Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

Language：English   Publishing type：Research paper (scientific journal)   Participation form：Joint(The vice charge)  

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The role of Na+-dependent inorganic phosphate (Pi) transporters in the human kidney is not fully clarified. Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is caused by loss-of-function mutations in the IIc Na+-dependent Pi transporter (NPT2c/Npt2c/NaPi-IIc) gene. Another Na+-dependent type II transporter, (NPT2A/Npt2a/NaPi-IIa), is also important for renal Pi reabsorption in humans. In mice, Npt2c deletion does not lead to hypophosphatemia and rickets because Npt2a compensates for the impaired Pi reabsorption. To clarify the differences between mouse and human, we investigated the relation between NaPi-IIa and NaPi-IIc functions in opossum kidney (OK) cells. METHODS: We cloned NaPi-IIc from OK cells and created opossum NaPi-IIc (oNaPi-IIc) antibodies. We used oNaPi-IIc small interference (si)RNA and investigated the role of NaPi-IIc in Pi transport in OK cells. RESULTS: We cloned opossum kidney NaPi-IIc cDNAs encoding 622 amino acid proteins (variant1) and examined their pH- and sodium-dependency. The antibodies reacted specifically with 75-kDa and 150-kDa protein bands, and the siRNA of NaPi-IIc markedly suppressed endogenous oNaPi-IIc in OK cells. Treatment with siRNA significantly suppressed the expression of NaPi-4 (NaPi-IIa) protein and mRNA. oNaPi-IIc siRNA also suppressed Na+/H+ exchanger regulatory factor 1 expression in OK cells. CONCLUSION: These findings suggest that NaPi-IIc is important for the expression of NaPi-IIa (NaPi-4) protein in OK cells. Suppression of Npt2c may downregulate Npt2a function in HHRH patients.

DOI： 10.1007/s10157-018-1653-4

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Participation form：Joint(The vice charge)  

DOI： 10.1007/s00424-018-2204-2

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Inorganic phosphate (Pi) secretion from the salivary glands and dietary Pi are key Pi sources. The regulatory mechanisms of Pi homeostasis in the salivary glands are unknown. We investigated how salivary Pi concentrations are regulated by dietary Pi in mouse models. Dietary manipulation significantly changed the levels of Npt2b protein in the salivary gland ductal cells. In addition, rapid feeding on a high-Pi diet increased the saliva Pi concentrations and led to rapid endocytosis of Npt2b in the apical membranes of the duct cells. Global Npt2b± mice exhibited increased salivary Pi concentrations and intestine-specific deletion of Npt2b after high Pi loading increased the salivary Pi concentrations. These findings indicate that Npt2b levels in the salivary glands affect the salivary Pi concentration and are regulated by dietary Pi. Intestinal Npt2b levels might also affect salivary Pi concentrations as well as renal Pi excretion. These findings suggest Pi is endogenously recycled by salivary Pi secretion, intestinal Pi absorption, and renal Pi excretion.

DOI： 10.1007/s00424-018-2242-9

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Language：English   Publishing type：Research paper (scientific journal)   Participation form：Joint(The vice charge)  

Language：English   Publishing type：Research paper (scientific journal)   Participation form：Joint(The vice charge)  

Language：English   Publishing type：Research paper (scientific journal)  

X-linked hypophosphatemia (XLH), the most common form of inheritable rickets, is caused by inactivation of phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and leads to fibroblast growth factor (FGF) 23-dependent renal inorganic phosphate (Pi) wasting. In the present study, we investigated whether maintaining Pi homeostasis with a potent vitamin D3 analog, eldecalcitol [1α,25-dihydroxy-2β-(3-hydroxypropyloxy) vitamin D3; ED71], could improve hypophosphatemic rickets in a murine model of XLH, the Hyp mouse. Vehicle, ED71, or 1,25-dihydroxyvitamin D was subcutaneously injected five times weekly in wild-type (WT) and Hyp mice for 4 weeks, from 4 to 8 weeks of age. Injection of ED71 into WT mice suppressed the synthesis of renal 1,25-dihydroxyvitamin D and promoted phosphaturic activity. In contrast, administration of ED71 to Hyp mice completely restored renal Pi transport and NaPi-2a protein levels, although the plasma-intact FGF23 levels were further increased. In addition, ED71 markedly increased the levels of the scaffold proteins, renal sodium-hydrogen exchanger regulatory factor 1, and ezrin in the Hyp mouse kidney. Treatment with ED71 increased the body weight and improved hypophosphatemia, the bone volume/total volume, bone mineral content, and growth plate structure in Hyp mice. Thus, ED71 causes FGF23 resistance for phosphate reabsorption and improves rachitic bone phenotypes in Hyp mice. In conclusion, ED71 has opposite effects on phosphate homeostasis in WT and Hyp mice. Analysis of Hyp mice treated with ED71 could result in an additional model for elucidating PHEX abnormalities.

DOI： 10.1210/en.2018-00109

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

Background: Hyperphosphatemia is common in chronic kidney disease and is associated with morbidity and mortality. The intestinal Na+-dependent phosphate transporter Npt2b is thought to be an important molecular target for the prevention of hyperphosphatemia. The role of Npt2b in the net absorption of inorganic phosphate (Pi), however, is controversial. Methods: In the present study, we made tamoxifen-inducible Npt2b conditional knockout (CKO) mice to analyze systemic Pi metabolism, including intestinal Pi absorption. Results: Although the Na+-dependent Pi transport in brush-border membrane vesicle uptake levels was significantly decreased in the distal intestine of Npt2b CKO mice compared with control mice, plasma Pi and fecal Pi excretion levels were not significantly different. Data obtained using the intestinal loop technique showed that Pi uptake in Npt2b CKO mice was not affected at a Pi concentration of 4 mM, which is considered the typical luminal Pi concentration after meals in mice. Claudin, which may be involved in paracellular pathways, as well as claudin-2, 12, and 15 protein levels were significantly decreased in the Npt2b CKO mice. Thus, Npt2b deficiency did not affect Pi absorption within the range of Pi concentrations that normally occurs after meals. Conclusion: These findings indicate that abnormal Pi metabolism may also be involved in tight junction molecules such as Cldns that are affected by Npt2b deficiency.

DOI： 10.1007/s10157-017-1497-3

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Circulating inorganic phosphate exhibits a remarkable daily oscillation based on food intake. In humans and rodents, the daily oscillation in response to food intake may be coordinated to control the intestinal absorption, renal excretion, cellular shifts, and extracellular concentration of inorganic phosphate. However, mechanisms regulating the resulting oscillation are unknown. Here we investigated the roles of the sodium phosphate cotransporter SLC34 (Npt2) family and nicotinamide phosphoribosyltransferase (Nampt) in the daily oscillation of plasma inorganic phosphate levels. First, it is roughly linked to urinary inorganic phosphate excretion. Second, expression of renal Npt2a and Npt2c, and intestinal Npt2b proteins also exhibit a dynamic daily oscillation. Analyses of Npt2a, Npt2b, and Npt2c knockout mice revealed the importance of renal inorganic phosphate reabsorption and cellular inorganic phosphate shifts in the daily oscillation. Third, experiments in which nicotinamide and a specific Nampt inhibitor (FK866) were administered in the active and rest phases revealed that the Nampt/NAD+ system is involved in renal inorganic phosphate excretion. Additionally, for cellular shifts, liver-specific Nampt deletion disturbed the daily oscillation of plasma phosphate during the rest but not the active phase. In systemic Nampt+/− mice, NAD levels were significantly reduced in the liver, kidney, and intestine, and the daily oscillation (active and rest phases) of the plasma phosphate concentration was attenuated. Thus, the Nampt/NAD+ system for Npt2 regulation and cellular shifts to tissues such as the liver play an important role in generating daily oscillation of plasma inorganic phosphate levels.

DOI： 10.1016/j.kint.2017.11.022

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Participation form：Joint(The main charge)  

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIMS: Hyperphosphatemia is a serious complication of late-stage chronic kidney disease (CKD). Intestinal inorganic phosphate (Pi) handling plays an important role in Pi homeostasis in CKD. We investigated whether intestinal alkaline phosphatase 3 (Akp3), the enzyme that hydrolyzes dietary Pi compounds, is a target for the treatment of hyperphosphatemia in CKD. METHODS: We investigated Pi homeostasis in Akp3 knockout mice (Akp3-/-). We also studied the progression of renal failure in an Akp3-/- mouse adenine treated renal failure model. Plasma, fecal, and urinary Pi and Ca concentration were measured with commercially available kit, and plasma fibroblast growth factor 23, parathyroid hormone, and 1,25(OH)2D3 concentration were measured with ELISA. Brush border membrane vesicles were prepared from mouse intestine using the Ca2+ precipitation method and used for Pi transport activity and alkaline phosphatase activity. In vivo intestinal Pi absorption was measured with oral 32P administration. RESULTS: Akp3-/- mice exhibited reduced intestinal type II sodium-dependent Pi transporter (Npt2b) protein levels and Na-dependent Pi co-transport activity. In addition, plasma active vitamin D levels were significantly increased in Akp3-/- mice compared with wild-type animals. In the adenine-induced renal failure model, Akp3 gene deletion suppressed hyperphosphatemia. CONCLUSION: The present findings indicate that intestinal Akp3 deletion affects Na+-dependent Pi transport in the small intestine. In the adenine-induced renal failure model, Akp3 is predicted to be a factor contributing to suppression of the plasma Pi concentration.

DOI： 10.1159/000493379

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Participation form：Joint(The main charge)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：FRONTIERS MEDIA SA  

In response to kidney damage, osteocytes increase the production of several hormones critically involved in mineral metabolism. Recent studies suggest that osteocyte function is altered very early in the course of chronic kidney disease. In the present study, to clarify the role of osteocytes and the canalicular network in mineral homeostasis, we performed four experiments. In Experiment 1, we investigated renal and intestinal Pi handling in osteocyte-less (OCL) model mice [transgenic mice with the dentin matrix protein-1 promoter-driven diphtheria toxin (DT)-receptor that were injected with DT]. In Experiment 2, we administered granulocyte colony-stimulating factor to mice to disrupt the osteocyte canalicular network. In Experiment 3, we investigated the role of osteocytes in dietary Pi signaling. In Experiment 4, we analyzed gene expression level fluctuations in the intestine and liver by comparing mice fed a high Pi diet and OCL mice. Together, the findings of these experiments indicate that osteocyte ablation caused rapid renal Pi excretion (P < 0.01) before the plasma fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) levels increased. At the same time, we observed a rapid suppression of renal Klotho (P < 0.01), type II sodium phosphate transporters Npt2a (P < 0.01) and Npt2c (P < 0.05), and an increase in intestinal Npt2b (P < 0.01) protein. In OCL mice, Pi excretion in feces was markedly reduced (P < 0.01). Together, these effects of osteocyte ablation are predicted to markedly increase intestinal Pi absorption (P < 0.01), thus suggesting that increased intestinal Pi absorption stimulates renal Pi excretion in OCL mice. In addition, the ablation of osteocytes and feeding of a high Pi diet affected FGF15/bile acid metabolism and controlled Npt2b expression. In conclusion, OCL mice exhibited increased renal Pi excretion due to enhanced intestinal Pi absorption. We discuss the role of FGF23-Klotho on renal and intestinal Pi metabolism in OCL mice.

DOI： 10.3389/fendo.2017.00359

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Language：English   Publishing type：Research paper (scientific journal)   Participation form：Joint(The vice charge)  

Language：English   Publisher：SPRINGER  

The prevention and correction of hyperphosphatemia are major goals of the treatment of chronic kidney disease (CKD)-bone mineral disorders, and thus, Pi balance requires special attention. Pi balance is maintained by intestinal absorption, renal excretion, and bone accretion. The kidney is mainly responsible for the plasma Pi concentration. In CKD, reduced glomerular filtration rate leads to various Pi metabolism abnormalities, and Pi absorption in the small intestine also has an important role in Pi metabolism. Disturbances in Pi metabolism are mediated by a series of complex changes in regulatory hormones originating from the skeleton, intestine, parathyroid gland, and kidney. In this review, we describe the regulation of type II sodium-dependent Pi co-transporters by the kidney and intestine, including the regulation of Pi transport, circadian rhythm, and the vicious circle between salivary Pi secretion and intestinal Pi absorption in animals with and without CKD.

DOI： 10.1007/s10157-016-1359-4

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Language：English   Publishing type：Part of collection (book)   Publisher：Elsevier Inc.  

The sodium-dependent phosphate cotransporter (NaPi) family plays a critical role in Pi homeostasis in mammals via several mechanisms, including renal tubular reabsorption, intestinal absorption, and exchange with intracellular or bone storage. The type II NaPi transport family (SLC34) is especially important for renal and intestinal Pi handling. SLC34 protein dysfunction causes several abnormalities, such as hypophosphatemic hereditary rickets/osteomalacia and hyperphosphatemia-induced vascular disease. Expression of SLC34 family members is regulated at several steps, including transcription, translation, protein degradation, and cellular trafficking. Both hormonal (1,25-dihydroxyvitamin D3, fibroblast growth factor 23, estrogen, T3, and epidermal growth factor) and nonhormonal (dietary Pi, Ca, and vitamin A) factors regulate the transcriptional step. Here, we describe the transcriptional regulation of the SLC34 genes in the small intestine and kidney.

DOI： 10.1016/B978-0-12-802168-2.00036-1

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Language：Japanese   Publisher：The Japanese Pharmacological Society  

DOI： 10.1254/fpj.147.84

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CiNii Books

Other Link： https://jlc.jst.go.jp/DN/JLC/20020492838?from=CiNii

Language：English   Publisher：SPRINGER JAPAN KK  

In this review, we focus on the interconnection of inorganic phosphate (Pi) homeostasis in the network of the bone-kidney, parathyroid-kidney, intestine-kidney, and liver-kidney axes. Such a network of organ communication is important for body Pi homeostasis. Normalization of serum Pi levels is a clinical target in patients with chronic kidney disease (CKD). Particularly, disorders of the fibroblast growth factor 23/klotho system are observed in early CKD. Identification of phosphaturic factors from the intestine and liver may enhance our understanding of body Pi homeostasis and Pi metabolism disturbances in CKD patients.

DOI： 10.1007/s00774-015-0705-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：University of Tokushima  

NaPi-IIc/SLC34A3 is a sodium-dependent inorganic phosphate (Pi) transporter in the renal proximal tubules and its mutations cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). In the present study, we created a specific antibody for opossum SLC34A3, NaPi-IIc (oNaPi-IIc), and analyzed its localization and regulation in opossum kidney cells (a tissue culture model of proximal tubular cells). Immunoreactive oNaPi-IIc protein levels increased during the proliferative phase and decreased during differentiation. Moreover, stimulating cell growth upregulated oNaPi-IIc protein levels, whereas suppressing cell proliferation downregulated oNaPi-IIc protein levels. Immunocytochemistry revealed that endogenous and exogenous oNaPi-IIc proteins localized at the protrusion of the plasma membrane, which is a phosphatidylinositol 4,5-bisphosphate (PIP2) rich-membrane, and at the intracellular vacuolar membrane. Exogenous NaPi-IIc also induced cellular vacuoles and localized in the plasma membrane. The ability to form vacuoles is specific to electroneutral NaPi-IIc, and not electrogenic NaPi-IIa or NaPi-IIb. In addition, mutations of NaPi-IIc (S138F and R468W) in HHRH did not cause cellular PIP2-rich vacuoles. In conclusion, our data anticipate that NaPi-IIc may regulate PIP2 production at the plasma membrane and cellular vesicle formation.

DOI： 10.2152/jmi.62.209

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Language：English   Publishing type：Research paper (scientific journal)   Participation form：Joint(The vice charge)  

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：CENTER ACADEMIC PUBL JAPAN  

Chronic kidney disease (CKD) is an increasing problem worldwide. The number of end-stage renal disease patients requiring treatment by dialysis is estimated to be increasing by 10,000 patients per year in Japan. Furthermore, an estimated 13 million people are living with CKD in Japan. Various complications are associated with CKD, including cardiovascular disease (CVD). More than one-third of CKD patients die from CVD. Thus, prevention of CVD is a primary concern for the treatment of CKD patients. CKD-mineral and bone disorder (CKD-MBD) is a serious complication that typically leads to CVD. Hyperphosphatemia is thought to be a central-risk factor for CKD-MBD. Therefore, managing hyperphosphatemia is crucial to prevent CKD-MBD and CVD. It is difficult to achieve the target serum phosphate level through dietary modifications alone in patients with hyperphosphatemia, because most foods contain phosphate. Thus, phosphate binders such as calcium carbonate are commonly prescribed to CKD patients with hyperphosphatemia, but these have undesirable side effects. Inhibition of intestinal phosphate transport activity has also been investigated as an alternative approach for controlling serum phosphate levels in CKD patients. Nicotinamide, which is the amide of niacin, can inhibit intestinal phosphate transport. Niacin and related compounds have also been developed as drugs for hyperlipidemia conditions, especially hypertriglyceridemia with low high-density lipoprotein. This type of dyslipidemia is frequently observed in CKD patients and is a modifiable risk factor for CVD. Thus, niacin and related compounds may have utility for the treatment of both hyperphosphatemia and dyslipidemia in CKD patients to prevent CVD.

DOI： 10.3177/jnsv.61.S173

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Participation form：Joint(The vice charge)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Itai-itai disease is thought to be the result of chronic cadmium (Cd) intoxication. Renal proximal tubules are a major target of Cd toxicity. The whole mechanism of the adverse effects of Cd remains unresolved, especially how renal damage is related to the development of bone lesions. Fibroblast growth factor 23 (FGF23) is a bone-derived phosphaturic factor that regulates vitamin D and inorganic phosphate metabolism in the kidney. To clarify the role of FGF23 on Cd toxicity, we investigated the mechanisms of Cd-induced FGF23 production in the bone. Cd injection into mice significantly increased plasma FGF23 concentrations, but did not change FGF23 mRNA expression in bone. GalNAc-T3 is involved in secreting intact FGF23. To determine potential roles of GalNAc-T3 in Cd-induced FGF23 production, we examined the effect of Cd on GalNAc-T3 mRNA expression in vivo and in vitro. GalNAc-T3 gene expression was significantly increased in the bones of Cd-injected mice. Cd also enhanced the expression of GalNAc-T3 in cultured osteosarcoma UMR106 cells and primary osteocytes. Cd activated aryl hydrocarbon receptors (AhR) and AhR were required for GalNAc-T3 gene expression induced by Cd. In addition, Cd-dependent FGF23 production was completely inhibited by an AhR antagonist. AhR siRNA markedly suppressed the stimulation of transcriptional activity by Cd. Furthermore, Cd induced AhR activation via phosphorylation of Ser-68 by p38 kinase in the nuclear export signal of AhR. Thus, Cd stimulated GalNAc-T3 gene transcription via enhanced AhR binding to the GalNAc-T3 promoter. These findings suggest that the Cd-induced increase in GalNAc-T3 suppresses proteolytic processing of FGF23 and increases serum FGF23 concentrations.

DOI： 10.1093/toxsci/kfu043

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC NEPHROLOGY  

Marked hypophosphatemia is common after major hepatic resection, but the pathophysiologic mechanism remains unknown. We used a partial hepatectomy (PH) rat model to investigate the molecular basis of hypophosphatemia. PH rats exhibited hypophosphatemia and hyperphosphaturia. In renal and intestinal brush-border membrane vesicles isolated from PH rats, Na+-dependent phosphate (Pi) uptake decreased by 50%-60%. PH rats also exhibited significantly decreased levels of renal and intestinal Na+-dependent Pi transporter proteins (NaPi-IIa [NaPi-4], NaPi-IIb, and NaPi-IIc). Parathyroid hormone was elevated at 6 hours after PH. Hyperphosphaturia persisted, however, even after thyroparathyroidectomy in PH rats. Moreover, DNA microarray data revealed elevated levels of nicotinamide phosphoribosyltransferase (Nampt) mRNA in the kidney after PH, and Nampt protein levels and total NAD concentration increased significantly in the proximal tubules. PH rats also exhibited markedly increased levels of the Nampt substrate, urinary nicotinamide (NAM), and NAM catabolites. In vitro analyses using opossum kidney cells revealed that NAM alone did not affect endogenous NaPi-4 levels. However, in cells overexpressing Nampt, the addition of NAM led to a marked decrease in cell surface expression of NaPi-4 that was blocked by treatment with FK866, a specific Nampt inhibitor. Furthermore, FK866-treated mice showed elevated renal Pi reabsorption and hypophosphaturia. These findings indicate that hepatectomy-induced hypophosphatemia is due to abnormal NAM metabolism, including Nampt activation in renal proximal tubular cells.

DOI： 10.1681/ASN.2013060569

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：University of Tokushima  

Dietary inorganic phosphate (Pi) is the most important factor in the regulation of renal Pi excretion. Recent studies suggest the presence of an enteric-renal signaling axis for dietary Pi as well as the existence of a mechanism by which the intestine detects changes in luminal Pi concentrations. The mechanisms of intestinal Pi sensing, however, are unknown. In the present study, we focused on Pi depletion signals and investigated the effects of dietary components on intestinal Pi sensing. After feeding rats experimental diets for 3 days, we investigated urinary Pi excretion and plasma biochemical parameters. Renal Pi excretion was suppressed in rats fed a low-Pi diet (0.02% Pi). Elimination of dietary calcium (Ca) completely blocked the suppression of Pi excretion, suggesting that the presence of Ca is essential for the Pi depletion signal. Furthermore, a minimum Ca content of more than 0.02% was necessary for the Pi depletion signal. Magnesium, lanthanum, and strontium, which are agonists of calcium sensing receptor, instead of Ca, reduced Pi excretion. Therefore, dietary Ca appears to be important for the Pi depletion-sensing mechanism in the gastrointestinal tract. In addition, the calcium sensing receptor may be involved in the Pi depletion signal.

DOI： 10.2152/jmi.61.162

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PubMed

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Language：English   Publishing type：Research paper (scientific journal)   Participation form：Joint(The vice charge)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：F HERNANDEZ  

The purpose of this study was to examine histological alterations on osteoblasts from the alveolar bone of transgenic mice with targeted ablation of osteoctyes. Eighteen weeks-old transgenic mice based on the diphtheria toxin (DT) receptor-mediated cell knockout (TRECK) system were used in these experiments. Mice were injected intraperitoneally with 50 mu g/kg of DT in PBS, or only PBS as control. Two weeks after injections, mice were subjected to transcardiac perfusion with 4% paraformaldehyde in 0.1M phosphate buffer (pH 7.4), and the available alveolar bone was removed for histochemical analyses. Approximately 75% of osteocytes from alveolar bones became apoptotic after DT administration, and most osteocytic lacunae became empty. Osteoblastic numbers and alkaline phosphatase (ALP) activity were markedly reduced at the endosteum of alveolar bone after DT administration compared with the control. Osteoblastic ALP activity in the periodontal ligament region, on the other hand, hardly showed any differences between the two groups even though numbers were reduced in the experiment group. Silver impregnation showed a difference in the distribution of bone canaliculi between the portions near the endosteum and the periodontal ligament: the former appeared regularly arranged in contrast to the latter's irregular distribution. Under transmission electron microscopy (TEM), the osteoblasts in the periodontal ligament showed direct contact with the Sharpey's fibers. Thus, osteoblastic activity was affected by osteocyte ablation in general, but osteoblasts in contact with the periodontal ligament were less affected than endosteal osteoblasts.

DOI： 10.14670/HH-28.327

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

The type II sodium-dependent Pi (NaPi) cotransporters (NaPi-IIa, NaPi-IIb and NaPi-IIc) contribute to renal and intestinal Pi absorption. 1,25-Dihydroxyvitamin D [1,25(OH)(2)D-3] is an important factor for NaPi-II transporters in the small intestine and kidney. In a previous study, low levels of 1,25(OH)(2)D-3 appeared to suppress the expression of renal NaPi cotransporters. We identified a functional vitamin D receptor-responsive element in the human NaPi-IIa and NaPi-lIc genes in renal epithelial cells. In an analysis of vitamin D receptor (VDR)-null mice, we observed early onset of hypophosphatemia. The cause of the hypophosphatemia in VDR-null mice before weaning appeared to be increased plasma parathyroid hormone (PTH) levels during the suckling periods. A rescue diet (high calcium diet) decreased plasma PTH levels in VDR-null mice. The reduced plasma PTH levels normalized the renal Npt2a and Npt2c protein levels in weanling animals. Thus, the dietary intervention completely normalized the expression of the renal Pi transporters (Npt2a/Npt2c) in VDR-null mice, suggesting that the lack of VDR activity was not the cause of the impaired renal Pi reabsorption. In suckling animals, 1,25(OH)(2)D-3 may be essential for the prevention of the phosphaturic action of PTH. In adult animals, 1,25(OH)(2)D-3 is thought to be an important factor for posttranscriptional regulation of the Npt2b gene in the small intestine. Fibroblast growth factor 23 (FGF23) is a novel phosphaturic factor that influences vitamin D metabolism and renal reabsorption of Pi. We characterized the role of the VDR in the action of FGF23 using VDR-null mice. FGF23 reduced renal Pi transport and 25-hydroxyvitamin D 1a-hydroxylase levels by a mechanism that was independent of the VDR. By contrast, the induction of 25-hydroxyvitamin D 24-hydroxylase and the reduction in serum 1,25(OH)(2)D-3 levels induced by FGF23 were dependent on the VDR. Thus, the VDR is not essential for the phosphaturic action of FGF23, but is essential for control of the plasma 1,25(OH)(2)D-3 level. Moreover, FGF23 reduces intestinal NaPi transport activity and Npt2b protein levels by a mechanism that is dependent on the VDR. Klotho functions as a co-receptor for FGF23 and is increased by 1,25(OH)(2)D-3. Klotho induces phosphaturia by inhibiting the renal NaPi-Ila transporter. In this review, we discuss the roles of 1,25(OH)(2)D-3/VDR in the regulation of renal type II NaPi cotransporters in the kidney and small intestine. Copyright (C) 2013 S. Karger AG, Basel

DOI： 10.1159/000346786

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PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)  

Hyperphosphatemia is a common disorder in patients with chronic kidney disease (CKD) , and may result in hyperparathyroidism and renal osteodystrophy. Hyperphosphatemia also may contribute to deterioration vascular calcification and increase mortality. Hence, correction and prevention of hyperphosphatemia is a main component of the management of CKD. This goal is usually approached both by administering phosphorus binders and by restricting dietary phosphorus (P) intake. Dietary intake of phosphorus (P) is derived largely from foods with high protein content or food additives and is an important determinant of P balance in patient with CKD. Food additives (PO4) can dramatically increase the amount of P consumed in the daily diet, especially because P is more readily absorbed in its inorganic form. In addition, information about the P content and type in prepared foods is often unavailable or misleading. Therefore, during dietary counseling of patients with CKD, we recommended that they consider both the absolute dietary P content and the P-to-protein ratio of foods and meals including food additives.

PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)  

Inorganic phosphate (Pi) is an essential nutrient for several biological functions, including intracellular signal transduction, the production and function of cell membranes, and energy exchange. To achieve these functions, a transport system is required to transfer Pi across hydrophobic cell membranes. Pi (re) absorption in the small intestine and renal proximal tubules is important for Pi homeostasis. Three types of NaPi transporters (types I - III ) have been identified : solute carrier series SLC17A1 (NPT1/NaPi- I /OATv1) , SLC34 (NaPi- II a, NaPi- II b, NaPi- II c) , and SLC20 (PiT1, PiT2) , respectively. In this review, we discuss the role of NaPi transporters in Pi homeostasis.

PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)  

Small intestine plays an important role in the sensing of various nutrients. There is information that would imply the existence of a dietary phosphate sensing mechanism within the intestine. Recent studies suggest that intestinal factors may involve in the alteration of renal phosphate transport. The elucidation of the phosphate sensing mechanism is expected to provide molecular basis for the prevention of the hyperphosphatemia in chronic kidney disease patients.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHYSIOLOGICAL SOC  

Haito-Sugino S, Ito M, Ohi A, Shiozaki Y, Kangawa N, Nishiyama T, Aranami F, Sasaki S, Mori A, Kido S, Tatsumi S, Segawa H, Miyamoto K. Processing and stability of type IIc sodium-dependent phosphate cotransporter mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria. Am J Physiol Cell Physiol 302: C1316-C1330, 2012. First published December 7, 2012; doi:10.1152/ajpcell.00314.2011.-Mutations in the apically located Na+-dependent phosphate (NaPi) cotransporter, SLC34A3 (NaPi-IIc), are a cause of hereditary hypophosphatemic rickets with hypercalciuria (HHRH). We have characterized the impact of several HHRH mutations on the processing and stability of human NaPi-IIc. Mutations S138F, G196R, R468W, R564C, and c. 228delC in human NaPi-IIc significantly decreased the levels of NaPi cotransport activities in Xenopus oocytes. In S138F and R564C mutant proteins, this reduction is a result of a decrease in the V-max for P-i, but not the K-m. G196R, R468W, and c. 228delC mutants were not localized to oocyte membranes. In opossum kidney (OK) cells, cell surface labeling, microscopic confocal imaging, and pulse-chase experiments showed that G196R and R468W mutations resulted in an absence of cell surface expression owing to endoplasmic reticulum (ER) retention. G196R and R468W mutants could be partially stabilized by low temperature. In blue native-polyacrylamide gel electrophoresis analysis, G196R and R468W mutants were either denatured or present in an aggregation complex. In contrast, S138F and R564C mutants were trafficked to the cell surface, but more rapidly degraded than WT protein. The c. 228delC mutant did not affect endogenous NaPi uptake in OK cells. Thus, G196R and R468W mutations cause ER retention, while S138F and R564C mutations stimulate degradation of human NaPi-IIc in renal epithelial cells. Together, these data suggest that the NaPi-IIc mutants in HHRH show defective processing and stability.

DOI： 10.1152/ajpcell.00314.2011

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Language：English   Publishing type：Research paper (scientific journal)  

Mutations in the SLC34A3 gene, a sodium-dependent inorganic phosphate (Pi) cotransporter, also referred to as NaPi IIc, causes hereditary hypophosphatemic rickets with hypercalciuria (HHRH), an autosomal recessive disorder. In human and rodent, NaPi IIc is mainly localized in the apical membrane of renal proximal tubular cells. In this study, we identified mouse NaPi IIc variant (Npt2c-v1) that lacks the part of the exon 3 sequence that includes the assumed translation initiation site of Npt2c. Microinjection of mouse Npt2c-v1 cRNA into Xenopus oocytes demonstrated that Npt2c-v1 showed sodium-dependent Pi cotransport activity. The characterization of pH dependency showed activation at extracellular alkaline-pH. Furthermore, Npt2c-v1 mediated Pi transport activity was significantly higher at any pH value than those of Npt2c. In an in vitro study, the localization of the Npt2c-v1 protein was detected in the apical membrane in opossum kidney cells. The expression of Npt2c-v1 mRNA was detected in the heart, spleen, testis, uterus, placenta, femur, cerebellum, hippocampus, diencephalon and brain stem of mouse. Using mouse bone primary cultured cells, we showed the expression of Npt2c-v1 mRNA. In addition, the Npt2c protein was detected in the spermatozoa head. Thus, Npt2c-v1 was expressed in extra-renal tissues such as epididymal spermatozoa and may function as a sodium-dependent phosphate transporter.

DOI： 10.2152/jmi.59.116

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Phosphaturia has been documented following cadmium (Cd) exposure in both humans and experimental animals. Fibroblast growth factor 23 (FGF23) serves as an essential phosphate homeostasis pathway in the bone-kidney axis. In the present study, we investigated the effects of Cd on phosphate (Pi) homeostasis in mice. Following Cd injection into C57BL/6J mice, plasma FGF23 concentration significantly increased. The urinary Pi excretion level was significantly higher in the Cd-injected C57BL/6J mice than in the control group. Plasma Pi concentration decreased only slightly in the Cd-injected mice compared with the control group. No changes were observed in the concentration of the plasma parathyroid hormone and 1,25-dihydroxy vitamin D(3) in both groups of mice. We observed a decrease in phosphate transport activity and also a decrease in the expression level of renal phosphate transporter Npt2c, but not that of Npt2a. Furthermore, we examined the effect of Cd on Npt2c in Npt2a-knockout (KO) mice, which expresses Npt2c as a major NaPi cotransporter. Injecting Cd to Npt2aKO mice induced a significant increase in plasma FGF23 concentration and urinary Pi excretion level. Furthermore, we observed decreases in phosphate transport activity and renal Npt2c expression level in the Cd-injected Npt2a KO mice. The present study suggests that hypophosphatemia induced by Cd may be closely associated with FGF23.

DOI： 10.1265/jjh.67.464

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Language：English   Publishing type：Research paper (scientific journal)   Participation form：Joint(The vice charge)  

Language：English   Publishing type：Research paper (scientific journal)  

An inorganic phosphate (P i)-restricted diet is important for patients with chronic kidney disease and patients on hemodialysis. Phosphate binders are essential for preventing hyperphosphatemia and ectopic calcification. The sodium-dependent P i (Na/P i) transport system is involved in intestinal Pi absorption and is regulated by several factors. The type II sodium-dependent P i transporter Npt2b is expressed in the brush-border membrane in intestinal epithelial cells and transports Pi. In the present study, we analyzed the phenotype of Npt2b -/-and hetero +/-mice. Npt2b -/-mice died in utero soon after implantation, indicating that Npt2b is essential for early embryonic development. At 4 wk of age, Npt2b +/-mice showed hypophosphatemia and low urinary Pi excretion. Plasma fibroblast growth factor 23 levels were significantly decreased and 1,25(OH)2D3 levels were significantly increased in Npt2b +/-mice compared with Npt2b +/+ mice. Npt2b mRNA levels were reduced to 50% that in Npt2b +/+ mice. In contrast, renal Npt2a and Npt2c transporter protein levels were significantly increased in Npt2b +/-mice. At 20 wk of age, Npt2b +/-mice showed hypophosphaturia and reduced Na/P i cotransport activity in the distal intestine. Npt2b +/+ mice with adenine-induced renal failure had hyperphosphatemia and high plasma creatinine levels. Npt2b +/-mice treated with adenine had significantly reduced plasma Pi levels compared with Npt2b +/-mice. Intestinal Npt2b protein and Na +/P i transport activity levels were significantly lower in Npt2b +/-mice than in the Npt2b +/+ mice. The findings of the present studies suggest that Npt2b is an important target for the prevention of hyperphosphatemia. © 2011 the American Physiological Society.

DOI： 10.1152/ajprenal.00663.2010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHYSIOLOGICAL SOC  

Ohi A, Hanabusa E, Ueda O, Segawa H, Horiba N, Kaneko I, Kuwahara S, Mukai T, Sasaki S, Tominaga R, Furutani J, Aranami F, Ohtomo S, Oikawa Y, Kawase Y, Wada NA, Tachibe T, Kakefuda M, Tateishi H, Matsumoto K, Tatsumi S, Kido S, Fukushima N, Jishage K, Miyamoto K. Inorganic phosphate homeostasis in sodium-dependent phosphate cotransporter Npt2b(+/-) mice. Am J Physiol Renal Physiol 301: F1105-F1113, 2011. First published August 3, 2011; doi:10.1152/ajprenal.00663.2010.-An inorganic phosphate (P-i)-restricted diet is important for patients with chronic kidney disease and patients on hemodialysis. Phosphate binders are essential for preventing hyperphosphatemia and ectopic calcification. The sodium-dependent P-i (Na/P-i) transport system is involved in intestinal P-i absorption and is regulated by several factors. The type II sodium-dependent P-i transporter Npt2b is expressed in the brush-border membrane in intestinal epithelial cells and transports P-i. In the present study, we analyzed the phenotype of Npt2b(-/-) and hetero(+/-) mice. Npt2b(-/-) mice died in utero soon after implantation, indicating that Npt2b is essential for early embryonic development. At 4 wk of age, Npt2b(+/-) mice showed hypophosphatemia and low urinary P-i excretion. Plasma fibroblast growth factor 23 levels were significantly decreased and 1,25(OH)(2)D-3 levels were significantly increased in Npt2b(+/-) mice compared with Npt2b(+/+) mice. Npt2b mRNA levels were reduced to 50% that in Npt2b(+/+) mice. In contrast, renal Npt2a and Npt2c transporter protein levels were significantly increased in Npt2b(+/-) mice. At 20 wk of age, Npt2b(+/-) mice showed hypophosphaturia and reduced Na/P-i cotransport activity in the distal intestine. Npt2b(+/+) mice with adenine-induced renal failure had hyperphosphatemia and high plasma creatinine levels. Npt2b(+/-) mice treated with adenine had significantly reduced plasma Pi levels compared with Npt2b(+/+) mice. Intestinal Npt2b protein and Na+/P-i transport activity levels were significantly lower in Npt2b(+/-) mice than in the Npt2b(+/+) mice. The findings of the present studies suggest that Npt2b is an important target for the prevention of hyperphosphatemia.

DOI： 10.1152/ajprenal.00663.2010

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Language：English   Publisher：WILEY  

Inorganic phosphate (Pi) is an essential physiological compound, highlighted by the syndromes caused by hypo or hyperphosphatemic states. Hyperphosphatemia is associated with ectopic calcification, cardiovascular disease, and increased mortality in patients with chronic kidney disease (CKD). As phosphate control is not efficient with diet or dialysis, oral Pi binders are used in over 90% of patients with renal failure. However, achieving tight control of serum Pi is difficult, and lower levels of serum Pi (severe hypophosphatemia) do not lead to better outcomes. The inhibition of sodium-dependent Pi (NaPi) transporter would be a preferable method to control serum Pi levels in patients with CKD or patients undergoing dialysis. Three types of NaPi transporters (types I-III) have been identified: solute carrier series SLC17A1 (NPT1/NaPi-I/OATv1), SLC34 (NaPi-IIa, NaPi-IIb, NaPi-IIc), and SLC20 (PiT1, PiT2), respectively. Knockout mice have been created for types I-III NaPi transporters. In this review, we discuss the roles of the NaPi transporters in Pi homeostasis. (C) 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3719-3730, 2011

DOI： 10.1002/jps.22614

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Language：Japanese   Publisher：(一社)日本腎臓学会  

Language：Japanese   Publisher：(株)日本メディカルセンター  

Language：English   Publishing type：Research paper (scientific journal)   Participation form：Joint(The vice charge)  

Language：English   Publishing type：Research paper (scientific journal)  

The type IIc Na+-dependent phosphate cotransporter (NaPi-IIc) is specifically targeted to, and expressed on, the apical membrane of renal proximal tubular cells and mediates phosphate transport. In the present study, we investigated the signals that determine apical expression of NaPi-IIc with a focus on the role of the N- and the C-terminal tails of mouse NaPi-IIc in renal epithelial cells [opossum kidney (OK) and Madin-Darby canine kidney cells]. Wild-type NaPi-IIc, the cotransporter NaPi-IIa, as well as several IIa-IIc chimeras and deletion mutants, were fused to enhanced green fluorescent protein (EGFP), and their cellular localization was analyzed in polarized renal epithelial cells by confocal microscopy and by cell-surface biotinylation. Fluorescent EGFP-fused NaPi-IIc transporter proteins are correctly expressed in the apical membrane of OK cells. The apical expression of N-terminal deletion mutants (deletion of N-terminal 25, 50, or 69 amino acids) was not affected by truncation. In contrast, C-terminal deletion mutants (deletion of C-terminal 45, 50, or 62 amino acids) did not have correct apical expression. A more detailed mutational analysis indicated that a domain (amino acids WLHSL) in the cytoplasmic C terminus is required for apical expression of NaPi-IIc in renal epithelial cells. We conclude that targeting of NaPi-IIc to the apical cell surface is regulated by a unique amino acid motif in the cytoplasmic C-terminal domain. © 2010 the American Physiological Society.

DOI： 10.1152/ajprenal.00189.2009

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHYSIOLOGICAL SOC  

Ito M, Sakurai A, Hayashi K, Ohi A, Kangawa N, Nishiyama T, Sugino S, Uehata Y, Kamahara A, Sakata M, Tatsumi S, Kuwahata M, Taketani Y, Segawa H, Miyamoto K. An apical expression signal of the renal type IIc Na+-dependent phosphate cotransporter in renal epithelial cells. Am J Physiol Renal Physiol 299: F243-F254, 2010. First published April 21, 2010; doi: 10.1152/ajprenal.00189.2009.-The type IIc Na+-dependent phosphate cotransporter (NaPi-IIc) is specifically targeted to, and expressed on, the apical membrane of renal proximal tubular cells and mediates phosphate transport. In the present study, we investigated the signals that determine apical expression of NaPi-IIc with a focus on the role of the N- and the C-terminal tails of mouse NaPi-IIc in renal epithelial cells [opossum kidney (OK) and Madin-Darby canine kidney cells]. Wild-type NaPi-IIc, the cotransporter NaPi-IIa, as well as several IIa-IIc chimeras and deletion mutants, were fused to enhanced green fluorescent protein (EGFP), and their cellular localization was analyzed in polarized renal epithelial cells by confocal microscopy and by cell-surface biotinylation. Fluorescent EGFP-fused NaPi-IIc transporter proteins are correctly expressed in the apical membrane of OK cells. The apical expression of N-terminal deletion mutants (deletion of N-terminal 25, 50, or 69 amino acids) was not affected by truncation. In contrast, C-terminal deletion mutants (deletion of C-terminal 45, 50, or 62 amino acids) did not have correct apical expression. A more detailed mutational analysis indicated that a domain (amino acids WLHSL) in the cytoplasmic C terminus is required for apical expression of NaPi-IIc in renal epithelial cells. We conclude that targeting of NaPi-IIc to the apical cell surface is regulated by a unique amino acid motif in the cytoplasmic C-terminal domain.

DOI： 10.1152/ajprenal.00189.2009

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Language：English   Publishing type：Research paper (scientific journal)   Participation form：Joint(The vice charge)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHYSIOLOGICAL SOC  

Tomoe Y, Segawa H, Shiozawa K, Kaneko I, Tominaga R, Hanabusa E, Aranami F, Furutani J, Kuwahara S, Tatsumi S, Matsumoto M, Ito M, Miyamoto K. Phosphaturic action of fibroblast growth factor 23 in Npt2 null mice. Am J Physiol Renal Physiol 298: F1341-F1350, 2010. First published March 31, 2010; doi: 10.1152/ajprenal.00375.2009.-In the present study, we evaluated the roles of type II and type III sodium-dependent P(i) cotransporters in fibroblast growth factor 23 (FGF23) activity by administering a vector encoding FGF23 with the R179Q mutation (FGF23M) to wild-type (WT) mice, Npt2a knockout (KO) mice, Npt2c KO mice, and Npt2a(-/-)Npt2c(-/-) mice (DKO mice). In Npt2a KO mice, FGF23M induced severe hypophosphatemia and markedly decreased the levels of Npt2c, type III Na-dependent P(i) transporter (PiT2) protein, and renal Na/P(i) transport activity. In contrast, in Npt2c KO mice, FGF23M decreased plasma phosphate levels comparable to those in FGF23M-injected WT mice. In DKO mice with severe hypophosphatemia, FGF23M administration did not induce an additional increase in urinary phosphate excretion. FGF23 administration significantly decreased intestinal Npt2b protein levels in WT mice but had no effect in Npt2a, Npt2c, and DKO mice, despite marked suppression of plasma 1,25(OH)(2)D(3) levels in all the mutant mice. The main findings were as follow: 1) FGF23-dependent phosphaturic activity in Npt2a KO mice is dependent on renal Npt2c and PiT-2 protein; 2) in DKO mice, renal P(i) reabsorption is not further decreased by FGF23M, but renal vitamin D synthesis is suppressed; and 3) downregulation of intestinal Npt2b may be mediated by a factor(s) other than 1,25(OH)(2)D(3). These findings suggest that Npt2a, Npt2c, and PiT-2 are necessary for the phosphaturic activity of FGF23. Thus complementary regulation of Npt2 family proteins may be involved in systemic P(i) homeostasis.

DOI： 10.1152/ajprenal.00375.2009

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Language：English   Publishing type：Research paper (scientific journal)  

In the present study, we evaluated the roles of type II and type III sodium-dependent Pi cotransporters in fibroblast growth factor 23 (FGF23) activity by administering a vector encoding FGF23 with the R179Q mutation (FGF23M) to wild-type (WT) mice, Npt2a knockout (KO) mice, Npt2c KO mice, and Npt2a-/-Npt2c-/- mice (DKO mice). In Npt2a KO mice, FGF23M induced severe hypophosphatemia and markedly decreased the levels of Npt2c, type III Na-dependent Pi transporter (PiT2) protein, and renal Na/Pi transport activity. In contrast, in Npt2c KO mice, FGF23M decreased plasma phosphate levels comparable to those in FGF23M-injected WT mice. In DKO mice with severe hypophosphatemia, FGF23M administration did not induce an additional increase in urinary phosphate excretion. FGF23 administration significantly decreased intestinal Npt2b protein levels in WT mice but had no effect in Npt2a, Npt2c, and DKO mice, despite marked suppression of plasma 1,25(OH)2D3 levels in all the mutant mice. The main findings were as follow: 1) FGF23-dependent phosphaturic activity in Npt2a KO mice is dependent on renal Npt2c and PiT-2 protein
2) in DKO mice, renal Pi reabsorption is not further decreased by FGF23M, but renal vitamin D synthesis is suppressed
and 3) downregulation of intestinal Npt2b may be mediated by a factor(s) other than 1,25(OH)2D3. These findings suggest that Npt2a, Npt2c, and PiT-2 are necessary for the phosphaturic activity of FGF23. Thus complementary regulation of Npt2 family proteins may be involved in systemic Pi homeostasis. Copyright © 2010 the American Physiological Society.

DOI： 10.1152/ajprenal.00375.2009

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Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

Language：English   Publishing type：Research paper (scientific journal)   Participation form：Joint(The vice charge)  

Language：English   Publishing type：Research paper (scientific journal)  

Phosphaturia has been documented following cadmium (Cd) exposure in both humans and experimental animals. The fibroblast growth factor 23 (FGF23)/klotho axis serves as an essential phosphate homeostasis pathway in the bone-kidney axis. In the present study, we investigated the effects of Cd on phosphate (Pi) homeostasis in mice. Following Cd injection into WT mice, plasma FGF23 concentration was significantly increased. Urinary Pi excretion levels were significantly higher in Cd-injected WT mice than in control group. Plasma Pi concentration decreased only slightly compared with control group. No change was observed in plasma parathyroid hormone and 1,25-dihydroxy vitamin D3 in both group of mice. We observed a decrease in phosphate transport activity and also decrease in expression of renal phosphate transporter SLC34A3 [NaPi-IIc/NPT2c], but not SLC34A1 [NaPi-IIa/NPT2a]. Furthermore, we examined the effect of Cd on Npt2c in Npt2a-knockout (KO) mice which expresses Npt2c as a major NaPi co-transporter. Injecting Cd to Npt2aKO mice induced significant increase in plasma FGF23 concentration and urinary Pi excretion levels. Furthermore, we observed a decrease in phosphate transport activity and renal Npt2c expression in Cd-injected Npt2a KO mice. The present study suggests that hypophosphatemia induced by Cd may be closely associated with the FGF23/klotho axis.

DOI： 10.2152/jmi.57.95

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Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Long-term supplementation of branched-chain amino acids (BCAA) improves hypoalbuminemia in patients with cirrhosis. Our previous findings have suggested that the binding of polypyrimidine-tract-binding protein (PTB) to rat albumin mRNA attenuates its translation. The aim of the present study was to investigate the role of PTB in the regulation of albumin synthesis by BCAA in human hepatoma cells. HepG2 cells were cultured in a medium containing no amino acids (AA-free medium), a medium containing only I amino acid (a BCAA: valine, leucine or isoleucine) or a medium containing all 20 amino acids (AA-complete medium). HepG2 cells cultured in AA-complete medium secreted much more albumin than cells cultured in AA-free medium, with no difference in albumin mRNA levels. In cells cultured in AA-free medium, nuclear export of PTB was observed, and the level of the albumin mRNA-PTB complex was greater than in cells cultured in AA-complete medium. Addition of amino acids stimulated nuclear import of PTB. However, addition of amino acids with rapamycin inhibited the nuclear import of PTB. The addition of leucine, but not of valine or isoleucine, to AA-free medium increased albumin secretion and stimulated the nuclear import of PTB. These data indicate that the mammalian target of rapamycin is involved in the regulation of PTB localization and that leucine promotes albumin synthesis by inhibiting the formation of the albumin mRNA-PTB complex. (c) 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.jnutbio.2007.05.01

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CENTER ACADEMIC PUBL JAPAN  

Our recent study demonstrates that polypyrimidine tract-binding protein (PTB), which is a sequence specific RNA-binding protein, attenuates albumin synthesis in a cell-free translation system. In this study, the effects of food intake on regulation of albumin synthesis through binding of PTB to albumin messenger RNA (mRNA) were investigated. Rats were divided into 1 of 3 groups: fed; fasted for 36 h; or fasted for 36 h and then refed for 24 h. No significant differences in albumin mRNA levels were found among fed, fasted and refed rats. However, a decrease in the proportion of albumin mRNA associated with polysomes was identified in fasted rats. Furthermore, UV-cross linking analysis demonstrated that levels of albumin mRNA-PTB complex were increased in liver extracts from fasted rats. No significant differences in PTB levels in liver homogenate were found among the experimental groups. However, PTB level in the cytoplasmic fraction was higher in fasted rats than in fed rats. In refed rats, PTB level in the cytoplasmic fraction returned to a level comparable to that in fed rats, but was inhibited by treatment with rapamycin, a mammalian target of rapamycin (mTOR) inhibitor. These results suggest that localization of PTB is regulated by food intake through mTOR signaling, and alterations in level of albumin mRNA-PTB complex play a role in mediating the effects of food intake on albumin synthesis in the rat liver.

DOI： 10.3177/jnsv.54.142

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ENDOCRINE SOC  

Caloric restriction (CR) extends the lifespan of various organisms and slows the onset of age-related disorders; however, little is known about the long-term effects of CR per se on bone. In the present study, we have examined the effects of life-long CR vs. ad libitum (AD) feeding, mainly on the trabecular bone of proximal tibiae in male C57BL/ 6 mice and F344 rats. Micro-computed tomography scanning of tibiae revealed that CR for 3-9 months caused a substantial decrease in three-dimensional bone volume with structural derangements. Bone histomorphometry revealed the reduced bone mass was due mainly to suppression of bone formation. In db/ db mice with defective leptin receptor, CR was unable to decrease bone mass and suppress bone formation. The effect of CR on bone mass was inhibited by administration of a beta-adrenergic renergic blocker, propranolol. Thus, CR may regulate bone formation through leptin signaling and elevated sympathetic nervous tone. Interestingly, the difference in bone volume between the CR and AD groups disappeared after 1 yr of age, and mice and rats on an additional extension of CR to natural death maintained higher bone mass than the AD groups, with reduced bone turnover, suggesting that CR slows skeletal aging by regulating the rate of bone turnover. This is the first report, to our knowledge, that has examined the effects of lifelong CR on bone metabolism and trabecular microstructure and documents its contrasting effects during maturation vs. the postmaturational, involutional period.

DOI： 10.1210/en.2007-1089

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Language：English   Publishing type：Research paper (scientific journal)   Participation form：Joint(The vice charge)  

Language：English   Publishing type：Research paper (scientific journal)   Participation form：Joint(The vice charge)  

Language：English   Publishing type：Research paper (scientific journal)   Participation form：Joint(The main charge)  

Language：English   Publishing type：Research paper (scientific journal)   Participation form：Joint(The vice charge)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ENDOCRINE SOC  

We previously identified gamma-glutamyltransferase (GGT) by expression cloning as a factor inducing osteoclast formation in vitro. To examine its pathogenic role in vivo, we generated transgenic mice that overexpressed GGT in a tissue-specific manner utilizing the Cre-loxP recombination system. Systemic as well as local production of GGT accelerated osteoclast development and bone resorption in vivo by increasing the sensitivity of bone marrow macrophages to receptor activator of nuclear factor-kappa B ligand, an essential cytokine for osteoclastogenesis. Mutated GGT devoid of enzyme activity was as potent as the wild-type molecule in inducing osteoclast formation, suggesting that GGT acts not as an enzyme but as a cytokine. Recombinant GGT protein increased receptor activator of nuclear factor-kappa B ligand expression in marrow stromal cells and also stimulated osteoclastogenesis from bone marrow macrophages at lower concentrations. Thus, GGT is implicated as being involved in diseases characterized by accelerated osteoclast development and bone destruction and provides a new target for therapeutic intervention.

DOI： 10.1210/en.2007-0215

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

Bone remodeling is performed by osteoclasts and osteoblasts at the bone surface. Inside of bone is a network of numerous osteocytes, whose specific function hasremained anenigma. Here we describe a transgenic mouse model in which inducible and specific ablation of osteocytes is achieved in vivo through targeted expression of diphtheria toxin (DT) receptor. Following a single injection of DT, approximately 70%-80% of the osteocytes, but apparently no osteoblasts, were killed. Osteocyte-ablated mice exhibited fragile bone with intracortical porosity and microfractures, osteolblastic dysfunction, and trabecular bone loss with microstructural deterioration and adipose tissue proliferation in the marrow space, all of which are hallmarks of the aging skeleton. Strikingly, these "osteocyte-less" mice were resistant to unloading-induced bone loss, providing evidence for the role of osteocytes in mechano-transduction. Thus, osteocytes represent an attractive target for the development of diagnostics and therapeutics for bone diseases, such as osteoporosis.

DOI： 10.1016/j.cmet.2007.05.001

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Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Participation form：Joint(The vice charge)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

To investigate the mechanism of hypermsulinaemia in rats with acute liver failure induced by the administration of D-galactosamine (GaIN), we focused on the role of polyprimidine tract-binding protein (PTB) in islet insulin synthesis. Recent reports indicate that PTB binds and stabilizes mRNA encoding insulin and insulin secretory granule proteins, including islet cell autoantigen 512 (ICA512), prohormone convertase 1/3 (PC1/3), and PC2. In the present study, glucose-stimulated insulin secretion was significantly increased in GalN-treated rats compared to controls. Levels of mRNA encoding insulin 1, ICA512, and PC1/3 were increased in the pancreatic islets of GalN-treated rats. This mRNA level elevation was not prevented by pretreatment with actinomycin D. When the PTB-binding site in insulin I mRNA was incubated with the islet cytosolic fraction, the RNA-protein complex level was increased in the cytosolic fraction obtained from GalN-treated rats compared to the level in control rats. The cytosolic fraction obtained from pancreatic islets obtained from GalN-treated rats had an increased PTB level compared to the levels obtained from the pancreatic islets of control rats. These findings suggest that, in rats with acute liver failure, cytosolic PTB binds and stabilizes mRNA encoding insulin and its secretory granule proteins. (c) 2006 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.bbadis.2006.10.001

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DOI： 10.1016/j.bbadis.2006.10.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHYSIOLOGICAL SOC  

During bone resorption, a large amount of inorganic phosphate (P-i) is generated within the osteoclast hemivacuole. The mechanisms involved in the disposal of this P-i are not clear. In the present study, we investigated the efflux of P-i from osteoclast-like cells. P-i efflux was activated by acidic conditions in osteoclast-like cells derived by the treatment of RAW264.7 cells with receptor activator of nuclear factor-kappa B ligand. Acid-induced P-i influx was not observed in renal proximal tubule-like opossum kidney cells, osteoblast-like MC3T3-E1 cells, or untreated RAW264.7 cells. Furthermore, P-i efflux was stimulated by extracellular P-i and several P-i analogs [phosphonoformic acid (PFA), phosphonoacetic acid, arsenate, and pyrophosphate]. P-i efflux was time dependent, with 50% released into the medium after 10 min. The efflux of P-i was increased by various inhibitors that block P-i uptake, and extracellular P-i did not affect the transport of [C-14] PFA into the osteoclast-like cells. Preloading of cells with P-i did not stimulate P-i efflux by PFA, indicating that the effect of P-i was not due to transstimulation of P-i transport. P-i uptake was also enhanced under acidic conditions. Agents that prevent increases in cytosolic free Ca2+ concentration, including acetoxymethyl ester of 1,2-bis(2-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid, 2-aminoethoxydiphenyl borate, and bongkrekic acid, significantly inhibited P-i uptake in the osteoclast-like cells, suggesting that P-i uptake is regulated by Ca2+ signaling in the endoplasmic reticulum and mitochondria of osteoclast-like cells. These results suggest that osteoclast-like cells have a unique P-i uptake/efflux system and can prevent P-i accumulation within osteoclast hemivacuoles.

DOI： 10.1152/ajpcell.00357.2006

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Language：English   Publishing type：Research paper (international conference proceedings)  

In the present study, we investigated whether a diet deficient in inorganic phosphate (Pi) stimulates an ingestive behavior to seek sources of Pi. Male Wistar rats were placed in individual cages with unrestricted access to tap water and a low (LPD, 0.02% Pi) or normal (NPD, 0.6% Pi) Pi diet for 6 days. On day 7, LDP rats were given unlimited access to a solution of 25 mM potassium phosphate water (Pi-water) for 9 additional days. Rats fed LPD consumed 70-100% more Pi-water then those fed NPD. The increase in Pi-water intake resulted in a marked rise in the growth rate of rats fed LPD during day 9. A similar intake of Pi was induced after only 2 days of LPD and was associated with significant reductions in both plasma and cerebrospinal fluid (CSF) levels of Pi
these levels remained low throughout Pi restriction, despite a significant intake of Pi-water. Replenishment with a high-Pi diet rapidly quenched the appetite for Pi-water and was associated with restoration of both plasma and CSF Pi levels. These findings suggest that an appetite for Pi can be induced in rats, perhaps through lowered plasma and CSF Pi levels.

DOI： 10.2152/jmi.54.366

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DOI： 10.1152/ajprenal.00248.2006

Language：English   Publisher：KARGER  

Abnormalities of the inorganic phosphate ( Pi) reabsorption in the kidney result in various metabolic disorders. Na+-dependent Pi (Na/Pi) transporters in the brush border membrane of proximal tubular cells mediate the rate-limiting step in the overall Pi-reabsorptive process. Type IIa and type IIc Na/Pi cotransporters are expressed in the apical membrane of proximal tubular cells and mediate Na/Pi cotransport; the extent of Pi reabsorption in the proximal tubules is determined largely by the abundance of the type IIa Na/Pi cotransporter. However, several studies suggest that the type IIc cotransporter in Pi reabsorption may also play a role in this process. For example, mutation of the type IIc Na/Pi cotransporter gene results in hereditary hypophosphatemic rickets with hypercalciuria, suggesting that the type IIc transporter plays an important role in renal Pi reabsorption in humans and may be a key determinant of the plasma Pi concentration. The type IIc Na/Pi transporter is regulated by parathyroid hormone, dietary Pi, and fibroblast growth factor 23, and studies suggest a differential regulation of the IIa and IIc transporters. Indeed, differences in temporal and/or spatial expression of the type IIa and type IIc Na/Pi transporters may be required for normal phosphate homeostasis and bone development. This review will briefly summarize the regulation of renal Pi transporters in various Pi-wasting disorders and highlight the role of a relatively new member of the Na/Pi cotransporter family: the type IIc Na/Pi transporter/ SLC34A3. Copyright (c) 2007 S. Karger AG, Basel.

DOI： 10.1159/000107069

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Human RNPS1 was originally characterized as a pre-mRNA splicing activator in vitro and was shown to regulate alternative splicing in vivo. RNPS1 was also identified as a protein component of the splicing-dependent mRNP complex, or exon-exon junction complex (EJC), and a role for RNPS1 in postsplicing processes has been proposed. Here we demonstrate that RNPS1 incorporates into active spliceosomes, enhances the formation of the ATP-dependent A complex, and promotes the generation of both intermediate and final spliced products. RNPS1 is phosphorylated in vivo and interacts with the CK2 (casein kinase II) protein kinase. Serine 53 (Ser-53) of RNPS1 was identified as the major phosphorylation site for CK2 in vitro, and the same site is also phosphorylated in vivo. The phosphorylation status of Ser-53 significantly affects splicing activation in vitro, but it does not perturb the nuclear localization of RNPS1. In vivo experiments indicated that the phosphorylation of RNPS1 at Ser-53 influences the efficiencies of both splicing and translation. We propose that RNPS1 is a splicing regulator whose activator function is controlled in part by CK2 phosphorylation.

DOI： 10.1128/MCB.25.4.1446-1457.2005

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Human RNPS1 was originally purified and characterized as a pre-mRNA splicing activator, and its role in the postsplicing process has also been proposed recently. To search for factors that functionally interact with RNPS1, we performed a yeast two-hybrid screen with a human cDNA library. Four factors were identified: p54 (also called SRp54; a member of the SR protein family), human transformer 2beta (hTra2beta; an exonic splicing enhancer-binding protein), hLucA (a potential component of U1 snRNP), and pinin (also called DRS and MemA; a protein localized in nuclear speckles). The N-terminal region containing the serine-rich (S) domain, the central RNA recognition motif (RRM), and the C-terminal arginine/serine/proline-rich (RS/P) domain of RNPS1 interact with p54, pinin, and hTra2beta, respectively. Protein-protein binding between RNPS1 and these factors was verified in vitro and in vivo. Overexpression of RNPS1 in HeLa cells induced exon skipping in a model beta-globin pre-mRNA and a human tra-2beta pre-mRNA. Coexpression of RNPS1 with p54 cooperatively stimulated exon inclusion in an ATP synthase gamma-subunit pre-mRNA. The RS/P domain and RRM are necessary for the exon-skipping activity, whereas the S domain is important for the cooperative effect with p54. RNPS1 appears to be a versatile factor that regulates alternative splicing of a variety of pre-mRNAs.

DOI： 10.1128/MCB.24.3.1174-1187.2004

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Growth is critically dependent on the retention of a variety of nutrients. The kidney contributes to this positive external balance. In the present study, we isolated a cDNA from the human and rat kidney that encodes a growth-related Na+-dependent inorganic phosphate (P-i) cotransporter (type IIc). Microinjection of type IIc cRNA into Xenopus oocytes demonstrated sodium-dependent P-i cotransport activity. Affinity for P-i was 0.07 mm in 100 mm Na+. The transport activity was dependent on extracellular pH. In electrophysiological studies, type IIc Na/P-i cotransport was electroneutral, whereas type IIa was highly electrogenic. In Northern blotting analysis, the type IIc transcript was only expressed in the kidney and highly in weaning animals. In immunohistochemical analysis, the type IIc protein was shown to be localized at the apical membrane of the proximal tubular cells in superficial and midcortical nephrons of weaning rat kidney. Hybrid depletion experiments suggested that type IIc could function as a Na/P-i cotransporter in weaning animals, but its role is reduced in adults. The finding of the present study suggest that the type IIc is a growth-related renal Na/P-i cotransporter, which has a high affinity for P-i and is electroneutral.

DOI： 10.1074/jbc.M200943200

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We have isolated three unique NaPi-2-related protein cDNAs (NaPi-2 alpha, NaPi-2 beta and NaPi-2 gamma) from a rat kidney library. NaPi-2 alpha cDNA encodes 337 amino acids which have high homology to the N-terminal half of NaPi-2 containing three transmembrane domains. NaPi-2 beta encodes 327 amino acids which are identical to the N-terminal region of NaPi-2 containing four transmembrane domains, whereas the 146 amino acids in the C-terminal region are completely different. In contrast, NaPi-2 gamma encodes 268 amino acids which are identical to the C-terminal half of NaPi-2. An analysis of phage and cosmid clones indicated that the three related proteins were produced by alternative splicing in the NaPi-2 gene. In a rabbit reticulocyte lysate system, NaPi-2 alpha, beta and gamma were found to be 36, 36 and 29 kDa polypeptides, respectively. NaPi-2 alpha and NaPi-2 gamma were glycosylated and revealed to be 45 and 35 kDa proteins, respectively. A functional analysis demonstrated that NaPi-2 gamma and alpha markedly inhibited NaPi-2 activity in Xenopus oocytes. The results suggest that these short isoforms may function as a dominant-negative inhibitor of the full-length transporter.

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DOI： 10.1016/S0065-2571(99)00036-9

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DOI： 10.1042/0264-6021:3430705

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Background. We recently reported that the administration of niceritorol (a nicotinic acid derivative which improves lipid metabolism and peripheral circulation, and is used for the treatment of hyperlipidaemia and impaired peripheral circulation) to patients with hyperphosphataemia undergoing dialysis decreased the serum phosphate (Pi) concentration. We found that this was due to an acceleration of faecal Pi excretion by niceritrol.
Methods. Intestinal brush border membrane vesicles (BBMVs) were prepared from rat jejunum, and the Na+-dependent and Na+-independent Pi transport activities in these vesicles were measured. In addition, the functional Pi transporter from rat small intestine was injected in Xenopus oocytes, and the effect of nicotinamide on the levels of its expression were measured by northern blotting.
Results. The Na+-dependent component was significantly decreased in the BBMVs isolated from rats treated with nicotinamide, while the Na+-independent component was not changed. Kinetic studies demonstrated that the decreased activity was due to reduction of the V-max value and not an elevation of the K-m values. When poly(A)(+)RNA from rats treated with nicotinamide was microinjected into Xenopus oocytes, the Pi transport activity was significantly decreased compared with that in the control animals. In addition, there were no significant changes in Na/Pi cotransporters and activators, but the vitamin D receptor mRNA level was reduced to 80% of the control level.
Conclusions. These observations suggest that nicotinamide may regulate the expression of a major functional Na/Pi cotransporter in the rat small intestine.

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A cDNA encoding an Na+-P-i co-transporter, termed rat PiT-1, has now been isolated from rat parathyroid. Expression of rat PiT-1 in Xenopus oocytes revealed that it possesses Na+-dependent P-i co-transport activity. The amount of PiT-1 mRNA in the parathyroid of vitamin D-deficient rats was reduced compared with that in normal animals, and increased markedly after administration of 1,25-dihydroxyvitamin D3, Furthermore, the abundance of PiT-1 mRNA in the parathyroid was much greater in rats fed a low-P-i diet than in those fed a high-P-i diet. Thus, rat PiT-1 may contribute to the effects of P-i and vitamin D on parathyroid function.

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We have isolated three unique NaPi-2-related protein cDNAs (NaPi-2 alpha, NaPi-2 beta, and NaPi-2 gamma) from a rat kidney library. NaPi-2 alpha cDNA encodes 337 amino acids which have high homology to the N-terminal half of NaPi-2 containing 3 transmembrane domains. NaPi-2 beta encodes 327 amino acids which are identical to the N-terminal region of NaPi-2 containing 4 transmembrane domains, whereas the 146 amino acids in the C-terminal region are completely different. In contrast, NaPi-2 gamma encodes 268 amino acids which are identical to the C-terminal half of NaPi-2, An analysis of phage and cosmid clones indicated that the three related proteins were produced by alternative splicing in the NaPi-2 gene. In a rabbit reticulocyte lysate system, NaPi-2 alpha, beta, and gamma were found to be 36, 36, and 29 kDa amino acid polypeptides, respectively. NaPi-2 alpha: and NaPi-2 gamma were glycosylated and revealed to be 45- and 35-kDa proteins, respectively. In isolated brush-border membrane vesicles, an N-terminal antibody was reacted with 45- and 40-kDa, and a C-terminal antibody was reacted with 37-kDa protein. The sizes of these proteins corresponded to those in glycosylated forms.
A functional analysis demonstrated that NaPi-2 gamma and -2 alpha markedly inhibited NaPi-2 activity in Xenopus oocytes, The results suggest that these short isoforms may function as a dominant negative inhibitor of the full-length transporter.

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Vitamin D is an important regulator of phosphate homeostasis. The effects of vitamin D on the expression of renal Na+-dependent inorganic phosphate (P-i) transporters (types I and II) were investigated. In vitamin D-deficient rats, the amounts of type II Na+-dependent P-i transporter (NaPi-2) protein and mRNA were decreased in the juxtamedullary kidney cortex, but not in the superficial cortex, compared with control rats. The administration of 1,25-dihydroxyvitamin D-3 (1,25-(OH)(2)D-3) to vitamin D-deficient rats increased the initial rate of P-i uptake as well as the amounts of NaPi-2 mRNA and protein in the juxtamedullary cortex. The transcriptional activity of a luciferase reporter plasmid containing the promoter region of the human type II Na+-dependent P-i transporter NaPi-3 gene was increased markedly by 1,25-(OH)(2)D-3 in COS-7 cells expressing the human vitamin D receptor. A deletion and mutation analysis of the NaPi-3 gene promoter identified the vitamin D-responsive element as the sequence 5'-GGGGCAGCAAGGGCA-3' nucleotides -1977 to -1963 relative to the transcription start site. This element bound a heterodimer of the vitamin D receptor and retinoid X receptor, and it enhanced the basal transcriptional activity of the promoter of the herpes simplex virus thymidine kinase gene in an orientation-independent manner. Thus, one mechanism by which vitamin D regulates P-i homeostasis is through the modulation of the expression of type II Na+-dependent P-i transporter genes in the juxtamedullary kidney cortex.

DOI： 10.1074/jbc.273.23.14575

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DOI： 10.1210/endo.139.4.5925

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To elucidate the expression and regulation of the human type I Na+/phosphate transporter gene (NPT-I), the 5' flanking region of the NPT-1 gene was cloned, and its nucleotide sequence and function were determined. A genomic clone that contained approximately 14.0 kb of the 5'-flanking region of the NPT-1 gene was isolated. A single transcription start site was located 104 base pairs (bp) upstream of the 3' end of exon 1. In addition to the sequence of the S-flanking region contained a sequence weakly homologous to a TATA box at position -41 to -36 and many transcriptional regulatory elements.' Transient expression revealed that a 45-bp region of proximal to exon 1, which contained TATA-like sequence, was sufficient for promoting luciferase expression in OK-cells derived from opossum kidney proximal tubule. (C) 1998 Elsevier Science B.V.

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DOI： 10.1016/S0167-4781(97)00231-5

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Expression of a renal Na+-dependent inorganic phosphate (P(i)) cotransporter (NaP(i)-2) was studied in rat forebrain with reverse transcription and polymerase chain reaction (RT-PCR) and immunohistochemistry. RT-PCR analysis for total RNA from whole brain and sequencing of the PCR products showed expression of NaP(i)-2 mRNA in the brain. Immunohistochemical analysis revealed NaP(i)-2 staining in many nonpyramidal neurons of all six layers throughout neocortical areas and in neurons of proisocortical and periallocortical areas. NaP(i)-2-immunoreactive neurons were also detectable in the piriform cortex, hippocampal formation, caudate-putamen, amygdaloid nuclei and lateral geniculate nucleus. Furthermore, NaP(i)-2 staining was shown in ependymal cells and microvascular endothelial cells. The present results suggest that NaP(i)-2 is synthesized within the brain and involved in maintaining P(i) homeostasis of certain neurons and/or the entire brain.

DOI： 10.1016/S0006-8993(97)00884-6

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Alteration of the dietary intake of phosphate (P_i) leads to rapid changes in renal P_i transport activity. The present study, examined the underlying cellular mechanisms of the rapid regulation, with special reference to renal P, cotransporter. Rats were fed either a low-P_i (0. 02%) diet (CLP rats), the low-P_i diet followed by a high-P, (1. 2%) diet (AHP rats), or a normal (0. 6%) diet (control rats). Nat-dependent P_i transport activity in the brush border membrane was significantly increased in CLP rats compared with control rats, and this activity decreased rapidly within 2 h after the change of diet in AHP rats. Kinetic analysis of P_i transport in the AHP rats indicated that the reduction was accompanied by a decrease in the apparent V_max, for Na⁺-dependent P_i uptake. Northern blot analysis showed no difference in the abundance of NaP_i-2 mRNA of the kidney between AHP and CLP rats. In contrast, Western blot analysis of renal brush border membrane proteins of AHP rats indicated a significant decrease in the abundance of NaP_i-2 protein as compared with CLP rats. Immunoreactive signals for NaP_i-2 were detected in lysosomal fractions of AHP and CLP rats. Immunohistochemical analysis showed that, NaP_i-2 immunoreactivity in AHP rats was largely reduced in the apical membrane of the proximal tubular epithelial cells. Neither cycloheximide nor actinomycin D affected high-P_i-induced reduction of NaP_i-2 protein in the brush border membrane of AHP rats, indicating that de novo protein synthesis of an unidentified regulator protein was not involved in the mechanism of this reduction. In contrast, treatment with colchicine, which disrupts microtubulers, abolished the effect of high-P_i diet on NaP, -2 expression. These results suggested that rapid en-docytotic internalization of NaP, -2 may occur specificallyin the brush border membrane following an acute increase in dietary P_i intake.

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To investigate whether rBAT gene products function as a crystine transporter component or as a transport activator, we microinjected several C-terminal deletion mutants of rBAT cRNA into Xenopus oocytes, and measured transport activity for arginine, leucine and cystine in the presence and absence of sodium. Wild type rBAT significantly stimulated the uptake of all 3 amino acids 10-20 fold compared to control mutants. On the other hand, no mutant, except a Δ511-685 mutant, stimulated the uptake of these amino acids. However, the Δ511-685 mutant significantly increased the uptake of arginine. In the presence of sodium, the Δ511-685 mutant also increased the uptake of leucine. The Δ511-685 mutant did not stimulate crystine uptake in the presence and absence of sodium. Furthermore, inhibition of L-arginine uptake by L-homoserine was seen only in the presence of sodium. These results suggest that mutant rBAT stimulates the endogenous amino acid transport system y+ in oocytes. Finally, rBAT gene products, as the primary cause of cystinuria, may function as activators of the amino acid transport system in renal brush border membrane. © IUA/CLJ.

DOI： 10.1111/j.1442-2042.1996.tb00354.x

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リンは、普遍的に存在するミネラルである。ヒトにおける生理学的重要性にもかかわらず、リン代謝に関する多くの見解が明らかになってきたのは比較的最近である。特に、FGF23はリン恒常性の調節に関係する重要なホルモンであることがわかってきた。遺伝性リン代謝異常症の研究は、全体的なリン調節の複雑性を浮き彫りにし、これからの研究における新しい領域を開拓してきた。これらは、低リン血症性くる病/骨軟化症の病態のみならず、慢性腎臓病にみられるリン代謝異常と心血管障害との関係の理解に新しい知見を提示することが期待される。(著者抄録)

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無機リン酸(以下リン)は、細胞膜構成、エネルギー代謝、酵素反応を含むさまざま生理学的機能に必須な栄養素である。血中リン濃度の維持は主に腎臓、腸管および骨が担っている。そしてリンを輸送するトランスポーターの働きによって厳密に制御されているのである。このトランスポーターの発現調節は、古典的にはリン調節ホルモンである副甲状腺ホルモン(PTH)、1,25-dihydroxyvitamin D3によって知られてきた。近年、最初に同定されたフォスファトニンであるfibroblast growth factor 23(FGF23)のリン利尿作用についての研究が飛躍的に進んだ。FGF23は骨細胞から分泌され遠隔臓器である腎臓に作用しリン排泄を制御することから、リン代謝における骨-腎連関が重要であることが認識された。本稿では多臓器にわたる生体内リン恒常性維持機構について最近の知見を加えて概説する。(著者抄録)

DOI： 10.2745/dds.29.408

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無機リン酸(Pi)は、生体に必須のイオンであり、エネルギーの中間代謝、糖・蛋白質・脂質・核酸の代謝、酵素活性の調節、酸塩基平衡、骨基質の石灰化など様々な生理作用がある。生体内Pi恒常性は、腸管からの吸収、骨からの動員、腎臓での排泄・再吸収を調節することで厳密に維持されている。この生体内Pi恒常性維持において重要な役割を果たしているのが、ナトリウム依存性リン酸トランスポーターである。ナトリウム依存性リン酸トランスポーターは、その構造からtype I、II、IIIに分類される。本稿では、Pi恒常性におけるナトリウム依存性リントランスポーターの役割について概説する。(著者抄録)

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高リン血症は慢性腎臓病(CKD)患者に共通してみられる病態であり、副甲状腺機能亢進症や腎性骨症の原因となるばかりでなく、その悪化は血管石灰化の進行や心血管系イベントの増加を招き、死亡率の上昇を招く。これらのことから、CKD患者の病態管理において高リン血症の予防とその是正は非常に重要であり、これはリン吸着剤の投与と食事性リン制限の併用により行われる。我々が食事から摂取するリンは、主に高蛋白質食品または食品添加物に由来し、これはCKD患者において体内リンバランスを決定する重要な因子である。無機リン酸は有機リンに比べて吸収率が良いため、とりわけ添加物であるリン酸化合物(PO4)は日常の食生活で摂取するリンの量を著しく増加させる恐れがある。加えて、加工食品に含まれるリンの量やその種類に関する情報は提示されていないか、あるいは不正確であることが多い。以上から、CKD患者に対して献立や食事計画を考える場合には、食品および食事中に含まれるリンの絶対量(添加物としてのリンを含む)と蛋白質に対するリン含量比の両方を考慮すべきである。(著者抄録)

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腸管は、様々な栄養素(糖、脂質、アミノ酸など)のセンシングに係る臓器として重要である。食事中のリン含量に応答した腸管でのリンセンシングは、腸管リン吸収だけでなく、腎臓からのリン再吸収、排泄を制御する。腸管におけるリンセンシング機序の解明は、生体内リン恒常性維持機構の理解につながる。さらに、慢性腎臓病でのリン管理に有用であり、合併症である高リン血症予防の分子基盤として期待される。(著者抄録)

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Language：Japanese   Publisher：(一社)日本衛生学会  

カドミウム曝露はマウスの骨におけるFGF23産生を増加させるが、これはFGF23遺伝子の転写誘導ではなく、FGF23の翻訳後修飾に関わるO型糖鎖修飾酵素GalNAc-T3の誘導によるプロセシングの抑制に起因したものである可能性を明らかにした。また、カドミウムによるリン利尿の発症機序として、カドミウム曝露により増加したFGF23が標的臓器である腎臓に作用し、近位尿細管刷子縁膜に発現するリン輸送担体の抑制を介してリン利尿を引き起こす可能性が考えられる。「カドミウム曝露による腎障害・骨障害の発症とFGF23」「カドミウム曝露によるリン代謝障害とその分子機序」「カドミウム曝露によるFGF23産生亢進機序」について述べた。

Language：Japanese   Publisher：(一社)日本骨代謝学会  

J-GLOBAL

Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

J-GLOBAL

Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

J-GLOBAL

Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

J-GLOBAL

Language：Japanese   Publisher：徳島医学会  

J-GLOBAL

Language：Japanese   Publisher：(NPO)日本消化吸収学会  

ナトリウム依存性のリン輸送体として、SLCファミリーに属するSLC17、SLC20、SLC34が同定されている。SLC34はリン輸送の中心的な役割を担い、SLC20は細胞機能の維持に必要なリン輸送を担うと考えられているが、SLC17A1の役割は十分明らかにされていない。リン代謝に影響を与える因子として、食餌性リン、副甲状腺ホルモン、活性型ビタミンDが知られている。また、FGF23(フォスファトニン)はリン代謝・ビタミンD代謝に関与するが、慢性腎臓病マーカー候補としても注目されている。

J-GLOBAL

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CiNii Books

Other Link： http://search.jamas.or.jp/link/ui/2012270361

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

Language：Japanese   Publisher：(株)日本メディカルセンター  

J-GLOBAL

Language：Japanese   Publisher：(株)日本メディカルセンター  

J-GLOBAL

Language：Japanese   Publisher：(一社)日本腎臓学会  

J-GLOBAL

Language：Japanese   Publisher：(一社)日本骨代謝学会  

J-GLOBAL

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J-GLOBAL

Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

J-GLOBAL

Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

J-GLOBAL

Language：Japanese   Publisher：(株)メディカルドゥ  

リン代謝調節の中心臓器は腎臓であり,血中リン濃度維持の要である。腎近位尿細管にはNaPi-IIaおよびNaPi-IIcが局在しており,リン再吸収を担っている。これらの輸送体は,複数のタンパク質と複合体を形成することで副甲状腺ホルモンPTHやFGF23による調節を受けることが可能となる。特にNa+/H+exchanger regulatory factor1などNaPi-IIの調節を担う多くのタンパク質は,高リン血症や異所性石灰化の治療を考えるうえで興味ある分子標的である。(著者抄録)

Language：Japanese   Publisher：(公社)日本薬理学会  

無機リン酸(リン)代謝調節機構の中心は、腎臓におけるリン再吸収機構である。近位尿細管刷子縁膜に発現するナトリウム/リン共輸送体NaPi-IIaおよびNaPi-IIcが、血中リン濃度調節を担っている。NaPi-IIaは刷子縁膜付近で様々なタンパク質と複合体を形成し、その膜局在やホルモン調節を受ける。一方、遺伝性低リン血症性くる病の責任遺伝子であるNaPi-IIcは、ヒトにおけるリン再吸収の中心分子と考えられる。(著者抄録)

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J-GLOBAL

Language：Japanese   Publisher：(一社)日本病態栄養学会  

Language：Japanese   Publisher：(株)東京医学社  

J-GLOBAL

Language：Japanese   Publisher：(一社)日本骨代謝学会  

J-GLOBAL

Language：Japanese   Publisher：(一社)日本骨代謝学会  

J-GLOBAL

Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

J-GLOBAL

Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

J-GLOBAL

Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

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Language：Japanese   Publisher：(株)メディカルレビュー社  

開発中のリン調節薬について、最近の総説を基に簡単に解説した。本稿で示すように、次々と新しい薬剤開発が企画され、臨床試験が進行している。唾液中のリンを吸着することで、腸管からのリン吸収量を低下させ血中リンを低下させる新しい吸着法、さらにリントランスポーターを分子標的とした阻害薬開発など、リン調節薬の今後の行方に興味が持たれる。(著者抄録)

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Language：Japanese   Publisher：(一社)日本病態栄養学会  

Language：Japanese   Publisher：(一社)日本透析医学会  

J-GLOBAL

Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

J-GLOBAL

Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

J-GLOBAL

Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

J-GLOBAL

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J-GLOBAL

Language：Japanese   Publisher：(株)メディカルドゥ  

Language：Japanese   Publisher：(一社)日本病態栄養学会  

J-GLOBAL

Language：Japanese   Publisher：(一社)日本骨代謝学会  

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J-GLOBAL

Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

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Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

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Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

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Language：Japanese   Publisher：(一社)日本解剖学会  

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Language：Japanese   Publisher：(株)医薬ジャーナル社  

腎におけるリン(P)再吸収異常はさまざまな疾患に関係している。近位尿細管刷子縁膜のナトリウム(Na)依存性Pトランスポーター(NaPi-IIa/NaPi-IIc)はP再吸収の中心である。副甲状腺ホルモン(PTH)によるP利尿効果は、NaPi-II aの細胞内へのエンドサイトーシスを亢進させることにより生じる。NaPi-II aは細胞膜上で複数のPDZ([PSD-95/Disc-large/ZO-1]-binding proteins)タンパクと複合体を形成している。一方、NaPi-II cもPTHによるエンドサイトーシスを受けるが、その細胞内輸送経路はNaPi-II aとは異なるものと推察される。また、FGF23/klotho経路がミネラル代謝において重要な役割を担う事が明らかにされた。FGF23/klothoによるP再吸収機構調節についても要約する。(著者抄録)

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC BONE & MINERAL RES  

Web of Science

Language：Japanese   Publisher：(株)医薬ジャーナル社  

Klotho(kl/kl)マウスは、多彩な早期老化症状を呈し、カルシウム(Ca)/リン(P)代謝異常を示すモデルである。その原因遺伝子α klothoは、新しいP代謝調節因子であるfibroblast growth factor 23(FGF23)と協調してP代謝やビタミンD合成の制御に関与することが明らかにされた。我々は、kl/klマウスに見られる高P血症の発症機構について検討した。本マウスの高P血症は、腸管および腎におけるP吸収・再吸収を担うtype IIナトリウム依存性リン酸(Na/Pi)a,b,cトランスポーターの異常な発現増加によるものであった。kl/klマウスはFGF23の血中濃度が非常に高値であるが、α klotho発現が抑制されていることより、FGF23の作用に対する抵抗性が観察された。ビタミンD合成やP代謝におけるFGF23の作用には、α Klothoの存在が重要であることが示唆された。(著者抄録)

J-GLOBAL

Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

J-GLOBAL

Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

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Language：Japanese   Publisher：金原出版(株)  

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC BONE & MINERAL RES  

Web of Science

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CiNii Books

CiNii Research

Language：Japanese   Publisher：(一社)日本骨代謝学会  

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Language：Japanese   Publisher：医歯薬出版  

CiNii Books

Other Link： http://search.jamas.or.jp/link/ui/2006144277

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J-GLOBAL

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J-GLOBAL

Language：Japanese   Publisher：(一社)日本骨代謝学会  

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Language：English   Publisher：AMER SOC MICROBIOLOGY  

DOI： 10.1128/MCB.24.7.3068-2004

Web of Science

Language：Japanese   Publisher：(株)日本メディカルセンター  

J-GLOBAL

Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

J-GLOBAL

Language：English   Publisher：OXFORD UNIV PRESS  

Web of Science

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CiNii Books

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

Language：English   Publisher：OXFORD UNIV PRESS  

Web of Science

DOI： 10.1007/BF02479931

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Language：Japanese   Publisher：発達腎研究会  

各C末端欠損(Δ511-685)NBATはナトリウム非依存的に塩基性アミノ酸を認識し,ナトリウム依存的に中性アミノ酸認識し輸送するy+アミノ酸輸送システムの特性を示した.NBATがb0,+アミノ酸輸送担体であれば,C末端部の欠損により異なるy+輸送システムに転換するとは考え難い.NBATはアミノ酸輸送担体ではなく,細胞に内在する輸送システムを活性化及び調節する分子として機能している

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：BLACKWELL SCIENCE INC  

Web of Science

DOI： 10.1210/me.11.8.1165

PubMed

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CiNii Books

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：BLACKWELL SCIENCE INC  

Web of Science

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J-GLOBAL

Language：Japanese   Publisher：日本ビタミン学会  

CiNii Books

Language：English   Publisher：Jeff Corporation Co. Ltd  

The hypophosphatemic (Hyp) mouse is a useful model for studying certain genetic defects in renal phosphate (P(i)) handling in humans. Sodium-dependent phosphate transport activity was measured in brush border membrane vesicle (BBMV) prepared from renal cortex and in Xenopus oocytes that had been injected with renal poly(A)+RNA. Pi transport activity in Hyp mice was significantly reduced compared with the control. Northern blot analysis revealed that the level of NaP(i)-7 mRNA was reduced in Hyp mice. Hybrid depletion study showed that the decrease in P(i) transport activity in Hyp mice was primarily due to reduced expression of NaP(i)-7 mRNA. Immunohistochemical staining for control mice confirmed the localization of NaP(i)-7 protein in the brush border membrane (BBM) of proximal convoluted tubules. In contrast, the staining was decreased in the membrane, but increased in intracellular structures of Hyp mice, suggesting that an abnormality of endocytosis/exocytosis in BBM is also involved in Hyp mutation. In conclusion, the defect in renal phosphate reabsorption in Hyp mice resulted from a reduction in mRNA and protein for NaP(i)-7 in the proximal convoluted tubules of midcortical and superficial nephrons.

DOI： 10.1297/cpe.5.89

Scopus

DOI： 10.1074/jbc.271.28.16758

PubMed

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Language：Japanese   Publisher：(NPO)日本消化吸収学会  

日本人シスチン尿症患者にみられる新しい遺伝子変異を同定した.アミノ酸残基341番目のスレオニンと268番目のグルタミン酸は,これまでクローニングされたヒト,ラット及びウサギにおいて高度に保存されている部位であった

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CiNii Books

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CiNii Books

J-GLOBAL

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：BLACKWELL SCIENCE PUBL INC CAMBRIDGE  

Web of Science

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：BLACKWELL SCIENCE PUBL INC CAMBRIDGE  

Web of Science

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Venue：近畿大学　農学部  

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Venue：近畿大学　農学部  

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Language：Japanese   Presentation type：Oral presentation (invited, special)  

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Language：Japanese   Presentation type：Oral presentation (invited, special)