Correction of proximal tubule phosphate transport defect inHypmicein vivoandin vitrowith indomethacin

Baum, Michel; Loleh, Samer; Saini, Neel; Seikaly, Mouin G.; Dwarakanath, Vangipuram; Quigley, Raymond

doi:10.1073/pnas.1834060100

Cited by 22 publications

(28 citation statements)

References 48 publications

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“…We find that administration of FGF-23R176Q results in an increase in urinary PGE 2 / creatinine excretion. In our previous study, we found that Hyp mice had a twofold greater urinary to PGE 2 /Cr level compared with C57/B6 mice (5). In this study, we show that 24 h after administration of FGF-23R176Q, there was a 10-fold increase in urinary PGE 2 /Cr level.…”

Section: Discussionsupporting

confidence: 58%

“…We recently provided evidence that there is altered prostaglandin production in Hyp mice (5). We found that Hyp mice have higher urinary PGE 2 excretion than C57/B6 mice.…”

mentioning

confidence: 82%

“…Isolated segments of C57/B6 mouse proximal convoluted tubules were perfused as previously described (5). Briefly, tubules were dissected in Hanks' balanced salt solution containing (in mM) 137 NaCl, 5 KCl, 0.8 MgSO 4, 0.33 Na2HPO4, 0.44 KH2PO4, 1 MgCl2 10 Tris (hydroxymethyl) aminomethane hydrochloride, 0.25 CaCl2, 2 glutamine, and 2 L-lactate at 4°C.…”

Section: Methodsmentioning

confidence: 99%

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Fibroblast growth factor-23 increases mouse PGE₂production in vivo and in vitro

Syal

Schiavi

Chakravarty

et al. 2006

American Journal of Physiology-Renal Physiology

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Fibroblast growth factor-23 (FGF-23) has been implicated in the renal phosphate wasting in X-linked hypophosphatemia, tumor-induced osteomalacia, and autosomal dominant hypophosphatemic rickets. Recently, we demonstrated that Hyp mice have greater urinary PGE2 levels compared with C57/B6 mice and that indomethacin administration in vivo and in vitro ameliorates the phosphate transport defect in Hyp mice. To determine further whether altered prostaglandin metabolism plays a role in the renal phosphate transport defect in Hyp mice, we incubated renal proximal tubules with arachidonic acid. We find that PGE2 production was higher in Hyp mice than in C57/B6 mice. Incubation of C57/B6 mouse renal proximal tubules with FGF-23R176Q, an active mutant form of FGR23, increased tubular PGE 2 production, an effect that was inhibited by 50 M PD-98059 and 10 M SB-203580, inhibitors of the MAP kinase pathway. C57/B6 mice injected with FGF-23R176Q had a ϳ10-fold increase in PGE 2 excretion 24 h after intraperitoneal injection of FGF-23R176Q compared with vehicle-treated controls. Finally, we show that PGE 2 inhibited both phosphate and volume absorption in mouse proximal convoluted tubules perfused in vitro and reduced brush-border membrane vesicle NaPi-2a protein abundance from renal cortex incubated in vitro with PGE 2. In conclusion, FGF-23 increases urinary and renal tubular PGE 2 production via the MAP kinase pathway and PGE2 inhibits proximal tubule phosphate transport. volume absorption; in vitro microperfusion; NaPi-2a; rickets; prostaglandin E2 TUMOR-INDUCED osteomalacia, X-linked hypophosphatemia, and autosomal dominant hypophosphatemic rickets are characterized by hypophosphatemia, hyperphosphaturia, inappropriately normal 1,25(OH) 2 vitamin D levels for the degree of hypophosphatemia, and defective bone mineralization. Serum fibroblast growth factor-23 (FGF-23) levels are increased in these three disorders. In tumor-induced osteomalacia, a rare paraneoplastic disorder seen in patients with mesenchymal tumors, there is renal phosphate wasting due to increased FGF-23 production (8,9,17,37) and likely the secretion of other phosphaturic peptides previously known as phosphatonins (9). Tumor resection results in a reduction in FGF-23 to normal levels with concomitant correction of the disordered phosphate metabolism (39). X-linked hypophosphatemia is due to a mutation in the PHEX gene (11,15,24,31). The PHEX gene is a phosphate-regulating gene with endopeptidase activity, which is located on the X chromosome. X-linked hypophosphatemia may be due to failure to inactivate normal circulating FGF-23 (7). However, others have found that FGF-23 is not a PHEX substrate (13,20) and that in some way inactive PHEX results in increased production of . Most patients with X-linked hypophosphatemia have inappropriately high levels of 33,40), whereas patients with autosomal dominant hypophosphatemic rickets have a R176Q mutation in FGF-23 that resists proteolytic cleavage resulting in increased FGF-23R176Q serum levels (3,7,30,36,37).W...

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Section: Discussionsupporting

confidence: 58%

“…We recently provided evidence that there is altered prostaglandin production in Hyp mice (5). We found that Hyp mice have higher urinary PGE 2 excretion than C57/B6 mice.…”

mentioning

confidence: 82%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Fibroblast growth factor-23 increases mouse PGE₂production in vivo and in vitro

Syal

Schiavi

Chakravarty

et al. 2006

American Journal of Physiology-Renal Physiology

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“…Isolated segments of midcortical and juxtamedullary proximal convoluted tubules (PCT) were perfused as previously described for mice and rabbits (4,6,36,40,42,43). Briefly, tubules were dissected in Hanks' balanced salt solution containing (in mM) 137 NaCl, 5 KCl, 0.8 MgSO 4, 0.33 Na2HPO4, 0.44 KH 2PO4, 1 MgCl2, 10 Tris hydrochloride, 0.25 CaCl2, 2 glutamine, and 2 L-lactate at 4°C without the use of collagenase.…”

Section: Methodsmentioning

confidence: 99%

Claudins 6, 9, and 13 are developmentally expressed renal tight junction proteins

Abuazza¹,

Becker²,

Williams³

et al. 2006

American Journal of Physiology-Renal Physiology

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106

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The adult proximal tubule is a low-resistance epithelium where there are high rates of both active transcellular and passive paracellular NaCl transport. We have previously demonstrated that the neonatal rabbit and rat proximal tubule have substantively different passive paracellular transport properties than the adult proximal tubule, which results in a maturational change in the paracellular passive flux of ions. Neonatal proximal tubules have a higher PNa/PCl ratio and lower chloride and bicarbonate permeabilities than adult proximal tubules. Claudins are a large family of proteins which are the gate keepers of the paracellular pathway, and claudin isoform expression determines the permeability characteristics of the paracellular pathway. Previous studies have shown that claudins 1, 2, 3, 4, 5, 7, 8, 10, 11, 12, 15, and 16 are expressed in the adult mouse kidney. To determine whether there are developmental claudin isoforms, we compared the claudin isoforms present in the neonatal and adult kidney using RT-PCR to detect mRNA of claudin isoforms. Claudin 6, claudin 9, and claudin 13 were either not expressed or barely detectable in the adult mouse kidney using traditional PCR, but were expressed in the neonatal mouse kidney. Using real-time RT-PCR, we were able to detect a low level of claudin 6 mRNA expression in the adult kidney compared with the neonate, but claudin 9 and claudin 13 were only detected in the neonatal kidney. There was the same maturational decrease in these claudin proteins with Western blot analysis. Immunohistochemistry showed high levels of expression of claudin 6 in neonatal proximal tubules, thick ascending limb, distal convoluted tubules, and collecting ducts in a paracellular distribution but there was no expression of claudin 6 in the adult kidney. Using real-time RT-PCR claudin 6 and 9 mRNA were present in 1-day-old proximal convoluted tubules and were virtually undetectable in proximal convoluted tubules from adults. Claudin 13 was not detectable in neonatal or adult proximal convoluted tubules. In summary, we have identified developmentally expressed claudin isoforms, claudin 6, claudin 9, and claudin 13. These paracellular proteins may play a role in the maturational changes in paracellular permeability.

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“…Isolated segments of midcortical and juxtamedullary proximal convoluted tubules (PCT) and proximal straight tubules (PST) were perfused as previously described for mice and rabbits (6,7,22,26,28,29). Briefly, tubules were dissected in HBSS containing (in mM) 137 NaCl, 5 KCl, 0.8 MgSO 4, 0.33 Na 2HPO4, 0.44 KH2PO4, 1 MgCl2, 10 Tris (hydroxymethyl) aminomethane hydrochloride, 0.25 CaCl 2, 2 glutamine, and 2 Llactate at 4°C without the use of collagenase.…”

Section: Methodsmentioning

confidence: 99%

Maturation of rat proximal tubule chloride permeability

Baum¹,

Quigley²

2005

American Journal of Physiology-Regulatory, Integrative and Comp

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The surprising finding of lower chloride permeability in neonate proximals compared with adults impacts net chloride transport in this segment, which reabsorbs 60% of the filtered chloride in adults. However, this maturational difference in chloride permeability may not be applicable to other species. The present in vitro microperfusion study directly examined the chloride and mannitol permeability using in vitro perfused rat proximal tubules during postnatal maturation. Whereas there was no maturational change in mannitol permeability, chloride permeability was 6.3 Ϯ 1.3 ϫ 10 Ϫ5 cm/s in neonate rat proximal convoluted tubule and 16.1 Ϯ 2.3 ϫ 10 Ϫ5 cm/s in adult rat proximal convoluted tubule (P Ͻ 0.01). There was also a maturational increase in chloride permeability in the rat proximal straight tubule (5.1 Ϯ 0.6 ϫ 10 Ϫ5 cm/s vs. 9.3 Ϯ 0.6 ϫ 10 Ϫ5 cm/s, P Ͻ 0.01). There was no maturational change in bicarbonate-to-chloride permeabilities (P HCO3/PCl) in the rat proximal straight tubules (PST) and proximal convoluted tubules (PCT) or in the sodium-to-chloride permeability (PNa/PCl) in the proximal straight tubule; however, there was a significant maturational decrease in proximal convoluted tubule PNa/ P Cl with postnatal development (1.31 Ϯ 0.12 in neonates vs. 0.75 Ϯ 0.06 in adults, P Ͻ 0.001). There was no difference in the transepithelial resistance measured by current injection and cable analysis in the PCT, but there was a maturational decrease in the PST (7.2 Ϯ 0.8 vs. 4.6 Ϯ 0.1 ⍀ ⅐ cm 2 , P Ͻ 0.05). These studies demonstrate there are maturational changes in the rat paracellular pathway that impact net NaCl transport during development. paracellular pathway; mannitol permeability THE ADULT PROXIMAL TUBULE reabsorbs over half of the filtered chloride (2,5,6,18,27,28). Active transcellular chloride is via the parallel operation of the Na ϩ /H ϩ exchanger and a Cl/base exchanger (5, 27). The other half of chloride transport by the proximal tubule is passive, paracellular, and in large part, dependent on the chloride permeability. Thus the characteristics of the paracellular pathway can have a substantive effect on NaCl transport by the proximal tubule.Previous studies examining the maturational changes in paracellular permeability have been conflicting. In a study (17) where solutes were injected into the early proximal tubule of guinea pigs and the urine was collected from the ipsilateral kidney, recovery of sucrose and creatinine did not vary with age and were comparable to inulin. However, mannitol recovery increased from 92% at 1 day of age to 100% at 49 days of age (17). Whereas these studies were indirect and assessed mannitol absorption, a sugar that is not actively transported along the entire nephron, these data were consistent with a more permeable paracellular pathway in neonates than in adults.We have examined the permeability properties of the rabbit proximal tubule (23, 29). We found that the neonate had lower proximal tubule chloride permeability, but there was no maturational difference in th...

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Correction of proximal tubule phosphate transport defect inHypmicein vivoandin vitrowith indomethacin

Cited by 22 publications

References 48 publications

Fibroblast growth factor-23 increases mouse PGE₂production in vivo and in vitro

Fibroblast growth factor-23 increases mouse PGE₂production in vivo and in vitro

Claudins 6, 9, and 13 are developmentally expressed renal tight junction proteins

Maturation of rat proximal tubule chloride permeability

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Correction of proximal tubule phosphate transport defect inHypmicein vivoandin vitrowith indomethacin

Cited by 22 publications

References 48 publications

Fibroblast growth factor-23 increases mouse PGE2production in vivo and in vitro

Fibroblast growth factor-23 increases mouse PGE2production in vivo and in vitro

Claudins 6, 9, and 13 are developmentally expressed renal tight junction proteins

Maturation of rat proximal tubule chloride permeability

Contact Info

Product

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Fibroblast growth factor-23 increases mouse PGE₂production in vivo and in vitro

Fibroblast growth factor-23 increases mouse PGE₂production in vivo and in vitro