the signaling and cellular events that are caused by FGF23 in tissues lacking klotho, and we discuss FGF23’s potential role as a hormone with widespread pathologic actions. Since the soluble form of klotho can function as a circulating co-receptor for FGF23, we also discuss the potential inhibitory effects of soluble klotho on FGF23-mediated signaling which might—at least partially—underlie the pleiotropic tissue-protective functions of klotho.

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“…50 FGF9 and FGF20 play an important role in nephrogenesis, 50,51 whereas FGF23 expression was not found in the developing zebrafish kidney. 52 FGF23 belongs to the family of fibroblast growth factors, in which the majority of proteins regulate embryogenesis, growth, and angiogenesis and play an important role in organ regeneration and repair. 53 Whether kidney-derived FGF23 has an autocrine or paracrine function in the renal repair system merits further study.…”

Section: Discussionmentioning

confidence: 99%

Kidney fibroblast growth factor 23 does not contribute to elevation of its circulating levels in uremia

Mace

Gravesen

Nordholm

et al. 2017

Kidney International

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Fibroblast growth factor 23 (FGF23) secreted by osteocytes is a circulating factor essential for phosphate homeostasis. High plasma FGF23 levels are associated with cardiovascular complications and mortality. Increases of plasma FGF23 in uremia antedate high levels of phosphate, suggesting a disrupted feedback regulatory loop or an extra-skeletal source of this phosphatonin. Since induction of FGF23 expression in injured organs has been reported we decided to examine the regulation of FGF23 gene and protein expressions in the kidney and whether kidney-derived FGF23 contributes to the high plasma levels of FGF23 in uremia. FGF23 mRNA was not detected in normal kidneys, but was clearly demonstrated in injured kidneys, already after four hours in obstructive nephropathy and at 8 weeks in the remnant kidney of 5/6 nephrectomized rats. No renal extraction was found in uremic rats in contrast to normal rats. Removal of the remnant kidney had no effect on plasma FGF23 levels. Well-known regulators of FGF23 expression in bone, such as parathyroid hormone, calcitriol, and inhibition of the FGF receptor by PD173074, had no impact on kidney expression of FGF23. Thus, the only direct contribution of the injured kidney to circulating FGF23 levels in uremia appears to be reduced renal extraction of bone-derived FGF23. Kidney-derived FGF23 does not generate high plasma FGF23 levels in uremia and is regulated differently than the corresponding regulation of FGF23 gene expression in bone.

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Expression of fgf23 and klotho in developing embryonic tissues and adult kidney of the zebrafish, Danio rerio

Cited by 31 publications

References 31 publications

FGF23 in Cardiovascular Disease: Innocent Bystander or Active Mediator?

FGF23 in Cardiovascular Disease: Innocent Bystander or Active Mediator?

FGF23 Actions on Target Tissues—With and Without Klotho

Kidney fibroblast growth factor 23 does not contribute to elevation of its circulating levels in uremia

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