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Michel Baum - One of the best experts on this subject based on the ideXlab platform.
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Effect of fibroblast growth factor-23 on Phosphate Transport in proximal tubules
Kidney international, 2005Co-Authors: Michel Baum, Susan Schiavi, Vangipuram Dwarakanath, Raymond QuigleyAbstract:Effect of fibroblast growth factor-23 on Phosphate Transport in proximal tubules. Background Fibroblast growth factor-23 (FGF-23) has been implicated in the renal Phosphate wasting in tumor-induced osteomalacia, X-linked hypoPhosphatemia, and autosomal-dominant hypoPhosphatemic rickets. Methods In this in vitro microperfusion study we examined if FGF23R176Q, a stable mutant of FGF-23, impairs Phosphate Transport in rabbit proximal convoluted and proximal straight tubules perfused in vitro. We also examined if heparin, a molecule that is known to facilitate binding of FGFs to their receptor was necessary for the action of FGF23R176Q on Transport. Results In the presence of heparin, FGF23R176Q reduced Phosphate Transport from 10.8 ± 2.0 to 9.9 ± 1.9 pmol/mm/min in proximal convoluted tubules and 1.0 ± 0.2 to 0.8 ± 0.2 pmol/mm/min in proximal straight tubules (both P Conclusion These data demonstrate that the inhibition of Phosphate Transport by FGF23R176Q in vitro requires heparin. The action of FGF23R176Q is associated with a reduction in BBMV NaPi-2A protein abundance.
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Maturational effects of glucocorticoids on neonatal brush-border membrane Phosphate Transport
Pediatric Research, 1994Co-Authors: Mazen Y Arar, Moshe Levi, Michel BaumAbstract:ABSTRACT: Previous studies have implicated glucocorticoids as an important factor in the postnatal maturational increase in proximal tubule volume absorption, Na+/H+ antiporter, Na(HCO3)3 symporter, and Na+-K+-ATPase activity. The present study examined whether glucocorticoids are also a potentially important factor in the maturational decrease in proximal tubule Phosphate Transport. Renal BBMs were prepared from neonatal rabbits who received dexamethasone (10 μg/100 g body weight) or vehicle. Brush-border membrane vesicles from dexameth-asone-treated neonates had a lower rate of Na-Phosphate coTransport than controls (50.8 ± 3.6 versus 29.2 ± 2.6 pmol 32Pi/10 s/mg protein, p < 0.001). This decrease was due to a decrease in the Vmax with no change in the affinity of the Transporter for Phosphate. The dexamethasone-induced decrease in BBM Na-Phosphate Transport was not due to a reduction in Transporters as assayed by Phosphate-protectable Na-dependent equilibrium binding of phosphonoformic acid. Dexamethasone treatment caused an increase in the fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene and trimethylammonium-1,6-diphenyl-1,3,5-hexatriene (i.e. a decrease in membrane fluidity). Brush-border membranes from dexamethasone-treated neonates had a decrease in sphingomyelin and an increase in phosphatidylcholine and phosphatidylinositol content but no change in cholesterol or total phospholipid content. These data are consistent with glucocorticoids playing a role in the postnatal maturational decrease in proximal tubule Phosphate Transport by altering membrane characteristics.
Raymond Quigley - One of the best experts on this subject based on the ideXlab platform.
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Effect of fibroblast growth factor-23 on Phosphate Transport in proximal tubules
Kidney international, 2005Co-Authors: Michel Baum, Susan Schiavi, Vangipuram Dwarakanath, Raymond QuigleyAbstract:Effect of fibroblast growth factor-23 on Phosphate Transport in proximal tubules. Background Fibroblast growth factor-23 (FGF-23) has been implicated in the renal Phosphate wasting in tumor-induced osteomalacia, X-linked hypoPhosphatemia, and autosomal-dominant hypoPhosphatemic rickets. Methods In this in vitro microperfusion study we examined if FGF23R176Q, a stable mutant of FGF-23, impairs Phosphate Transport in rabbit proximal convoluted and proximal straight tubules perfused in vitro. We also examined if heparin, a molecule that is known to facilitate binding of FGFs to their receptor was necessary for the action of FGF23R176Q on Transport. Results In the presence of heparin, FGF23R176Q reduced Phosphate Transport from 10.8 ± 2.0 to 9.9 ± 1.9 pmol/mm/min in proximal convoluted tubules and 1.0 ± 0.2 to 0.8 ± 0.2 pmol/mm/min in proximal straight tubules (both P Conclusion These data demonstrate that the inhibition of Phosphate Transport by FGF23R176Q in vitro requires heparin. The action of FGF23R176Q is associated with a reduction in BBMV NaPi-2A protein abundance.
Edward J. Weinman - One of the best experts on this subject based on the ideXlab platform.
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fibroblast growth factor 23 mediated inhibition of renal Phosphate Transport in mice requires sodium hydrogen exchanger regulatory factor 1 nherf 1 and synergizes with parathyroid hormone
Journal of Biological Chemistry, 2011Co-Authors: Edward J. Weinman, Deborah Steplock, Shirish Shenolikar, Rajatsubhra BiswasAbstract:Abstract Fibroblast growth factor-23 (FGF-23) inhibits sodium-dependent Phosphate Transport in brush border membrane vesicles derived from hormone-treated kidney slices of the mouse and in mouse proximal tubule cells by processes involving mitogen-activated protein kinase (MAPK) but not protein kinase A (PKA) or protein kinase C (PKC). By contrast, Phosphate Transport in brush border membrane vesicles and proximal tubule cells from sodium-hydrogen exchanger regulatory factor-1 (NHERF-1)-null mice were resistant to the inhibitory effect of FGF-23 (10−9 m). Infection of NHERF-1-null proximal tubule cells with wild-type adenovirus-GFP-NHERF-1 increased basal Phosphate Transport and restored the inhibitory effect of FGF-23. Infection with adenovirus-GFP-NHERF-1 containing a S77A or T95D mutation also increased basal Phosphate Transport, but the cells remained resistant to FGF-23 (10−9 m). Low concentrations of FGF-23 (10−13 m) and PTH (10−11 m) individually did not inhibit Phosphate Transport or activate PKA, PKC, or MAPK. When combined, however, these hormones markedly inhibited Phosphate Transport associated with activation of PKC and PKA but not MAPK. These studies indicate that FGF-23 inhibits Phosphate Transport in the mouse kidney by processes that involve the scaffold protein NHERF-1. In addition, FGF-23 synergizes with PTH to inhibit Phosphate Transport by facilitating the activation of the PTH signal transduction pathway.
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The regulation of renal Phosphate Transport.
Advances in chronic kidney disease, 2011Co-Authors: Judith Blaine, Edward J. Weinman, Rochelle CunninghamAbstract:Renal Phosphate Transport is mediated by the abundance and activity of the sodium-dependent Phosphate Transporters, Npt2a, Npt2c, and PiT-2, present within the apical brush border membrane of the proximal tubule. Recent studies have demonstrated differential expression and activity of these sodium-dependent Phosphate Transporters within the proximal tubule. In general, Phosphate Transport is regulated by a variety of physiological stimuli, including parathyroid hormone, glucocorticoids, vitamin D3, estrogen, and thyroid hormone. Phosphatonins are now recognized as major regulators of Phosphate Transport activity. Other factors that affect Phosphate Transport include dopamine, dietary Phosphate, acid–base status, lipid composition, potassium deficiency, circadian rhythm, and hypertension. Studies have shown that the PDZ-containing sodium/hydrogen exchanger regulatory factor (NHERF) proteins, specifically NHERF-1 and NHERF-3, play a critical role in the physiological regulation of Phosphate Transport, particularly in response to dietary Phosphate. In addition, recent studies have found that NHERF-1 is also important in both the parathyroid hormone- and dopamine-mediated inhibition of Phosphate Transport. This review will detail the various hormones and agents involved in the regulation of Phosphate Transport as well as provide a brief summary of the signaling pathways and cytoskeletal proteins active in the Transport of Phosphate in the renal proximal tubule.
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cooperativity between the phosphorylation of thr95 and ser77 of nherf 1 in the hormonal regulation of renal Phosphate Transport
Journal of Biological Chemistry, 2010Co-Authors: Edward J. Weinman, Deborah Steplock, Yinghua Zhang, Rajatsubhra Biswas, Robert J Bloch, Shirish ShenolikarAbstract:The phosphorylation of the sodium-hydrogen exchanger regulatory factor-1 (NHERF-1) plays a key role in the regulation of renal Phosphate Transport by parathyroid hormone (PTH) and dopamine. Ser77 in the first PDZ domain of NHERF-1 is a downstream target of both hormones. The current experiments explore the role of Thr95, another Phosphate acceptor site in the PDZ I domain, on hormone-mediated regulation of Phosphate Transport in the proximal tubule of the kidney. The substitution of alanine for threonine at position 95 (T95A) significantly decreased the rate and extent of in vitro phosphorylation of Ser77 by PKC. In NHERF-1-null proximal tubule cells, neither PTH nor dopamine inhibited sodium-dependent Phosphate Transport. Infection of the cells with adenovirus expressing full-length WT GFP-NHERF-1 increased basal Phosphate Transport and restored the inhibitory effect of both PTH and dopamine. Infection with full-length NHERF-1 containing a T95A mutation, however, increased basal Phosphate Transport but not the responsiveness to either hormone. As determined by surface plasmon resonance, the substitution of serine for aspartic acid (S77D) in the PDZ I domain decreased the binding affinity to the sodium-dependent Phosphate Transporter 2a (Npt2a) as compared with WT PDZ I, but a T95D mutation had no effect on binding. Finally, cellular studies indicated that both PTH and dopamine treatment increased the phosphorylation of Thr95. These studies indicate a remarkable cooperativity between the phosphorylation of Thr95 and Ser77 of NHERF-1 in the hormonal regulation of renal Phosphate Transport. The phosphorylation of Thr95 facilitates the phosphorylation of Ser77. This, in turn, results in the dissociation of NHERF-1 from Npt2a and a decrease in Phosphate Transport in renal proximal tubule cells.
Susan Schiavi - One of the best experts on this subject based on the ideXlab platform.
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Intestinal Phosphate Transport
Advances in chronic kidney disease, 2011Co-Authors: Yves Sabbagh, Hector Giral, Yupanqui Caldas, Moshe Levi, Susan SchiaviAbstract:Phosphate is absorbed in the small intestine by a minimum of 2 distinct mechanisms: paracellular Phosphate Transport which is dependent on passive diffusion, and active Transport which occurs through the sodium-dependent Phosphate coTransporters. Despite evidence emerging for other ions, regulation of the Phosphate-specific paracellular pathways remains largely unexplored. In contrast, there is a growing body of evidence that active Transport through the sodium-dependent Phosphate coTransporter, Npt2b, is highly regulated by a diverse set of hormones and dietary conditions. Furthermore, conditional knockout of Npt2b suggests that it plays an important role in maintenance of Phosphate homeostasis by coordinating intestinal Phosphate absorption with renal Phosphate reabsorption. The knockout mouse also suggests that Npt2b is responsible for the majority of sodium-dependent Phosphate uptake. The type-III sodium-dependent Phosphate Transporters, Pit1 and Pit2, contribute to a minor role in total Phosphate uptake. Despite coexpression along the apical membrane, differential responses of Pit1 and Npt2b regulation to chronic versus dietary changes illustrates another layer of Phosphate Transport control. Finally, a major problem in patients with CKD is management of hyperPhosphatemia. The present evidence suggests that targeting key regulatory pathways of intestinal Phosphate Transport may provide novel therapeutic approaches for patients with CKD.
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Effect of fibroblast growth factor-23 on Phosphate Transport in proximal tubules
Kidney international, 2005Co-Authors: Michel Baum, Susan Schiavi, Vangipuram Dwarakanath, Raymond QuigleyAbstract:Effect of fibroblast growth factor-23 on Phosphate Transport in proximal tubules. Background Fibroblast growth factor-23 (FGF-23) has been implicated in the renal Phosphate wasting in tumor-induced osteomalacia, X-linked hypoPhosphatemia, and autosomal-dominant hypoPhosphatemic rickets. Methods In this in vitro microperfusion study we examined if FGF23R176Q, a stable mutant of FGF-23, impairs Phosphate Transport in rabbit proximal convoluted and proximal straight tubules perfused in vitro. We also examined if heparin, a molecule that is known to facilitate binding of FGFs to their receptor was necessary for the action of FGF23R176Q on Transport. Results In the presence of heparin, FGF23R176Q reduced Phosphate Transport from 10.8 ± 2.0 to 9.9 ± 1.9 pmol/mm/min in proximal convoluted tubules and 1.0 ± 0.2 to 0.8 ± 0.2 pmol/mm/min in proximal straight tubules (both P Conclusion These data demonstrate that the inhibition of Phosphate Transport by FGF23R176Q in vitro requires heparin. The action of FGF23R176Q is associated with a reduction in BBMV NaPi-2A protein abundance.
Richard Shimkets - One of the best experts on this subject based on the ideXlab platform.
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fibroblast growth factor 7 an inhibitor of Phosphate Transport derived from oncogenic osteomalacia causing tumors
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Thomas O. Carpenter, Bruce Ellis, William M Philbrick, John Sterpka, Karl L. Insogna, Richard ShimketsAbstract:Oncogenic osteomalacia (OO), a tumor-associated Phosphate-wasting syndrome, provides an opportunity to identify regulators of renal Phosphate homeostasis. We established cultures from OO-associated tumors. Conditioned medium from these cultures inhibited Phosphate uptake in renal tubular epithelial cells. We then compared RNA from tumor-derived cultures expressing inhibitory activity with RNA from tumor-derived cultures in which inhibitory activity was not evident and identified candidate mRNAs specifically expressed by cultures inhibiting renal Phosphate Transport. Testing of identified candidates revealed that one protein, fibroblast growth factor 7 (FGF7), was a potent and direct inhibitor of Phosphate uptake in vitro. A neutralizing monoclonal antibody to FGF7 reversed FGF7-dependent Phosphate Transport inhibition and inhibitory activity in conditioned medium from tumor cell cultures. Immunoassay revealed abundant FGF7 in inhibitory conditioned medium and minimal amounts in nonconditioned medium or co...
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Fibroblast Growth Factor 7: An Inhibitor of Phosphate Transport Derived from Oncogenic Osteomalacia-Causing Tumors
The Journal of clinical endocrinology and metabolism, 2004Co-Authors: Thomas O. Carpenter, Bruce Ellis, William M Philbrick, John Sterpka, Karl L. Insogna, Richard ShimketsAbstract:Oncogenic osteomalacia (OO), a tumor-associated Phosphate-wasting syndrome, provides an opportunity to identify regulators of renal Phosphate homeostasis. We established cultures from OO-associated tumors. Conditioned medium from these cultures inhibited Phosphate uptake in renal tubular epithelial cells. We then compared RNA from tumor-derived cultures expressing inhibitory activity with RNA from tumor-derived cultures in which inhibitory activity was not evident and identified candidate mRNAs specifically expressed by cultures inhibiting renal Phosphate Transport. Testing of identified candidates revealed that one protein, fibroblast growth factor 7 (FGF7), was a potent and direct inhibitor of Phosphate uptake in vitro. A neutralizing monoclonal antibody to FGF7 reversed FGF7-dependent Phosphate Transport inhibition and inhibitory activity in conditioned medium from tumor cell cultures. Immunoassay revealed abundant FGF7 in inhibitory conditioned medium and minimal amounts in nonconditioned medium or conditioned medium with no Phosphate Transport inhibitory activity. Furthermore, only small amounts of FGF23 were present in inhibitory conditioned medium, comparable to concentrations found in conditioned medium with no Phosphate Transport inhibitory activity. Thus, FGF7 was specifically identified when selecting for in vitro Phosphate Transport inhibitory activity of tumor-derived cultures and was confirmed as a potent inhibitor of Phosphate Transport. Finally, FGF7 message was confirmed in PCR products of mRNA extracted from fragments of each tumor. Members of the FGF family (other than FGF23) are expressed by OO-associated tumors and may play a role in mediating this syndrome.