Rostral ventrolateral medulla neuron activity is suppressed by Klotho and stimulated by FGF23 in newborn Wistar rats

Oshima, Naoki; Onimaru, Hiroshi; Yamagata, Akira; Itô, Seigo; Imakiire, Toshihiko; Kumagai, Hiroo

doi:10.1016/j.autneu.2020.102640

Cited by 5 publications

(7 citation statements)

References 33 publications

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“…Subsequent studies, however, did not find FGF23 gene expression in various other brain regions, including the hypothalamus and ventrolateral thalamic nucleus, which is in agreement with our results (Fon Tacer et al, 2010;Hensel et al, 2016;Kaminskas et al, 2019). Another study in newborn Wistar rats, studying neurons in the rostral ventrolateral medulla, also found FGF23 immunoreactivity in these neurons (Oshima et al, 2020). A study on hippocampal function and structural defects in FGF23-deficient mice, however, was unable to detect FGF23 immunoreactivity in the brain in their wild-type group (Laszczyk et al, 2019).…”

Section: Discussionsupporting

confidence: 91%

Localization of fibroblast growth factor 23 protein in the rat hypothalamus

Ursem

Diepenbroek

Bacic

et al. 2021

Eur J of Neuroscience

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Fibroblast growth factor 23 (FGF23) is an endocrine growth factor and known to play a pivotal role in phosphate homeostasis. Interestingly, several studies point towards a function of FGF23 in the hypothalamus. FGF23 classically activates the FGF receptor 1 in the presence of the co‐receptor αKlotho, of both gene expression in the brain was previously established. However, studies on gene and protein expression of FGF23 in the brain are scarce and have been inconsistent. Therefore, our aim was to localise FGF23 gene and protein expression in the rat brain with focus on the hypothalamus. Also, we investigated the protein expression of αKlotho. Adult rat brains were used to localise and visualise FGF23 and αKlotho protein in the hypothalamus by immunofluorescence labelling. Furthermore, western blots were used for assessing hypothalamic FGF23 protein expression. FGF23 gene expression was investigated by qPCR in punches of the arcuate nucleus, lateral hypothalamus, paraventricular nucleus, choroid plexus, ventrolateral thalamic nucleus and the ventromedial hypothalamus. Immunoreactivity for FGF23 and αKlotho protein was found in the hypothalamus, third ventricle lining and the choroid plexus. Western blot analysis of the hypothalamus confirmed the presence of FGF23. Gene expression of FGF23 was not detected, suggesting that the observed FGF23 protein is not brain‐derived. Several FGF receptors are known to be present in the brain. Therefore, we conclude that the machinery for FGF23 signal transduction is present in several brain areas, indeed suggesting a role for FGF23 in the brain.

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Section: Discussionsupporting

confidence: 91%

Localization of fibroblast growth factor 23 protein in the rat hypothalamus

Ursem

Diepenbroek

Bacic

et al. 2021

Eur J of Neuroscience

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“…However, the mechanistic link between FGF23 signaling and sympathoadrenergic activity has yet to be defined. It is interesting to note in this context that FGF23 has been shown to stimulate rostral ventrolateral medulla presympathetic neuron activity in the brainstem [ 49 ]. Conversely, it is also possible that sympathetic activation might be responsible for the changes in FGF23 serum levels in mice fed the CPD.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Excessive Dietary Phosphate Intake Increases Arterial Blood Pressure, Activates the Renin–Angiotensin–Aldosterone System, and Stimulates Sympathetic Tone in Mice

et al. 2022

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Increased dietary phosphate intake has been associated with severity of coronary artery disease, increased carotid intima–media thickness, left ventricular hypertrophy (LVH), and increased cardiovascular mortality and morbidity in individuals with normal renal function as well as in patients suffering from chronic kidney disease. However, the underlying mechanisms are still unclear. To further elucidate the cardiovascular sequelae of long-term elevated phosphate intake, we maintained male C57BL/6 mice on a calcium, phosphate, and lactose-enriched diet (CPD, 2% Ca, 1.25% P, 20% lactose) after weaning them for 14 months and compared them with age-matched male mice fed a normal mouse diet (ND, 1.0% Ca, 0.7% P). Notably, the CPD has a balanced calcium/phosphate ratio, allowing the effects of elevated dietary phosphate intake largely independent of changes in parathyroid hormone (PTH) to be investigated. In agreement with the rationale of this experiment, mice maintained on CPD for 14 months were characterized by unchanged serum PTH but showed elevated concentrations of circulating intact fibroblast growth factor-23 (FGF23) compared with mice on ND. Cardiovascular phenotyping did not provide evidence for LVH, as evidenced by unchanged LV chamber size, normal cardiomyocyte area, lack of fibrosis, and unchanged molecular markers of hypertrophy (Bnp) between the two groups. However, intra-arterial catheterization revealed increases in systolic pressure, mean arterial pressure, and pulse pressure in mice fed the CPD. Interestingly, chronically elevated dietary phosphate intake stimulated the renin–angiotensin–aldosterone system (RAAS) as evidenced by increased urinary aldosterone in animals fed the CPD, relative to the ND controls. Furthermore, the catecholamines epinephrine, norepinephrine, and dopamine as well as the catecholamine metabolites metanephrine. normetanephrine and methoxytyramine as measured by mass spectrometry were elevated in the urine of mice on CPD, relative to mice on the ND. These changes were partially reversed by switching 14-month-old mice on CPD back to ND for 2 weeks. In conclusion, our data suggest that excess dietary phosphate induces a rise in blood pressure independent of secondary hyperparathyroidism, and that this effect may be mediated through activation of the RAAS and stimulation of the sympathetic tone.

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“…46 The effect of FGF23 on neuronal depolarization remains to be elucidated, however a recent study did observe FGF23’s depolarizing potential in neurons. 47 In newborn Wistar rats, aged 0-5 days, the effect of FGF23 on the membrane potential of neurons in the rostral ventrolateral medulla (RVLM) was studied in vitro , in order to elucidate a possible mechanism behind the co-occurrence of hypertension and increased FGF23 levels in CKD. 47 Indeed, FGF23 depolarized RVLM cells, whereas a FGFR1 antagonist caused hyperpolarization.…”

Section: Discussionmentioning

confidence: 99%

“…47 In newborn Wistar rats, aged 0-5 days, the effect of FGF23 on the membrane potential of neurons in the rostral ventrolateral medulla (RVLM) was studied in vitro , in order to elucidate a possible mechanism behind the co-occurrence of hypertension and increased FGF23 levels in CKD. 47 Indeed, FGF23 depolarized RVLM cells, whereas a FGFR1 antagonist caused hyperpolarization. In light of these findings, it could be that our observed effects upon icv FGF23 infusion in vivo indeed are caused by depolarization of specific neuronal populations, but this would warrant further research.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Intracerebroventricular Fibroblast Growth Factor 23 on gene expression in the Rats’ Hypothalamus

Ursem

Diepenbroek

Kool

et al. 2022

Preprint

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Fibroblast growth factor 23 (FGF23) is a key regulator of systemic phosphate homeostasis, but also an interplay with glucose metabolism has been suggested. Several studies implicate a function of FGF23 in the brain, and indeed we have recently identified FGF23 protein in several brain areas in rats, such as the hypothalamus, third ventricle and choroid plexus. In the current study, we aimed to determine the effect of an intracerebroventricular (icv) injection of FGF23 in the third ventricle of rats on hypothalamic genes involved in glucose regulation. In addition, we assessed whether glycerol can be used safely for icv injections as glycerol is used as a stabilizing compound for FGF23 protein. Adult Wistar rats received an icv injection of recombinant rat FGF23 or vehicle. Dose dependent behavioral changes, suggestive of stress, were observed directly after infusion of FGF23. After 60 min animals were sacrificed and the arcuate nucleus, lateral hypothalamus and choroid plexus were isolated. In these brain regions gene expression was determined of the FGF23 receptor complex (FGFR1, alphaKlotho), NPY, POMC, phosphate transporters (SLC20 and SLC34 families) and markers of cellular ER stress (ATF4 and the ratio of spliced/unspliced XBP1). We showed that glycerol is well tolerated as stabilizer for icv injections. In FGF23-treated animals, cellular ER stress markers were increased in the arcuate nucleus. FGF23 injection did not affect expression of its receptor complex, NPY, POMC, or phosphate transporters. Future studies are warranted to investigate the effect of FGF23 in the brain on the protein level and on neuronal activation.

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Rostral ventrolateral medulla neuron activity is suppressed by Klotho and stimulated by FGF23 in newborn Wistar rats

Cited by 5 publications

References 33 publications

Localization of fibroblast growth factor 23 protein in the rat hypothalamus

Localization of fibroblast growth factor 23 protein in the rat hypothalamus

Long-Term Excessive Dietary Phosphate Intake Increases Arterial Blood Pressure, Activates the Renin–Angiotensin–Aldosterone System, and Stimulates Sympathetic Tone in Mice

The Effect of Intracerebroventricular Fibroblast Growth Factor 23 on gene expression in the Rats’ Hypothalamus

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