Disorders of Renal Tubular Phosphate Transport

Tenenhouse, Harriet S.; Murer, Heini

doi:10.1097/01.asn.0000045045.47494.71

Cited by 69 publications

(48 citation statements)

References 81 publications

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“…NaPi-IIc protein is maximally upregulated in NaPi-IIa knockout mice and therefore is a candidate for residual sodium -phosphate cotransport in BBMs of NaPi-IIa knockout mice. Its protein abundance is 2.7-fold greater in NaPi-IIa knockout mice than in wild-type littermates (21,22).…”

Section: Discussionmentioning

confidence: 98%

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Recovery of renal tubule phosphate reabsorption despite reduced levels of sodium-phosphate transporter

Friedlaender

Wald²,

Dranitzky-Elhalel³

et al. 2004

European Journal of Endocrinology

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Background: The acute effect of parathyroid hormone (PTH) on phosphate transport has been reported to be mediated by rapid downregulation of sodium-phosphate transporter (NaPi-IIa) protein, but the association was observed with pharmacological doses of PTH. Objective: To explore the effects of physiological doses of PTH on NaPi-IIa protein and its relationship to phosphate transport. Methods: Acute clearance studies were performed in parathyroidectomized rats given a bolus i.v. physiological dose (1 mg) of bovine PTH(1 -34) and NaPi-IIa protein concentrations were examined at different time intervals. Results: Fractional excretion of phosphate increased from 0.031^0.006 (mean^S.E.) to 0.238^0.059 (P , 0.01 compared with baseline and compared with controls) at 40 min and returned to control values by 120 min. Urinary cAMP concentrations were increased at 20 min only. Superficial cortex brush-border membrane (BBM) NaPi-IIa protein was decreased from baseline at both 40 and 120 min (P , 0.01) and did not recover at 240 min (P , 0.01 compared with baseline and compared with controls). Conclusion: These results confirm that PTH, even in physiological dosage, causes a rapid decrease in BBM NaPi-IIa, but subsequent recovery of phosphate reabsorption is poorly correlated with BBM concentrations of NaPi-IIa protein. This suggests that transport mechanisms other than NaPi-IIa are important in renal phosphate reabsorption.

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Section: Discussionmentioning

confidence: 98%

“…It has been proposed that they mediate basolateral phosphate uptake to support cellular energy metabolism. In this regard, they may be viewed as fulfilling a housekeeping function (22). NaPi-IIc, a second renal NaPi-II-related isoform, has been reported in rats and humans.…”

Section: Discussionmentioning

confidence: 99%

Recovery of renal tubule phosphate reabsorption despite reduced levels of sodium-phosphate transporter

Friedlaender

Wald²,

Dranitzky-Elhalel³

et al. 2004

European Journal of Endocrinology

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“…Moreover, TIO is an acquired form of HR, which is caused by a variety of benign primitive mesenchymal tumors that secrete FGF23 (2,7,13). HHRH is a rare hereditary disease and its underlying pathogenesis remains to be elucidated.Several studies of the molecular defects in XLH, ADHR, and TIO support a model of a common pathogenetic mechanism in these three diseases (2,6,14). In this model, FGF23 has been suggested to be the main circulating phosphaturic factor (2,6,14), and the circulating level of FGF23 is determined in part by the rate of its proteolytic cleavage by PHEX protease (9,13,15).…”

mentioning

confidence: 99%

“…In this model, FGF23 has been suggested to be the main circulating phosphaturic factor (2,6,14), and the circulating level of FGF23 is determined in part by the rate of its proteolytic cleavage by PHEX protease (9,13,15). The common abnormality shared by loss-of-function mutations in the PHEX gene (as in XLH), gain-of-function mutations in the FGF23 gene (as in ADHR), and overproduction of FGF23 by tumors (as in TIO) is an elevation of circulating FGF23 (2,(5)(6)(7)(8)13,14). However, current studies (16,17) fail to confirm PHEX-dependent cleavage of FGF23 and suggest that the increased circulating level of FGF23 in XLH reflects, at least in part, an increase in its production (17 …”

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confidence: 99%

A Clinical and Molecular Genetic Study of Hypophosphatemic Rickets in Children

et al. 2005

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X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets, hereditary hypophosphatemic rickets with hypercalciuria, and tumor-induced osteomalacia share clinical and biochemical features, and are collectively referred to as hypophosphatemic rickets (HR). Recently, the molecular bases of HR were elucidated. A review of medical records and mutational analyses of the PHEX and FGF23 genes were performed on 17 unrelated Korean children with HR. The male-to-female ratio was 3:14, and 5 patients were familial. Initial laboratory tests revealed typical features of HR. Seven different PHEX mutations were detected in 8 patients: 2 missense mutations, 2 nonsense mutations, and 3 short deletions. No functional FGF23 mutation was detected in any patient. Patients with the PHEX mutation tended to have more severe skeletal disease than those without. Of the patients with this mutation, no genotype-phenotype correlation and no gene dosage effect were noted. Treatment with vitamin D and phosphate resulted in only a partial growth improvement in most cases, and was frequently complicated by hypercalciuria, hypercalcemia, nephrocalcinosis, or hyperparathyroidism. Renal glycosuria was detected in six cases and was associated with more severe skeletal disease. We conclude that current HR treatment is not fully safe or effective, and that close monitoring of treatment effectiveness and for complications should be performed during long-term treatment.No genotype-phenotype correlation in XLH was detected in this study, but a large-scaled study on this topic is warranted. The large proportion of patients with a normal genetic study suggests the possibility of other causative gene(s HR is defined as a group of rachitic bone diseases associated with chronic hypophosphatemia, which results from defects in the renal tubular reabsorption of filtered phosphate (1-8). Clinically, XLH, ADHR, HHRH, and TIO can be categorized as HR (1-8).XLH is the most common form of hereditary HR (2-6) and is caused by loss-of-function mutations in the PHEX gene (phosphate regulating gene with homologies to endopeptidases on the X chromosome). On the other hand, ADHR is far less common than XLH (2-6), and is associated with a gain-offunction mutation in the FGF23 gene encoding FGF23. The mutant FGF23 molecule is resistant inactivation by proteolytic cleavage (2,(5)(6)(7)(8)(9)(10)(11)(12). Moreover, TIO is an acquired form of HR, which is caused by a variety of benign primitive mesenchymal tumors that secrete FGF23 (2,7,13). HHRH is a rare hereditary disease and its underlying pathogenesis remains to be elucidated.Several studies of the molecular defects in XLH, ADHR, and TIO support a model of a common pathogenetic mechanism in these three diseases (2,6,14). In this model, FGF23 has been suggested to be the main circulating phosphaturic factor (2,6,14), and the circulating level of FGF23 is determined in part by the rate of its proteolytic cleavage by PHEX protease (9,13,15). The common abnormality shared by loss-of-function mutation...

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“…In diseases of phosphorus (P) homeostasis, such as X-linked hypophosphatemia or oncogenic osteomalacia, there is a tremendous renal P loss with severe bone disease (1). In contrast, in chronic renal failure, the P retention leads to secondary hyperparathyroidism with disabling bone disease and vascular calcification associated with a high mortality (2).…”

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confidence: 99%

Calcineurin Aβ Is Central to the Expression of the Renal Type II Na/Pi Co-transporter Gene and to the Regulation of Renal Phosphate Transport

Moz¹,

Levi²,

Lavi-Moshayoff³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. The sensing and response to extracellular phosphate (Pi) concentration is preserved from prokaryotes to mammals and ensures an adequate supply of Pi in the face of large differences in its availability. In mammals, the kidneys are central to Pi homeostasis. Renal Pi reabsorption is mediated by a Na/Pi co-transporter that is regulated by a renal Pi sensing system and humoral factors. The signal transduction by which Pi regulates type II Na/Pi activity is largely unknown. It is shown that calcineurin inhibitors specifically and dramatically decrease type II Na/Pi gene expression in a proximal tubule cell line and in vivo. Mice with genetic deletion of the calcineurin A␤ gene had a marked decrease in type II Na/Pi mRNA levels and remarkably did not show the expected increase in type II Na/Pi mRNA levels after the challenge of a low-Pi diet. In contrast, the regulation of renal 25(OH)-vitamin D 1␣-hydroxylase gene expression by Pi was intact. This is the first demonstration that calcineurin has a crucial role in the signal transduction pathway regulating renal Pi homeostasis both in vitro and in vivo. These results suggest that the use of calcineurin inhibitors contributes to the renal Pi wasting seen in renal transplant patients.Phosphate (Pi) homeostasis is essential to life and is dependent on active renal reabsorption. In diseases of phosphorus (P) homeostasis, such as X-linked hypophosphatemia or oncogenic osteomalacia, there is a tremendous renal P loss with severe bone disease (1). In contrast, in chronic renal failure, the P retention leads to secondary hyperparathyroidism with disabling bone disease and vascular calcification associated with a high mortality (2). The kidney has an intrinsic P sensing system that regulates the activity of apical brush border membrane type II Na/Pi co-transporters (3). However, it is still not known how the organism senses changes in serum P.There are three mammalian Na/Pi co-transporter families: types I through III. Type II Na/Pi activity is responsible for Ͼ80% of renal P reabsorption and contains three isoforms-IIa through c-of which IIa is the major factor in renal P reabsorption and regulation in adult mice (4). Type II Na/Pi activity is increased by a low serum P and decreased by parathyroid hormone (PTH) and FGF23 (4 -8). The regulation of type II Na/Pi is at the level of recruitment of new transporters to the apical proximal tubule membrane, the level of synthesis of new transporters and their breakdown (5,9). In addition, there is regulation at the level of type II Na/Pi gene expression, which in vivo is mainly posttranscriptional (10,11). In the rat, a cis acting element in the type II Na/Pi co-transporter (Na/Pi-2) mRNA at the junction of the coding region and the 3'-untranslated region (UTR) interacts with trans acting renal cytosolic proteins and determines Na/Pi-2 mRNA stability in response to dietary P restriction (12). An additional level of regulation of Na/Pi-2 is its translational control by a low-P diet (10).The renal type II Na/Pi co-transporte...

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Disorders of Renal Tubular Phosphate Transport

Cited by 69 publications

References 81 publications

Recovery of renal tubule phosphate reabsorption despite reduced levels of sodium-phosphate transporter

Recovery of renal tubule phosphate reabsorption despite reduced levels of sodium-phosphate transporter

A Clinical and Molecular Genetic Study of Hypophosphatemic Rickets in Children

Calcineurin Aβ Is Central to the Expression of the Renal Type II Na/Pi Co-transporter Gene and to the Regulation of Renal Phosphate Transport

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