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Article: Phosphate transport: molecular basis, regulation and pathophysiology.

Tenenhouse, Harriet S

The Journal of steroid biochemistry and molecular biology

2007 Volume 103, Issue 3-5, Page(s) 572–577

Abstract: Inorganic phosphate (Pi) is fundamental to cellular metabolism and skeletal mineralization. Ingested Pi is absorbed by the small intestine, deposited in bone, and filtered by the kidney where it is reabsorbed and excreted in amounts determined by the ... ...

Abstract	Inorganic phosphate (Pi) is fundamental to cellular metabolism and skeletal mineralization. Ingested Pi is absorbed by the small intestine, deposited in bone, and filtered by the kidney where it is reabsorbed and excreted in amounts determined by the specific needs of the organism. Two distinct renal Na-dependent Pi transporters, type IIa (NPT2a, SLC34A1) and type IIc (NPT2c, SLC34A3), are expressed in brush border membrane of proximal tubular cells where the bulk of filtered Pi is reabsorbed. Both are regulated by dietary Pi intake and parathyroid hormone. Regulation is achieved by changes in transporter protein abundance in the brush border membrane and requires the interaction of the transporter with scaffolding and signaling proteins. The demonstration of hypophosphatemia secondary to decreased renal Pi reabsorption in mice homozygous for the disrupted type IIa gene underscores its crucial role in the maintenance of Pi homeostasis. Moreover, the recent identification of mutations in the type IIc gene in patients with hereditary hypophosphatemic rickets with hypercalciuria attests to the importance of this transporter in Pi conservation and subsequent skeletal mineralization. Two novel Pi regulating genes, PHEX and FGF23, play a role in the pathophysiology of inherited and acquired hypophosphatemic skeletal disorders and studies are underway to define their mechanism of action on renal Pi handling in health and disease.
MeSH term(s)	Animals ; Biological Transport ; Familial Hypophosphatemic Rickets/complications ; Familial Hypophosphatemic Rickets/metabolism ; Familial Hypophosphatemic Rickets/physiopathology ; Fibroblast Growth Factors/biosynthesis ; Humans ; Hypercalciuria/complications ; Hypercalciuria/metabolism ; Hypercalciuria/physiopathology ; Mice ; Mice, Knockout ; Phosphates/metabolism ; Sodium-Phosphate Cotransporter Proteins, Type IIa/genetics
Chemical Substances	Phosphates ; Sodium-Phosphate Cotransporter Proteins, Type IIa ; Fibroblast Growth Factors (62031-54-3)
Language	English
Publishing date	2007-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1049188-0
ISSN	1879-1220 ; 0960-0760
ISSN (online)	1879-1220
ISSN	0960-0760
DOI	10.1016/j.jsbmb.2006.12.090
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Article: Regulation of phosphorus homeostasis by the type iia na/phosphate cotransporter.

Tenenhouse, Harriet S

Annual review of nutrition

2005 Volume 25, Page(s) 197–214

Abstract: The type IIa Na/phosphate (Pi) cotransporter (Npt2a) is expressed in the brush border membrane (BBM) of renal proximal tubular cells where the bulk of filtered Pi is reabsorbed. Disruption of the Npt2a gene in mice elicits hypophosphatemia, renal Pi ... ...

Abstract	The type IIa Na/phosphate (Pi) cotransporter (Npt2a) is expressed in the brush border membrane (BBM) of renal proximal tubular cells where the bulk of filtered Pi is reabsorbed. Disruption of the Npt2a gene in mice elicits hypophosphatemia, renal Pi wasting, and an 80% decrease in renal BBM Na/Pi cotransport, and led to the demonstration that Npt2a is the target for hormonal and dietary regulation of renal Pi reabsorption. Regulation is achieved by changes in BBM abundance of Npt2a protein and requires the interaction of Npt2a with various scaffolding and regulatory proteins. Molecular studies in patients with renal Pi wasting resulted in the identification of novel regulators of Pi homeostasis: fibroblast growth factor-23 (FGF-23) and a phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX). In mouse models, increased FGF-23 production or loss of Phex function causes hypophosphatemia and decreased renal Pi reabsorption, secondary to decreased BBM Npt2a protein abundance. Thus, Npt2a plays a major role in the maintenance of Pi homeostasis in both health and disease.
MeSH term(s)	Absorption ; Animals ; Calcium/metabolism ; Diet ; Homeostasis ; Humans ; Kidney/metabolism ; Mice ; Mice, Knockout ; Parathyroid Hormone/physiology ; Phosphates/administration & dosage ; Phosphates/deficiency ; Phosphorus/metabolism ; Sodium-Phosphate Cotransporter Proteins ; Sodium-Phosphate Cotransporter Proteins, Type IIa ; Symporters/deficiency ; Symporters/genetics ; Symporters/physiology
Chemical Substances	Parathyroid Hormone ; Phosphates ; SLC34A1 protein, human ; Slc34a1 protein, mouse ; Sodium-Phosphate Cotransporter Proteins ; Sodium-Phosphate Cotransporter Proteins, Type IIa ; Symporters ; Phosphorus (27YLU75U4W) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2005
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	406980-8
ISSN	1545-4312 ; 0199-9885
ISSN (online)	1545-4312
ISSN	0199-9885
DOI	10.1146/annurev.nutr.25.050304.092642
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Zs.A 1786: Show issues

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Article ; Online: Nephrolithiasis, osteoporosis, and mutations in the type 2a sodium-phosphate cotransporter.

Scheinman, Steven J / Tenenhouse, Harriet S

The New England journal of medicine

2003 Volume 348, Issue 3, Page(s) 264–5; author reply 264–5

MeSH term(s)	Animals ; Genotype ; Humans ; Hypophosphatemia/genetics ; Kidney Calculi/genetics ; Mice ; Mice, Mutant Strains ; Osteoporosis/genetics ; Phosphates/metabolism ; Point Mutation ; Sodium-Phosphate Cotransporter Proteins ; Symporters/genetics
Chemical Substances	Phosphates ; Sodium-Phosphate Cotransporter Proteins ; Symporters
Language	English
Publishing date	2003-01-16
Publishing country	United States
Document type	Comment ; Letter
ZDB-ID	207154-x
ISSN	1533-4406 ; 0028-4793
ISSN (online)	1533-4406
ISSN	0028-4793
DOI	10.1056/NEJM200301163480319
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Article: Disorders of renal tubular phosphate transport.

Tenenhouse, Harriet S / Murer, Heini

Journal of the American Society of Nephrology : JASN

2002 Volume 14, Issue 1, Page(s) 240–248

MeSH term(s)	Biological Transport ; Humans ; Kidney Diseases/metabolism ; Kidney Tubules/metabolism ; Phosphates/metabolism ; Sodium-Phosphate Cotransporter Proteins ; Structure-Activity Relationship ; Symporters/chemistry ; Symporters/metabolism
Chemical Substances	Phosphates ; Sodium-Phosphate Cotransporter Proteins ; Symporters
Language	English
Publishing date	2002-12-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1097/01.asn.0000045045.47494.71
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Article: 1,25(OH)2D, the preferred substrate for CYP24.

Jones, Glenville / Tenenhouse, Harriet S

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

2002 Volume 17, Issue 1, Page(s) 179–181

MeSH term(s)	Animals ; Calcitriol/metabolism ; Cytochrome P-450 Enzyme System/metabolism ; In Vitro Techniques ; Kidney/enzymology ; Kinetics ; Mice ; Mitochondria/enzymology ; Steroid Hydroxylases/metabolism ; Substrate Specificity ; Vitamin D3 24-Hydroxylase
Chemical Substances	Cytochrome P-450 Enzyme System (9035-51-2) ; Steroid Hydroxylases (EC 1.14.-) ; Vitamin D3 24-Hydroxylase (EC 1.14.15.16) ; Calcitriol (FXC9231JVH)
Language	English
Publishing date	2002-01
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	632783-7
ISSN	1523-4681 ; 0884-0431
ISSN (online)	1523-4681
ISSN	0884-0431
DOI	10.1359/jbmr.2002.17.1.179
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Article: Novel phosphate-regulating genes in the pathogenesis of renal phosphate wasting disorders.

Tenenhouse, Harriet S / Sabbagh, Yves

Pflugers Archiv : European journal of physiology

2002 Volume 444, Issue 3, Page(s) 317–326

Abstract: Over the past decade, three classes of Na/Pi cotransporters have been identified in mammalian kidney. The type IIa Na/Pi cotransporter, Npt2, is the most abundant and is expressed in the brush-border membrane of renal proximal tubular cells where the ... ...

Abstract	Over the past decade, three classes of Na/Pi cotransporters have been identified in mammalian kidney. The type IIa Na/Pi cotransporter, Npt2, is the most abundant and is expressed in the brush-border membrane of renal proximal tubular cells where the bulk of filtered inorganic phosphate (Pi) is reabsorbed. Disruption of the Npt2 gene in mice underscored the importance of Npt2 in the overall maintenance of Pi homeostasis and demonstrated that Npt2 is the target for regulation of proximal tubular Pi reabsorption by parathyroid hormone and dietary Pi. The regulation is post-transcriptional and largely occurs by brush-border membrane retrieval and insertion of Npt2 protein. Of great interest is the recent identification of novel Pi regulating genes, PHEX and FGF23, that play a role in the pathophysiology of inherited (X-linked hypophosphatemia and autosomal dominant hypophosphatemic rickets) and acquired (oncogenic hypophosphatemic rickets) disorders characterized by renal Pi wasting and associated skeletal abnormalities. Studies are currently underway to elucidate the molecular basis for impaired renal Pi reabsorption in these disorders and to determine the precise physiological role of PHEX and FGF-23 in the regulation of Pi homeostasis.
MeSH term(s)	Animals ; Humans ; Hypophosphatemia/etiology ; Hypophosphatemia/genetics ; Hypophosphatemia, Familial/etiology ; Hypophosphatemia, Familial/genetics ; Kidney Diseases/etiology ; Kidney Diseases/genetics ; Sodium-Phosphate Cotransporter Proteins ; Sodium-Phosphate Cotransporter Proteins, Type I ; Sodium-Phosphate Cotransporter Proteins, Type III ; Sodium-Phosphate Cotransporter Proteins, Type IIa ; Symporters/genetics ; Symporters/metabolism
Chemical Substances	SLC17A2 protein, human ; SLC34A1 protein, human ; Sodium-Phosphate Cotransporter Proteins ; Sodium-Phosphate Cotransporter Proteins, Type I ; Sodium-Phosphate Cotransporter Proteins, Type III ; Sodium-Phosphate Cotransporter Proteins, Type IIa ; Symporters
Language	English
Publishing date	2002-06
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	6380-0
ISSN	1432-2013 ; 0031-6768
ISSN (online)	1432-2013
ISSN	0031-6768
DOI	10.1007/s00424-002-0839-4
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Article: Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1alpha-hydroxylase expression in vitro.

Perwad, Farzana / Zhang, Martin Y H / Tenenhouse, Harriet S / Portale, Anthony A

American journal of physiology. Renal physiology

2007 Volume 293, Issue 5, Page(s) F1577–83

Abstract: Fibroblast growth factor-23 (FGF-23) is critical to the pathogenesis of a distinct group of renal phosphate wasting disorders: tumor-induced osteomalacia, X-linked hypophosphatemia, and autosomal dominant and autosomal recessive hypophosphatemic rickets. ...

Abstract	Fibroblast growth factor-23 (FGF-23) is critical to the pathogenesis of a distinct group of renal phosphate wasting disorders: tumor-induced osteomalacia, X-linked hypophosphatemia, and autosomal dominant and autosomal recessive hypophosphatemic rickets. Excess circulating FGF-23 is responsible for their major phenotypic features which include hypophosphatemia due to renal phosphate wasting and inappropriately low serum 1,25(OH)2D concentrations. To characterize the effects of FGF-23 on renal sodium-phosphate (Na/P(i)) cotransport and vitamin D metabolism, we administered FGF-23(R176Q) to normal mice. A single injection (0.33 microg/g body wt) induced significant hypophosphatemia, 20 and 29% decreases (P < 0.001) in brush-border membrane (BBM) Na/Pi cotransport at 5 and 17 h after injection, respectively, and comparable decreases in the abundance of type IIa Na/P(i) cotransporter protein in BBM. Multiple injections (6, 12, and 24 mug/day for 4 days) induced dose-dependent decreases (38, 63, and 75%, respectively) in renal abundance of 1alpha-hydroxylase mRNA (P < 0.05). To determine whether FGF-23(R176Q) exerts a direct action on 1alpha-hydroxylase gene expression, we examined its effects in cultured human (HKC-8) and mouse (MCT) renal proximal tubule cells. FGF-23(R176Q) (1 to 10 ng/ml) induced a dose-dependent decrease in 1alpha-hydroxylase mRNA with a maximum suppression of 37% (P < 0.05). Suppression was detectable after 6 h of exposure and maximal after 21 h. In MCT cells, FGF-23(R176Q) suppressed 1alpha-hydroxylase mRNA and activated the ERK1/2 signaling pathway. The MAPK inhibitor PD98059 effectively abolished FGF-23-induced suppression of 1alpha-hydroxylase mRNA by blocking signal transduction via ERK1/2. These novel findings provide evidence that FGF-23 directly regulates renal 1alpha-hydroxylase gene expression via activation of the ERK1/2 signaling pathway.
MeSH term(s)	25-Hydroxyvitamin D3 1-alpha-Hydroxylase/antagonists & inhibitors ; 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/genetics ; Animals ; Arginine ; Cell Line ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Fibroblast Growth Factors/genetics ; Fibroblast Growth Factors/pharmacology ; Glucuronidase/genetics ; Glutamine ; Humans ; Kidney/metabolism ; MAP Kinase Signaling System/drug effects ; Mice ; Mice, Inbred C57BL ; Microvilli/metabolism ; Phosphorus/blood ; Phosphorus/metabolism ; Protein Isoforms/genetics ; RNA, Messenger/metabolism ; Receptors, Fibroblast Growth Factor/genetics ; Recombinant Proteins/genetics ; Recombinant Proteins/pharmacology ; Steroid Hydroxylases/genetics ; Vitamin D/metabolism ; Vitamin D3 24-Hydroxylase
Chemical Substances	Protein Isoforms ; RNA, Messenger ; Receptors, Fibroblast Growth Factor ; Recombinant Proteins ; fibroblast growth factor 23 ; Glutamine (0RH81L854J) ; Vitamin D (1406-16-2) ; Phosphorus (27YLU75U4W) ; Fibroblast Growth Factors (62031-54-3) ; Arginine (94ZLA3W45F) ; Steroid Hydroxylases (EC 1.14.-) ; 25-Hydroxyvitamin D3 1-alpha-Hydroxylase (EC 1.14.13.13) ; Vitamin D3 24-Hydroxylase (EC 1.14.15.16) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; Glucuronidase (EC 3.2.1.31) ; klotho protein (EC 3.2.1.31)
Language	English
Publishing date	2007-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	603837-2
ISSN	1522-1466 ; 1931-857X ; 0363-6127
ISSN (online)	1522-1466
ISSN	1931-857X ; 0363-6127
DOI	10.1152/ajprenal.00463.2006
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Article ; Online: A missense mutation in the sodium phosphate co-transporter Slc34a1 impairs phosphate homeostasis.

Iwaki, Takayuki / Sandoval-Cooper, Mayra J / Tenenhouse, Harriet S / Castellino, Francis J

Journal of the American Society of Nephrology : JASN

2008 Volume 19, Issue 9, Page(s) 1753–1762

Abstract: The sodium phosphate co-transporters Npt2a and Npt2c play important roles in the regulation of phosphate homeostasis. Slc34a1, the gene encoding Npt2a, resides downstream of the gene encoding coagulation factor XII (f12) and was inadvertently modified ... ...

Abstract	The sodium phosphate co-transporters Npt2a and Npt2c play important roles in the regulation of phosphate homeostasis. Slc34a1, the gene encoding Npt2a, resides downstream of the gene encoding coagulation factor XII (f12) and was inadvertently modified while generating f12(-/-) mice. In this report, the renal consequences of this modification are described. The combined single allelic mutant Slc34a1m contains two point mutations in exon 13: A499V is located in intracellular loop 5, and V528M is located in transmembrane domain 11. In addition to the expected coagulopathy of the f12(-/-) phenotype, mice homozygous for the double allelic modification (f12(-/-)/slc34a1(m/m)) displayed hypophosphatemia, hypercalcemia, elevated levels of alkaline phosphatase, urolithiasis, and hydronephrosis. Strategic cross-breedings demonstrated that the kidney-related pathology was associated only with autosomal recessive transmission of the slc34a1(m) gene and was not influenced by the simultaneous inactivation of f12. Npt2a[V528M] could be properly expressed in opossum kidney cells, but Npt2a[A499V] could not. These results suggest that a single amino acid substitution in Npt2a can lead to improper translocation of the protein to the cell membrane, disturbance of phosphate homeostasis, and renal calcification. Whether point mutations in the SLC34A1 gene can lead to hypophosphatemia and nephrolithiasis in humans remains unknown.
MeSH term(s)	Amino Acid Sequence ; Animals ; Body Weight ; Breeding ; Calcium/blood ; Calcium/urine ; Cell Line ; DNA Mutational Analysis ; Factor XII/genetics ; Factor XII/metabolism ; Female ; Gene Silencing ; Homeostasis ; Hydronephrosis/genetics ; Hydronephrosis/metabolism ; Kidney/pathology ; Kidney Diseases/genetics ; Kidney Diseases/metabolism ; Kidney Diseases/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Molecular Sequence Data ; Mutation, Missense ; Opossums ; Phosphates/blood ; Phosphates/metabolism ; Phosphates/urine ; Profilins/genetics ; Sodium-Phosphate Cotransporter Proteins, Type IIa/genetics ; Sodium-Phosphate Cotransporter Proteins, Type IIa/metabolism ; Urolithiasis/genetics ; Urolithiasis/metabolism
Chemical Substances	Pfn3 protein, mouse ; Phosphates ; Profilins ; Slc34a1 protein, mouse ; Sodium-Phosphate Cotransporter Proteins, Type IIa ; Factor XII (9001-30-3) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2008-06-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2007121360
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Article: 1alpha-Hydroxylase gene ablation and Pi supplementation inhibit renal calcification in mice homozygous for the disrupted Npt2a gene.

Tenenhouse, Harriet S / Gauthier, Claude / Chau, Hien / St-Arnaud, René

American journal of physiology. Renal physiology

2004 Volume 286, Issue 4, Page(s) F675–81

Abstract: Disruption of the major renal Na-phosphate (Pi) cotransporter gene Npt2a in mice leads to a substantial decrease in renal brush-border membrane Na-Pi cotransport, hypophosphatemia, and appropriate adaptive increases in renal 25-hydroxyvitamin D3-1alpha- ... ...

Abstract	Disruption of the major renal Na-phosphate (Pi) cotransporter gene Npt2a in mice leads to a substantial decrease in renal brush-border membrane Na-Pi cotransport, hypophosphatemia, and appropriate adaptive increases in renal 25-hydroxyvitamin D3-1alpha-hydroxylase (1alphaOHase) activity and the serum concentration of 1,25-dihydroxyvitamin D3 [1,25(OH)2D]. The latter is associated with increased intestinal Ca absorption, hypercalcemia, hypercalciuria, and renal calcification in Npt2-/- mice. To determine the contribution of elevated serum 1,25(OH)2D levels to the development of hypercalciuria and nephrocalcinosis in Npt2-/- mice, we examined the effects of 1alphaOHase gene ablation and long-term Pi supplementation on urinary Ca excretion and renal calcification by microcomputed tomography. We show that the urinary Ca/creatinine ratio is significantly decreased in Npt2-/-/1alphaOHase-/- mice compared with Npt2-/- mice. In addition, renal calcification, determined by estimating the calcified volume to total renal volume (CV/TV), is reduced by 80% in Npt2-/-/1alphaOHase-/- mice compared with that in Npt2-/- mice. In Npt2-/- mice derived from dams fed a 1% Pi diet and maintained on the same diet, we observed a significant decrease in urinary Ca/creatinine that was also associated with 80% reduction in CV/TV when compared with counterparts fed a 0.6% diet. Taken together, the present data demonstrate that both 1alphaOHase gene ablation and Pi supplementation inhibit renal calcification in Npt2-/- mice and that 1,25(OH)2D is essential for the development of hypercalciuria and nephrocalcinosis in the mutant strain.
MeSH term(s)	25-Hydroxyvitamin D3 1-alpha-Hydroxylase/genetics ; Animals ; Calcinosis/physiopathology ; Calcitriol/blood ; Calcium/blood ; Calcium/urine ; Female ; Homozygote ; Kidney/pathology ; Kidney/physiopathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Nephrocalcinosis/pathology ; Nephrocalcinosis/physiopathology ; Phosphorus, Dietary/pharmacology ; Sodium-Phosphate Cotransporter Proteins ; Sodium-Phosphate Cotransporter Proteins, Type I ; Sodium-Phosphate Cotransporter Proteins, Type III ; Symporters/genetics
Chemical Substances	Phosphorus, Dietary ; Slc17a2 protein, mouse ; Sodium-Phosphate Cotransporter Proteins ; Sodium-Phosphate Cotransporter Proteins, Type I ; Sodium-Phosphate Cotransporter Proteins, Type III ; Symporters ; 25-Hydroxyvitamin D3 1-alpha-Hydroxylase (EC 1.14.13.13) ; Calcitriol (FXC9231JVH) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2004-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	603837-2
ISSN	1522-1466 ; 1931-857X ; 0363-6127
ISSN (online)	1522-1466
ISSN	1931-857X ; 0363-6127
DOI	10.1152/ajprenal.00362.2003
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Article: Differential regulation of PHEX expression in bone and parathyroid gland by chronic renal insufficiency and 1,25-dihydroxyvitamin D3.

Brewer, Angela J / Canaff, Lucie / Hendy, Geoffrey N / Tenenhouse, Harriet S

American journal of physiology. Renal physiology

2004 Volume 286, Issue 4, Page(s) F739–48

Abstract: Mutations in the PHEX gene are responsible for X-linked hypophosphatemia, a renal phosphate-wasting disorder associated with defective skeletal mineralization. PHEX is predominantly expressed in bones and teeth and in the parathyroid gland of patients ... ...

Abstract	Mutations in the PHEX gene are responsible for X-linked hypophosphatemia, a renal phosphate-wasting disorder associated with defective skeletal mineralization. PHEX is predominantly expressed in bones and teeth and in the parathyroid gland of patients with chronic renal failure and tertiary hyperparathyroidism. The purpose of the present study was to examine the effects of renal insufficiency and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on the regulation of PHEX expression in rat tibia and parathyroid gland. In rats fed a high-phosphate (Pi) diet, nephrectomy elicited a significant increase in the serum parathyroid hormone (PTH) concentration that was associated with a significant increase in the abundance of PHEX mRNA and protein in the tibia and a significant increase in PHEX mRNA in the parathyroid gland. In contrast, 1,25(OH)2D3 administration to intact rats fed a control diet elicited a significant decrease in the serum PTH concentration that was accompanied by a significant decrease in PHEX mRNA and protein abundance in the tibia and a significant decrease in PHEX mRNA in the parathyroid gland. In addition, the increases in serum PTH levels and PHEX mRNA in the tibia and parathyroid gland in nephrectomized rats fed a high-Pi diet were blunted by 1,25(OH)2D3. Serum PTH concentration was positively and significantly correlated with tibial PHEX mRNA and protein abundance. In summary, we demonstrate that PHEX expression in the tibia and parathyroid gland is increased by chronic renal insufficiency and decreased by 1,25(OH)2D3 administration and suggest that PTH status may play an important role in mediating these changes in PHEX expression.
MeSH term(s)	Animals ; Calcitriol/analogs & derivatives ; Calcitriol/pharmacology ; Calcium/blood ; Calcium/urine ; Creatinine/blood ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/physiology ; Kidney Failure, Chronic/physiopathology ; Male ; Nephrectomy ; PHEX Phosphate Regulating Neutral Endopeptidase ; Parathyroid Glands/physiology ; Parathyroid Hormone/blood ; Phosphorus, Dietary/blood ; Phosphorus, Dietary/pharmacology ; Phosphorus, Dietary/urine ; Proteins/genetics ; RNA, Messenger/analysis ; Rats ; Rats, Sprague-Dawley ; Tibia/physiology ; Urea/blood
Chemical Substances	1,25-dihydroxy-18-norvitamin D3 ; Parathyroid Hormone ; Phosphorus, Dietary ; Proteins ; RNA, Messenger ; Urea (8W8T17847W) ; Creatinine (AYI8EX34EU) ; PHEX Phosphate Regulating Neutral Endopeptidase (EC 3.4.24.-) ; Phex protein, rat (EC 3.4.24.-) ; Calcitriol (FXC9231JVH) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2004-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	603837-2
ISSN	1522-1466 ; 1931-857X ; 0363-6127
ISSN (online)	1522-1466
ISSN	1931-857X ; 0363-6127
DOI	10.1152/ajprenal.00321.2003
Database	MEDical Literature Analysis and Retrieval System OnLINE

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