“Phosphatonins” and the regulation of phosphorus homeostasis

Berndt, Theresa J.; Schiavi, Susan C.; Kumar, Rajiv

doi:10.1152/ajprenal.00072.2005

Cited by 188 publications

(114 citation statements)

References 122 publications

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“…Phosphorus balance in mammals is controlled by the absorption of phosphorus from the diet in the duodenum and jejunum and the tubular reabsorption of inorganic phosphate by the kidney (8)(9)(10)(11)(12)(13). The efficiency of these processes is controlled by a number of hormones and peptides including the vitamin D-endocrine system (14)(15)(16)(17)(18)(19), parathyroid hormone (PTH) (20)(21)(22), and the phosphatonins such as FGF-23 and secreted frizzled related protein-4 (sFRP-4) (8,12,23,24), which act to increase intestinal phosphate absorption or reduce the amount of phosphate retained by the kidney. The efficiency of intestinal phosphate absorption is increased by 1␣, 25-dihydroxyvitamin D [1␣, 25(OH) 2 D], the hormonal form of vitamin D, as well as by vitamin Dindependent processes that depend on the amount of phosphorus in the diet (14-16, 18, 25).…”

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confidence: 99%

“…The synthesis of 1␣, 25(OH) 2 D is regulated by serum phosphate concentrations such that decreases in serum phosphate are associated with an increase in the synthesis of the hormone (18). The efficiency of renal phosphate reabsorption is reduced by PTH (20,21), FGF-23, and sFRP-4, all of which cause a redistribution of sodium phosphate cotransporters from the surface of the proximal tubular cell to compartments within the cell, thereby decreasing the efficiency of phosphate uptake in the kidney (8,10,12,13,(26)(27)(28)(29).…”

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confidence: 99%

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Evidence for a signaling axis by which intestinal phosphate rapidly modulates renal phosphate reabsorption

Berndt

Thomas

Craig

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The mechanisms by which phosphorus homeostasis is preserved in mammals are not completely understood. We demonstrate the presence of a mechanism by which the intestine detects the presence of increased dietary phosphate and rapidly increases renal phosphate excretion. The mechanism is of physiological relevance because it maintains plasma phosphate concentrations in the normal range after ingestion of a phosphate-containing meal. When inorganic phosphate is infused into the duodenum, there is a rapid increase in the renal fractional excretion of phosphate (FE Pi). The phosphaturic effect of intestinal phosphate is specific for phosphate because administration of sodium chloride does not elicit a similar response. Phosphaturia after intestinal phosphate administration occurs in thyro-parathyroidectomized rats, demonstrating that parathyroid hormone is not essential for this effect. The increase in renal FE Pi in response to the intestinal administration of phosphate occurs without changes in plasma concentrations of phosphate (filtered load), parathyroid hormone, FGF-23, or secreted frizzled related protein-4. Denervation of the kidney does not attenuate phosphaturia elicited after intestinal phosphate administration. Phosphaturia is not elicited when phosphate is instilled in other parts of the gastrointestinal tract such as the stomach. Infusion of homogenates of the duodenal mucosa increases FE Pi, which demonstrates the presence of one or more substances within the intestinal mucosa that directly modulate renal phosphate reabsorption. Our experiments demonstrate the presence of a previously unrecognized phosphate gut–renal axis that rapidly modulates renal phosphate excretion after the intestinal administration of phosphate.

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confidence: 99%

mentioning

confidence: 99%

Evidence for a signaling axis by which intestinal phosphate rapidly modulates renal phosphate reabsorption

Berndt

Thomas

Craig

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

152

127

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“…PTH exerts several actions in the renal proximal tubule that include control of phosphate transport and induction of 1,25(OH) 2 D 3 -1␣-hydroxylase (CYP27B1) mRNA (15)(16)(17). The receptor for PTH is a another member of the GPCR family capable of coordinating bidirectional signaling through pathways involving adenylate cyclase or activation of protein kinase C depending on the concentration of PTH and the specific cell type (18,19).…”

Section: Extracellular Ionized Calcium [Ca 2ϩmentioning

confidence: 99%

Extracellular Calcium-sensing Receptor Activation Induces Vitamin D Receptor Levels in Proximal Kidney HK-2G Cells by a Mechanism That Requires Phosphorylation of p38α MAPK

Maiti

Hait

Beckman

2008

Journal of Biological Chemistry

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2؉ ] e concentration in the physiological range is capable of directly increasing renal proximal VDR expression, and the induction mechanism requires activation of the CaSR and signal mediation by the p38␣ MAP kinase pathway.Extracellular ionized calcium [Ca 2ϩ ] e is a critical mediator of cell signaling for the storage and release of both parathyroid hormone (PTH) 2 and calcitonin. Homeostasis of [Ca 2ϩ ] e is important to proper neuromuscular contractions, cellular integrity, and the deposition of mineral in skeletal structures (1). A multi-organ system coordinates and maintains [Ca 2ϩ ] e homeostasis within a narrow physiological range (2). Activation of the an extracellular calcium sensing receptor (CaSR) when [Ca 2ϩ ] e concentrations are high maintains the storage form of PTH in the parathyroid gland (3,4). Release of PTH from the parathyroid gland is a direct result of a decrease in serum [Ca 2ϩ ] e (5, 6). PTH is a potent stimulus of 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) biosynthesis in the kidney proximal convoluted tubule by its induction of 1␣-hydoxylation (7). Resultant increase in [Ca 2ϩ ] e by 1,25(OH) 2 D 3 regulates PTH at two levels; where CaSR signaling shuts down PTH secretion (8, 9) and 1,25(OH) 2 D 3 through transactivation of its nuclear receptor (VDR) inhibits prepro-PTH transcription (10).[Ca 2ϩ ] e is also a potent mediator of the balance between cellular proliferation and differentiation while VDR mediates biological functions of 1,25(OH) 2 D 3 and is expressed in many different cell types (11). Past work has focused on the role of VDR in mineral homeostasis, with VDR activators used mainly to treat hyperparathyroidism secondary to chronic kidney disease (12). A more recent perspective includes the use of vitamin D analogs in combination with calcimimetics and phosphate binders in the management of hyperparathyroid disorders (13). It is therefore important to identify the mechanisms whereby CaSR signaling and VDR activation coincide in the tissues that co-express these two receptors. We previously reported for the first time that [Ca 2ϩ ] e is a direct regulator of VDR in proximal human kidney . The present study was designed to better explore the mechanism by which [Ca 2ϩ ] e influences VDR increase in these cells.PTH exerts several actions in the renal proximal tubule that include control of phosphate transport and induction of 1,25(OH) 2 D 3 -1␣-hydroxylase (CYP27B1) mRNA (15-17). The receptor for PTH is a another member of the GPCR family capable of coordinating bidirectional signaling through pathways involving adenylate cyclase or activation of protein kinase C depending on the concentration of PTH and the specific cell type (18,19). In proximal tubule epithelial cells, PTH stimulates 1␣-hydroxylation, mediates 1,25(OH) 2 D 3 -24-hydroxylase (CYP24) down-regulation and represses 1,25(OH) 2 D 3 -receptor (VDR) transcription all by increasing cAMP and activating the cAMP-dependent response element-binding protein (CREB) (20 -22). However, the set of ...

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“…The role of FGF23 in XLH is not very well understood at the moment. There is some evidence that it may be the phosphaturic factor (phosphatonin) in this disease [25,26,27], although the theory that FGF23 is a substrate of PHEX could not be proven [28, 29]. However, recombinant FGF23 is known to cause phosphaturia and hypophosphatemia in vivo [27, 30].…”

Section: Discussionmentioning

confidence: 99%

Novel PHEX Mutation Associated with Hypophosphatemic Rickets

et al. 2007

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Background: X-linked hypophosphatemia (XLH) is the most prevalent heritable form of rickets. It is a dominantly inherited disorder, characterized by renal phosphate wasting, abnormal vitamin D and PTH metabolism, and defective bone mineralization. Inactivating mutations in the gene encoding PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) have been found to be associated with XLH. Methods: We report about a 54-year-old male patient who exhibited the typical features of XLH, and in whom mutational analysis using PCR and sequencing was performed. Additionally, extensive laboratory and radiological investigations were carried out. Results: A 1-bp deletion in exon 2 of the PHEX gene was detected (177delC), which, to the best of our knowledge, has not been reported yet. This deletion results in a premature stop codon (C59X), suggesting a truncation of the PHEX protein. Furthermore, elevated FGF23 and PTH levels as well as an increased axial bone mineral density score were measured. Conclusions: We present a male patient with XLH, who harbors a novel mutation in the PHEX gene, which might be the cause for his disease. Our data support previous findings and therefore contribute to the decipherment of the pathogenetic pathways of XLH.

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“Phosphatonins” and the regulation of phosphorus homeostasis

Cited by 188 publications

References 122 publications

Evidence for a signaling axis by which intestinal phosphate rapidly modulates renal phosphate reabsorption

Evidence for a signaling axis by which intestinal phosphate rapidly modulates renal phosphate reabsorption

Extracellular Calcium-sensing Receptor Activation Induces Vitamin D Receptor Levels in Proximal Kidney HK-2G Cells by a Mechanism That Requires Phosphorylation of p38α MAPK

Novel PHEX Mutation Associated with Hypophosphatemic Rickets

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