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FGF23 Is Not Associated With Age-Related Changes in Phosphate, but Enhances Renal Calcium Reabsorption in Girls.

ABSTRACT: Fibroblast growth factor (FGF)23 is a critical determinant of phosphate homeostasis. The role of FGF23, however, in regulating physiologic changes in serum phosphate and renal phosphate handling across childhood is not well described. In addition, animal models have suggested a role for FGF23 in regulating renal calcium excretion.To assess changes in FGF23 concentrations across childhood in relation to changes in mineral ions and hormones of mineral ion homeostasis.This was a cross-sectional study.The study was conducted at a Clinical Research Center at a tertiary care hospital.Ninety healthy girls ages 9 to 18 years were recruited from the surrounding community.The associations of intact and C-terminal FGF23 concentrations with measures of mineral ion homeostasis were determined by univariable and multivariable linear regression.Serum phosphate and renal phosphate excretion varied with age, as expected (R = -0.49, P < 0.001 and R = -0.48, P < 0.001, respectively). Neither intact nor C-terminal FGF23 varied with age, and FGF23 was not correlated with serum or urinary phosphate. Intact FGF23 was positively correlated with serum calcium (R = 0.39, P < 0.001) and negatively correlated with urinary calcium/creatinine ratio (R = -0.27, P = 0.011).The changes in serum and urinary phosphate handling across childhood do not appear to be determined by alterations in FGF23 concentrations. These data may point to a role for FGF23 in calcium regulation in human physiology.

SUBMITTER: Mitchell DM

PROVIDER: S-EPMC5460726 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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FGF23 Is Not Associated With Age-Related Changes in Phosphate, but Enhances Renal Calcium Reabsorption in Girls.

Mitchell Deborah M DM Jüppner Harald H Burnett-Bowie Sherri-Ann M SM

The Journal of clinical endocrinology and metabolism 20170401 4

<h4>Context</h4>Fibroblast growth factor (FGF)23 is a critical determinant of phosphate homeostasis. The role of FGF23, however, in regulating physiologic changes in serum phosphate and renal phosphate handling across childhood is not well described. In addition, animal models have suggested a role for FGF23 in regulating renal calcium excretion.<h4>Objective</h4>To assess changes in FGF23 concentrations across childhood in relation to changes in mineral ions and hormones of mineral ion homeosta ...[more]

PMID: 28323960

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Project description:Excess fibroblast growth factor 23 (FGF23), excess PTH, and an increase in extracellular calcium cause hypophosphatemia by lowering the maximum renal phosphate reabsorption threshold (TmP/GFR). We recently reported two cases of X-linked hypophosphatemia (XLH) with severe tertiary hyperparathyroidism who had normalization of TmP/GFR upon being rendered hypoparathyroid following total parathyroidectomy, despite marked excess in both C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23). We explored the effects of FGF23, PTH, and calcium on TmP/GFR in a cross-sectional study (n =?74) across a spectrum of clinical cases with abnormalities in TmP/GFR, PTH, and FGF23. This comprised three groups: FGF23-dependent hypophosphatemia (n =?27), hypoparathyroidism (HOPT; n =?17), and chronic kidney disease (n =?30). Measurements included TmP/GFR, cFGF23, PTH, ionized calcium, vitamin D metabolites, and bone turnover markers. The combined effect of cFGF23, PTH, and ionized calcium on TmP/GFR was modeled using hierarchical multiple regression and was probed by moderation analysis with PROCESS. Modeling analysis showed independent effects on TmP/GFR by cFGF23, PTH, and ionized calcium in conjunction with a weak but significant effect of the interaction term for PTH and FGF23; probing showed that the effect was most prominent during PTH deficiency. Teriparatide 20??g daily was self-administered for 28?days by one case of X-linked hypophosphatemia with hypoparathyroidism (XLH-HOPT) to assess the response of TmP/GFR, cFGF23, iFGF23, nephrogenous cyclic adenosine monophosphate (NcAMP), vitamin D metabolites, and bone turnover markers. After 28?days, TmP/GFR was lowered from 1.10?mmol/L to 0.48?mmol/L; this was accompanied by increases in NcAMP, ionized calcium, and bone turnover markers. In conclusion, the effect of FGF23 excess on TmP/GFR is altered by PTH such that the effect is ameliorated by hypoparathyroidism and the effect is augmented by hyperparathyroidism. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Project description:Background: Recently, chronic kidney disease (CKD)-mineral and bone disorder (MBD) has become one of common complications occurring in CKD patients. Therefore, development of a new treatment for CKD-MBD is very important in the clinic. In China, Fucoidan (FPS), a natural compound of Laminaria japonica has been frequently used to improve renal dysfunction in CKD. However, it remains elusive whether FPS can ameliorate CKD-MBD. FGF23-Klotho signaling axis is reported to be useful for regulating mineral and bone metabolic disorder in CKD-MBD. This study thereby aimed to clarify therapeutic effects of FPS in the CKD-MBD model rats and its underlying mechanisms in vivo and in vitro, compared to Calcitriol (CTR). Methods: All male rats were divided into four groups: Sham, CKD-MBD, FPS and CTR. The CKD-MBD rat models were induced by adenine administration and uninephrectomy, and received either FPS or CTR or vehicle after induction of renal injury for 21 days. The changes in parameters related to renal dysfunction and renal tubulointerstitial damage, calcium-phosphorus metabolic disorder and bone lesion were analyzed, respectively. Furthermore, at sacrifice, the kidneys and bone were isolated for histomorphometry, immunohistochemistry and Western blot. In vitro, the murine NRK-52E cells were used to investigate regulative actions of FPS or CTR on FGF23-Klotho signaling axis, ERK1/2-SGK1-NHERF-1-NaPi-2a pathway and Klotho deficiency. Results: Using the modified CKD-MBD rat model and the cultured NRK-52E cells, we indicated that FPS and CTR alleviated renal dysfunction and renal tubulointerstitial damage, improved calcium-phosphorus metabolic disorder and bone lesion, and regulated FGF23-Klotho signaling axis and ERK1/2-SGK1-NHERF-1-NaPi-2a pathway in the kidney. In addition, using the shRNA-Klotho plasmid-transfected cells, we also detected, FPS accurately activated ERK1/2-SGK1-NHERF-1-NaPi-2a pathway through Klotho loss reversal. Conclusion: In this study, we emphatically demonstrated that FPS, a natural anti-renal dysfunction drug, similar to CTR, improves renal injury-related calcium-phosphorus metabolic disorder and bone abnormality in the CKD-MBD model rats. More importantly, we firstly found that beneficial effects in vivo and in vitro of FPS on phosphorus reabsorption are closely associated with regulation of FGF23-Klotho signaling axis and ERK1/2-SGK1-NHERF-1-NaPi-2a pathway in the kidney. This study provided pharmacological evidences that FPS directly contributes to the treatment of CKD-MBD.

Dataset Information

FGF23 Is Not Associated With Age-Related Changes in Phosphate, but Enhances Renal Calcium Reabsorption in Girls.

Publications

FGF23 Is Not Associated With Age-Related Changes in Phosphate, but Enhances Renal Calcium Reabsorption in Girls.

Similar Datasets

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