Overview of the FGF23-Klotho axis

Kuro‐o, Makoto

doi:10.1007/s00467-009-1260-4

Cited by 140 publications

(137 citation statements)

References 93 publications

(108 reference statements)

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“…The effect of FGF23 on 1,25(OH) 2 D 3 formation requires αKlotho as a co-receptor [7,8]. Mice lacking functional αKlotho similarly suffer from extensive vascular calcifications, early onset of multiple age-related disorders and severe shortening of life span [8].…”

Section: Introductionmentioning

confidence: 99%

NFκB-sensitive Orai1 expression in the regulation of FGF23 release

et al. 2015

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Fibroblast growth factor (FGF23) plasma levels are elevated in cardiac and renal failure and correlate with poor clinical prognosis of those disorders. Both disorders are associated with inflammation and activation of the inflammatory transcription factor NFB. An excessive FGF23 level is further observed in Klotho-deficient mice. The present study explored a putative sensitivity of FGF23 expression to transcription factor NFB, which is known to upregulate Orai1, the Ca(2+) channel accomplishing storeoperated Ca(2+) entry (SOCE). In osteoblastic cells (UMR106) and immortalized primary periosteal (IPO) cells, protein abundance was determined by Western blotting, and in UMR106 cells, transcript levels were quantified by RT-PCR, cytosolic Ca(2+) activity utilizing Fura-2-fluorescence, and SOCE from Ca(2+) entry following store depletion by thapsigargin. As a result, UMR106 and IPO cells expressed Ca(2+) channel Orai1. SOCE was lowered by NFB inhibitor wogonin as well as by Orai1 inhibitors 2-APB and YM58483. UMR106 cell Fgf23 transcripts were increased by stimulation of SOCE and Ca(2+) ionophore ionomycin and decreased by Orai inhibitors 2-APB, YM58483 and SKF96365, by Orai1 silencing, as well as by NFB inhibitors wogonin, withaferin A, and CAS 545380-34-5. In conclusion, Fgf23 expression is upregulated by stimulation of NFB-sensitive, store-operated Ca(2+) entry. KEY MES-SAGES Osteoblast UMR106 and IPO cells express Ca(2+) channel Orai1. Osteoblast store-operated Ca(2+) entry is accomplished by NFB-sensitive Orai1. Osteoblast Fgf23 transcription is upregulated by increase in the cytosolic Ca(2+) activity.

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Section: Introductionmentioning

confidence: 99%

NFκB-sensitive Orai1 expression in the regulation of FGF23 release

et al. 2015

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“…Moreover, FGF23 has been shown to inhibit renal 25-hydroxyvitamin D 1a-hydroxylase (Cyp27b1) and to stimulate 25-hydroxyvitamin D 24-hydroxylase (Cyp24a1) thereby suppressing the formation and favoring the catabolism of the biologically active form of vitamin D, 1,25-dihydroxyvitamin D 3 (1,25 (OH) 2 D 3 ; calcitriol) (20,(23)(24)(25). Therefore, FGF23 lowers the plasma level of both 1,25(OH) 2 D 3 and phosphate.FGF23 requires aKlotho as a coreceptor to mediate its renal effects (26,27). In contrast, FGF23 induces hypertrophy of the left ventricle without aKlotho (28, 29).…”

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confidence: 99%

“…In contrast, FGF23 induces hypertrophy of the left ventricle without aKlotho (28, 29). FGF23-or aKlotho-deficient mouse models exhibit rapid aging and age-related diseases that replicate human aging (24,27). …”

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Enhanced FGF23 production in mice expressing PI3K‐insensitive GSK3 is normalized by β‐blocker treatment

Fajol¹,

Chen²,

Umbach³

et al. 2015

FASEB j.

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Glycogen synthase kinase (GSK)-3 is a ubiquitously expressed kinase inhibited by insulindependent Akt/PKB/SGK. Mice expressing Akt/PKB/ SGK-resistant GSK3a/GSK3b (gsk3 KI ) exhibit enhanced sympathetic nervous activity and phosphaturia with decreased bone density. Hormones participating in phosphate homeostasis include fibroblast growth factor (FGF)-23, a bone-derived hormone that inhibits 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ; calcitriol) formation and phosphate reabsorption in the kidney and counteracts vascular calcification and aging. FGF23 secretion is stimulated by the sympathetic nervous system. We studied the role of GSK3-controlled sympathetic activity in FGF23 production and phosphate metabolism. Serum FGF23, 1,25(OH) 2 D 3 , and urinary vanillylmandelic acid (VMA) were measured by ELISA, and serum and urinary phosphate and calcium were measured by photometry in gsk3 KI and gsk3 WT mice, before and after 1 wk of oral treatment with the b-blocker propranolol. Urinary VMA excretion, serum FGF23, and renal phosphate and calcium excretion were significantly higher, and serum 1,25(OH) 2 D 3 and phosphate concentrations were lower in gsk3 KI mice than in gsk3 WT mice. Propranolol treatment decreased serum FGF23 and loss of renal calcium and phosphate and increased serum phosphate concentration in gsk3 KI mice. We conclude that Akt/ PKB/SGK-sensitive GSK3 inhibition participates in the regulation of FGF23 release, 1,25(OH) 2 D 3 formation, and thus mineral metabolism, by controlling the activity of the sympathetic nervous system.-Fajol, A., Chen, H., Umbach, A. T., Quarles, L. D., Lang, F., Föller, M. Enhanced FGF23 production in mice expressing PI3K-insensitive GSK3 is normalized by b-blocker treatment. Insulin mainly regulates glucose homeostasis, but also affects renal phosphate handling (1, 2). Cellular insulin's effects are in large part mediated by activation of PI3K resulting in the stimulation of Akt/PKB and serum-and glucocorticoid-inducible kinase (SGK) isoforms (3, 4). Upon activation, Akt/PKB (5) and SGK (6, 7) isoforms can phosphorylate numerous cellular targets, including glycogen synthase kinase (GSK)-3, thereby rendering this kinase inactive. Loss of Akt2 or of SGK3 activity in mouse models results in decreased renal phosphate reabsorption and, hence, phosphate loss (8, 9). Moreover, transgenic mice expressing Akt/PKB/SGK-resistant GSK3a/b [gsk-3 knockin (gsk-3 KI )] have hypophosphatemia, phosphaturia, and decreased bone density, illustrating the significance of PI3K signaling for renal phosphate handling (10). A direct inhibitory effect of GSK3 on renal sodium-dependent phosphate transporter IIa (NaPiIIa) (10) is likely to contribute to the phosphaturia of gsk-3 KI mice, but may not fully explain it. Gsk-3 KI mice also have hypertension and a faster heart rate caused by enhanced sympathetic activity (11).Fibroblast growth factor (FGF)-23 is a bone-derived hormone that controls phosphate and calcium metabolism (12-14). Its main target is the kidney, where FGF23 inhibits tubular p...

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“…5 Klotho homozygous mutant mice (kl/kl) display premature aging and vascular calcification due to hyperphosphatemia, presenting the symptoms of CKDassociated bone and mineral disorder. 6 Although the mechanisms of vascular calcification are not fully understood, abnormalities in mineral metabolism are considered to be important risk factors. Epidemiological studies have highlighted the impact of dysregulated mineral metabolism and have linked elevated Pi and Ca to accelerated vascular calcification.…”

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confidence: 99%

MicroRNAs that target Ca2+ transporters are involved in vascular smooth muscle cell calcification

Gui

Zhou

Sun

et al. 2012

Laboratory Investigation

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The role of microRNAs (miRNAs) in vascular calcification is currently unclear. To examine how miRNAs are involved in vascular smooth muscle cell (VSMC) calcification, we explored the alteration of miRNAs in VSMC calcification in vitro and in vivo. Klotho homozygous mutant mice (kl/kl) display vascular calcification and have perturbations of calcium handling. We therefore hypothesized that the calcium perturbations in VSMCs could be mediated by miRNAs. Using an miRNA array analysis, we demonstrated that miRNAs are aberrantly expressed in the aortic media of 3-week-old kl/kl mice compared with wild-type (WT) mice. The expression levels of miR-135a*, miR-762, miR-714, and miR-712* in the aortic media of kl/kl mice were significantly higher than in WT mice. We used quantitative real-time reverse transcriptase polymerase chain reaction to further confirm that these miRNAs were increased in the aortic media of kl/kl mice and in cultured VSMCs treated with high phosphate and calcium. A search of the miRNA database indicated that the Ca 2 þ efflux proteins NCX1, PMCA1, and NCKX4 frequently appeared as potential targets of these miRNAs. The transfection of miRNA mimics into cultured VSMCs reduced the protein levels of each potential target. Conversely, miRNA inhibitors reduced phosphate and calcium-induced VSMC calcification. Furthermore, these inhibitors decreased the intracellular Ca 2 þ concentration in cultured VSMCs after treatment with phosphate and calcium. Our results suggest that increased expression of miR-135a*, miR-762, miR-714, and miR-712* in VSMCs may be involved in VSMC calcification by disrupting Ca 2 þ efflux proteins.

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Overview of the FGF23-Klotho axis

Cited by 140 publications

References 93 publications

NFκB-sensitive Orai1 expression in the regulation of FGF23 release

NFκB-sensitive Orai1 expression in the regulation of FGF23 release

Enhanced FGF23 production in mice expressing PI3K‐insensitive GSK3 is normalized by β‐blocker treatment

MicroRNAs that target Ca2+ transporters are involved in vascular smooth muscle cell calcification

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