Role of the vitamin D receptor in FGF23 action on phosphate metabolism

Inoue, Yoshio; Segawa, Hiroko; Kaneko, Ichiro; Yamanaka, Setsuko; Kusano, Koji; Kawakami, Eri; Furutani, Junya; Ito, Mikiko; Kuwahata, Masashi; Saitô, Hitoshi; Fukushima, Naoshi; Kato, Shigeaki; Kanayama, Hiro‐omi; Miyamoto, Ken‐ichi

doi:10.1042/bj20041799

Cited by 160 publications

(121 citation statements)

References 27 publications

(76 reference statements)

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“…However, the fact that mutations in GALNT3 and in FGF23 result in a similar phenotype (Topaz et al 2004;Benet-Page`s et al 2005), and the fact that FGF23 levels are perturbed in patients with ppGalNacT3 deficiency (Topaz et al 2004) indicate that the two proteins participate in a common regulatory pathway. FGF23 decreases circulating phosphate levels by downregulation of NaPiIIa (Shimada et al 2005), the major phosphate transporter in the renal proximal tubule, by inhibition of NaPiIIb, responsible for trans-intestinal phosphate transport , and by down-regulation of 1-alpha-hydroxylation of 25-hydroxycholecalciferol (Inoue et al 2005). Proteolytic degradation of FGF23 is believed to play a major role in regulating these activities (Saito et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Hyperphosphatemic familial tumoral calcinosis caused by a mutation in GALNT3 in a European kindred

et al. 2006

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Hyperphosphatemic familial tumoral calcinosis (HFTC) is an autosomal recessive metabolic disorder characterized by extensive phenotypic and genetic heterogeneity. HFTC was shown recently to result from mutations in two genes: GALNT3, coding for a glycosyltransferase responsible for initiating O-glycosylation, and FGF23, coding for a potent phosphaturic protein.All GALNT3 mutations reported so far have been identified in patients of either Middle Eastern or African-American extraction, corroborating numerous historical reports of the disorder in Africa and in the Middle East. In the present study, we describe a patient of Northern European origin displaying typical features of HFTC. Mutation analysis revealed that this patient carries a homozygous novel nonsense mutation in GALNT3 predicted to result in the synthesis of a significantly truncated protein. The present results expand the spectrum of known mutations in GALNT3 and demonstrate the existence of HFTC-causing mutations in this gene outside the Middle Eastern and AfricanAmerican populations.

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Section: Discussionmentioning

confidence: 99%

Hyperphosphatemic familial tumoral calcinosis caused by a mutation in GALNT3 in a European kindred

et al. 2006

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“…FGF-23 is known to inhibit 25-hydroxyvitamin D-1a-hydroxylase (1a-hydroxylase) and stimulate 25-hydroxyvitamin D-24-hydroxylase, thereby simultaneously inhibiting the activation and enhancing the catabolism of 25(OH)D, respectively (5,18). In the overall sample, significant negative correlations were found between FGF-23 and both 25(OH)D and 1,25 (OH) 2 is possible that FGF-23 contributed to decreased synthesis of 1,25(OH) 2 D through its known inhibition of 1a-hydroxylase.…”

Section: Discussionmentioning

confidence: 99%

FGF-23 Levels in Patients with AKI and Risk of Adverse Outcomes

Leaf

Wolf

Waikar

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Fibroblast growth factor 23 plays an important role in regulating phosphate and vitamin D homeostasis. Elevated levels of fibroblast growth factor 23 are independently associated with mortality in patients with CKD and ESRD. Whether fibroblast growth factor 23 levels are elevated and associated with adverse outcomes in patients with AKI has not been studied.Design, setting, participants, & measurements This study had 30 participants with AKI, which was defined as an increase in serum creatinine$0.3 mg/dl or $50% from baseline, and 30 controls from the general hospital wards and intensive care units. Plasma levels of C-terminal fibroblast growth factor 23 and vitamin D metabolites were measured within 24 hours of AKI onset and 5 days later. The composite endpoint was death or need for renal replacement therapy.Results Enrollment fibroblast growth factor 23 levels were significantly higher among participants with AKI than controls (median [interquartile range]=1471 [224-2534] versus 263 [96-574] RU/ml, P=0.003). Enrollment fibroblast growth factor 23 correlated negatively with 25-hydroxyvitamin D (r=20.43, P,0.001) and 1,25-dihydroxyvitamin D (r=20.39, P=0.003) and positively with phosphate (r=0.32, P=0.02) and parathyroid hormone (r=0.37, P=0.005). Among participants with AKI, enrollment fibroblast growth factor 23 (but not other serum parameters) was significantly associated with the composite endpoint, even after adjusting for age and enrollment serum creatinine (11 events; adjusted odds ratio per 1 SD higher ln[fibroblast growth factor 23]=13.73, 95% confidence interval=1.75-107.50).Conclusions Among patients with AKI, fibroblast growth factor 23 levels are elevated and associated with greater risk of death or need for renal replacement therapy.

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“…18 Concentration of urinary Cr was determined by the Creatinine-Wako test (Wako). Concentrations of plasma PTH were determined using the PTH ELISA kit (Immunotopics Inc., San Clemente, CA).…”

Section: Plasma and Urine Parametersmentioning

confidence: 99%

Type IIc Sodium–Dependent Phosphate Transporter Regulates Calcium Metabolism

Segawa¹,

Onitsuka²,

Kuwahata³

et al. 2009

Journal of the American Society of Nephrology

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Primary renal inorganic phosphate (Pi) wasting leads to hypophosphatemia, which is associated with skeletal mineralization defects. In humans, mutations in the gene encoding the type IIc sodiumdependent phosphate transporter lead to hereditary hypophophatemic rickets with hypercalciuria, but whether Pi wasting directly causes the bone disorder is unknown. Here, we generated Npt2c-null mice to define the contribution of Npt2c to Pi homeostasis and to bone abnormalities. Homozygous mutants (Npt2c Ϫ/Ϫ ) exhibited hypercalcemia, hypercalciuria, and elevated plasma 1,25-dihydroxyvitamin D 3 levels, but they did not develop hypophosphatemia, hyperphosphaturia, renal calcification, rickets, or osteomalacia. The increased levels of 1,25-dihydroxyvitamin D 3 in Npt2c Ϫ/Ϫ mice compared with age-matched Npt2c ϩ/ϩ mice may be the result of reduced catabolism, because we observed significantly reduced expression of renal 25-hydroxyvitamin D-24-hydroxylase mRNA but no change in 1␣-hydroxylase mRNA levels. Enhanced intestinal absorption of calcium (Ca) contributed to the hypercalcemia and increased urinary Ca excretion. Furthermore, plasma levels of the phosphaturic protein fibroblast growth factor 23 were significantly decreased in Npt2c Ϫ/Ϫ mice. Sodium-dependent Pi co-transport at the renal brush border membrane, however, was not different among Npt2c ϩ/ϩ , Npt2c ϩ/Ϫ , and Npt2c Ϫ/Ϫ mice.In summary, these data suggest that Npt2c maintains normal Ca metabolism, in part by modulating the vitamin D/fibroblast growth factor 23 axis. 20: 104 -113, 200920: 104 -113, . doi: 10.1681 Inorganic phosphate (Pi) is an essential nutrient in terms of both cellular metabolism and skeletal mineralization. The kidney is a major regulator of Pi homeostasis and can increase or decrease its Pi reabsorptive capacity to accommodate Pi needs. Up to 70% of filtered Pi is reabsorbed in the proximal tubule in which sodium (Na)-dependent Pi transport systems in the brush border membrane (BBM) mediated the rate-limiting step in the overall Pi reabsorptive process. J Am Soc Nephrol

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Role of the vitamin D receptor in FGF23 action on phosphate metabolism

Cited by 160 publications

References 27 publications

Hyperphosphatemic familial tumoral calcinosis caused by a mutation in GALNT3 in a European kindred

Hyperphosphatemic familial tumoral calcinosis caused by a mutation in GALNT3 in a European kindred

FGF-23 Levels in Patients with AKI and Risk of Adverse Outcomes

Type IIc Sodium–Dependent Phosphate Transporter Regulates Calcium Metabolism

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