研究者詳細 - 辰巳佐和子

Role of the putative PKC phosphorylation sites of the type IIc sodium-dependent phosphate transporter in parathyroid hormone regulation. 査読国際誌

Fujii T, Segawa H, Hanazaki A, Nishiguchi S, Minoshima S, Ohi A, Tominaga R, Sasaki S, Tanifuji K, Koike M, Arima Y, Shiozaki Y, Kaneko I, Ito M, Tatsumi S, Miyamoto KI.

Clin Exp Nephrol. 23 ( 7 ) 898 - 907 2019年7月

Role of the putative PKC phosphorylation sites of the type IIc sodium-dependent phosphate transporter in parathyroid hormone regulation. 査読

Fujii T, Segawa H, Hanazaki A, Nishiguchi S, Minoshima S, Ohi A, Tominaga R, Sasaki S, Tanifuji K, Koike M, Arima Y, Shiozaki Y, Kaneko I, Ito M, Tatsumi S, Miyamoto KI

Clinical and experimental nephrology 23 ( 7 ) 898 - 907 2019年7月

リン代謝における肝臓Nampt/NAD経路の役割

辰巳佐和子, 中辻翔也, 斎満帆, 桑原頌治, 金子一郎, 瀬川博子, 宮本賢一

日本栄養・食糧学会大会講演要旨集 73回 296 - 296 2019年4月

Analysis of opossum kidney NaPi-IIc sodium-dependent phosphate transporter to understand Pi handling in human kidney. 査読国際誌

Fujii T, Shiozaki Y, Segawa H, Nishiguchi S, Hanazaki A, Noguchi M, Kirino R, Sasaki S, Tanifuji K, Koike M, Yokoyama M, Arima Y, Kaneko I, Tatsumi S, Ito M, Miyamoto KI.

Clin Exp Nephrol. 2019年3月

Analysis of opossum kidney NaPi-IIc sodium-dependent phosphate transporter to understand Pi handling in human kidney. 査読

Fujii T, Shiozaki Y, Segawa H, Nishiguchi S, Hanazaki A, Noguchi M, Kirino R, Sasaki S, Tanifuji K, Koike M, Yokoyama M, Arima Y, Kaneko I, Tatsumi S, Ito M, Miyamoto KI

Clinical and experimental nephrology 23 ( 3 ) 313 - 324 2019年3月

Systemic network for dietary inorganic phosphate adaptation among three organs. 査読国際誌

Ikuta K, Segawa H, Hanazaki A, Fujii T, Kaneko I, Shiozaki Y, Tatsumi S, Ishikawa Y, Miyamoto KI.

Pflugers Arch 2019年1月

NAD metabolism and the SLC34 family: evidence for a liver-kidney axis regulating inorganic phosphate. 査読

Tatsumi S, Katai K, Kaneko I, Segawa H, Miyamoto KI

Pflugers Archiv : European journal of physiology 471 ( 1 ) 109 - 122 2019年1月

Systemic network for dietary inorganic phosphate adaptation among three organs. 査読国際誌

Ikuta K, Segawa H, Hanazaki A, Fujii T, Kaneko I, Shiozaki Y, Tatsumi S, Ishikawa Y, Miyamoto KI

Pflugers Archiv : European journal of physiology 471 ( 1 ) 123 - 136 2019年1月

A Role of Intestinal Alkaline Phosphatase 3 (Akp3) in Inorganic Phosphate Homeostasis. 査読国際誌

Sasaki S, Segawa H, Hanazaki A, Kirino R, Fujii T, Ikuta K, Noguchi M, Sasaki S, Koike M, Tanifuji K, Shiozaki Y, Kaneko I, Tatsumi S, Shimohata T, Kawai Y, Narisawa S, Millán JL, Miyamoto KI.

Kidney Blood Press Res. 2018年9月

Eldecalcitol Causes FGF23 Resistance for Pi Reabsorption and Improves Rachitic Bone Phenotypes in the Male Hyp Mouse. 査読国際誌

Kaneko I, Segawa H, Ikuta K, Hanazaki A, Fujii T, Tatsumi S, Kido S, Hasegawa T, Amizuka N, Saito H, Miyamoto KI.

Endocrinology 2018年7月

Eldecalcitol Causes FGF23 Resistance for Pi Reabsorption and Improves Rachitic Bone Phenotypes in the Male Hyp Mouse. 査読国際誌

Kaneko I, Segawa H, Ikuta K, Hanazaki A, Fujii T, Tatsumi S, Kido S, Hasegawa T, Amizuka N, Saito H, Miyamoto KI

Endocrinology 159 ( 7 ) 2741 - 2758 2018年7月

Effect of Npt2b deletion on intestinal and renal inorganic phosphate (Pi) handling 査読

Kayo Ikuta, Hiroko Segawa, Shohei Sasaki, Ai Hanazaki, Toru Fujii, Aoi Kushi, Yuka Kawabata, Ruri Kirino, Sumire Sasaki, Miwa Noguchi, Ichiro Kaneko, Sawako Tatsumi, Otoya Ueda, Naoko A. Wada, Hiromi Tateishi, Mami Kakefuda, Yosuke Kawase, Shuichi Ohtomo, Yasuhiro Ichida, Akira Maeda, Kou-ichi Jishage, Naoshi Horiba, Ken-ichi Miyamoto

Clinical and Experimental Nephrology 22 ( 3 ) 517 - 528 2018年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

The sodium phosphate cotransporter family and nicotinamide phosphoribosyltransferase contribute to the daily oscillation of plasma inorganic phosphate concentration 査読

Atsumi Miyagawa, Sawako Tatsumi, Wako Takahama, Osamu Fujii, Kenta Nagamoto, Emi Kinoshita, Kengo Nomura, Kayo Ikuta, Toru Fujii, Ai Hanazaki, Ichiro Kaneko, Hiroko Segawa, Ken-ichi Miyamoto

Kidney International 93 ( 5 ) 1073 - 1085 2018年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

The sodium phosphate cotransporter family and nicotinamide phosphoribosyltransferase contribute to the daily oscillation of plasma inorganic phosphate concentration. 国際誌

Miyagawa A, Tatsumi S*, Takahama W, Fujii O, Nagamoto K, Kinoshita E, Nomura K, Ikuta K, Fujii T, Hanazaki A, Kaneko I, Segawa H, Miyamoto KI*.

Kidney International 2018年2月

A Role of Intestinal Alkaline Phosphatase 3 (Akp3) in Inorganic Phosphate Homeostasis. 査読国際誌

Sasaki S, Segawa H, Hanazaki A, Kirino R, Fujii T, Ikuta K, Noguchi M, Sasaki S, Koike M, Tanifuji K, Shiozaki Y, Kaneko I, Tatsumi S, Shimohata T, Kawai Y, Narisawa S, Millán JL, Miyamoto KI

Kidney & blood pressure research 43 ( 5 ) 1409 - 1424 2018年

Effect of Osteocyte-Ablation on Inorganic Phosphate Metabolism: Analysis of Bone-Kidney-Gut Axis. 国際誌

Fujii O, Tatsumi S*, Ogata M, Arakaki T, Sakaguchi H, Nomura K, Miyagawa A, Ikuta K, Hanazaki A, Kaneko I, Segawa H, Miyamoto KI*.

Frontiers in Endocrinology 8 2017年12月

Effect of Osteocyte-Ablation on Inogranic Phosphate Metabolism: Analysis of Bone-Kidney-Gut Axis 査読

Osamu Fujii, Sawako Tatsumi, Mao Ogata, Tomohiro Arakaki, Haruna Sakaguchi, Kengo Nomura, Atsumi Miyagawa, Kayo Ikuta, Ai Hanazaki, Ichiro Kaneko, Hiroko Segawa, Ken-ichi Miyamoto

FRONTIERS IN ENDOCRINOLOGY 8 359 2017年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

Effect of Npt2b deletion on intestinal and renal inorganic phosphate (Pi) handling. 国際誌

Ikuta K, Segawa H, Sasaki S, Hanazaki A, Fujii T, Kushi A, Kawabata Y, Kirino R, Sasaki S, Noguchi M, Kaneko I, Tatsumi S, Ueda O, Wada NA, Tateishi H, Kakefuda M, Kawase Y, Ohtomo S, Ichida Y, Maeda A, Jishage KI, Horiba N, Miyamoto KI.

Clin Exp Nephrol. 2017年11月

Control of phosphate balance by the kidney and intestine. 招待国際誌

Kaneko I, Tatsumi S, Segawa H, Miyamoto KI.

Clin Exp Nephrol. 21 ( Supplement 1 ) 21 - 26 2017年3月

Control of phosphate balance by the kidney and intestine 査読

Ichiro Kaneko, Sawako Tatsumi, Hiroko Segawa, Ken-ichi Miyamoto

CLINICAL AND EXPERIMENTAL NEPHROLOGY 21 ( 1 ) 21 - 26 2017年3月

記述言語：英語出版者・発行元：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

Transcriptional Regulation of Sodium-Phosphate Cotransporter Gene Expression 査読

Ichiro Kaneko, Hironori Yamamoto, Kayo Ikuta, Sawako Tatsumi, Hiroko Segawa, Ken-Ichi Miyamoto

Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals 437 - 445 2016年9月

記述言語：英語掲載種別：論文集(書籍)内論文出版者・発行元：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

Regulation of inorganic phosphate ion homeostasis: crosstalk kidney and other organs. 査読

Tatsumi S, Miyamoto K

Nihon yakurigaku zasshi. Folia pharmacologica Japonica 147 ( 2 ) 84 - 88 2016年2月

記述言語：日本語出版者・発行元：公益社団法人日本薬理学会

無機リン酸（Pi）は生体にとって必須のイオンであり，エネルギーの中間代謝，糖，タンパク質，脂質，核酸代謝，酵素活性の調節，細胞内シグナル伝達，骨格形成の基質など多数の生理機能を有している．血中リン濃度は，おもに腸管吸収，骨代謝（骨形成・吸収），腎臓における排泄と再吸収により維持されている．腎臓からの再吸収能は，リン恒常性維持に重要な役割を果たしているため，その調節は生体内リン恒常性維持の中核と考えられている．これまでの研究から，腎臓尿細管におけるリン再吸収・排泄を制御する巧妙な調節系が存在し，複数の臓器と相互作用していることが分かってきた．とくに，慢性腎臓病（CKD）では，骨と腎臓を結ぶリン代謝系に異常が観察され，CKD早期から骨細胞における線維芽細胞様増殖因子23（FGF23）の発現は亢進し，リン過剰を呈していることが報告されている．また古くより，肝臓がん患者や生体肝移植のドナーに肝臓切除手術を施すと，術後急激に，腎臓によるリン排泄亢進に起因して低リン血症を呈することが知られていた．最近，これらの原因が検討され，肝臓と腎臓を結ぶリン代謝系が明らかにされた．肝臓切除後の尿中リン排泄亢進の原因は，何らかの因子によるNamptの活性化を介した腎臓内ニコチンアミド代謝促進である可能性がわかった．本稿では，新しいリン調節経路を加えて，腎臓を中心とした多臓器にわたるリン恒常性維持機構について概説する．

DOI： 10.1254/fpj.147.84

CiNii Books

その他リンク： https://jlc.jst.go.jp/DN/JLC/20020492838?from=CiNii

Regulation of renal phosphate handling: inter-organ communication in health and disease 査読

Sawako Tatsumi, Atsumi Miyagawa, Ichiro Kaneko, Yuji Shiozaki, Hiroko Segawa, Ken-ichi Miyamoto

JOURNAL OF BONE AND MINERAL METABOLISM 34 ( 1 ) 1 - 10 2016年1月

記述言語：英語出版者・発行元：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

Niacin and Chronic Kidney Disease. 招待国際誌

Taketani Y, Masuda M, Yamanaka-Okumura H, Tatsumi S, Segawa H, Miyamoto K, Takeda E, Yamamoto H.

J Nutr Sci Vitaminol (Tokyo). 61 ( Supplement ) 173 - 175 2015年11月

Relationship between sodium-dependent phosphate transporter (NaPi-IIc) function and cellular vacuole formation in opossum kidney cells 査読

Yuji Shiozaki, Hiroko Segawa, Saori Ohnishi, Akiko Ohi, Mikiko Ito, Ichiro Kaneko, Shinsuke Kido, Sawako Tatsumi, Ken-ichi Miyamoto

Journal of Medical Investigation 62 ( 3 ) 209 - 218 2015年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

Regulation of renal phosphate handling: inter-organ communication in health and disease. 招待国際誌

Tatsumi S*, Miyagawa A, Kaneko I, Shiozaki Y, Segawa H, Miyamoto K.

J Bone Miner Metab. 34 ( 1 ) 1 - 10 2015年8月

Relationship between sodium-dependent phosphate transporter (NaPi-IIc) function and cellular vacuole formation in opossum kidney cells. 国際誌

Shiozaki Y, Segawa H, Ohnishi S, Ohi A, Ito M, Kaneko I, Kido S, Tatsumi S, Miyamoto K.

J Med Invest. 62 ( 3.4 ) 209 - 218 2015年8月

[Bone and Nutrition. Sclerostin and bone metabolism]. 査読

Tatsumi S, Nagamoto K, Ogata M, Miyamoto K

Clinical calcium 25 ( 7 ) 1043 - 1047 2015年7月

Niacin and Chronic Kidney Disease 査読

Yutaka Taketani, Masashi Masuda, Hisami Yamanaka-Okumura, Sawako Tatsumi, Hiroko Segawa, Ken-ichi Miyamoto, Eiji Takeda, Hironori Yamamoto

JOURNAL OF NUTRITIONAL SCIENCE AND VITAMINOLOGY 61 S173 - S175 2015年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

[Genetic diseases of renal phosphate handling]. 査読

Kaneko I, Segawa H, Tatsumi S, Miyamoto K

Nihon Jinzo Gakkai shi 57 ( 4 ) 758 - 765 2015年

Molecular mechanisms of cadmium-induced fibroblast growth factor 23 upregulation in osteoblast-like cells. 国際誌

Kido S, Fujihara M, Nomura K, Sasaki S, Mukai R, Ohnishi R, Kaneko I, Segawa H, Tatsumi S, Izumi H, Kohno K, Miyamoto K.

Toxicol Sci. 139 ( 2 ) 301 - 316 2014年6月

Molecular Mechanisms of Cadmium-Induced Fibroblast Growth Factor 23 Upregulation in Osteoblast-Like Cells 査読

Shinsuke Kido, Marina Fujihara, Kengo Nomura, Shohei Sasaki, Rie Mukai, Ritsuko Ohnishi, Ichiro Kaneko, Hiroko Segawa, Sawako Tatsumi, Hiroto Izumi, Kimitoshi Kohno, Ken-ichi Miyamoto

TOXICOLOGICAL SCIENCES 139 ( 2 ) 301 - 316 2014年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

Hepatectomy-related hypophosphatemia: a novel phosphaturic factor in the liver-kidney axis. 国際誌

Nomura K, Tatsumi S#, Miyagawa A, Shiozaki Y, Sasaki S, Kaneko I, Ito M, Kido S, Segawa H, Sano M, Fukuwatari T, Shibata K, Miyamoto K.

J Am Soc Nephrol. 25 ( 4 ) 761 - 772 2014年4月

Hepatectomy-Related Hypophosphatemia: A Novel Phosphaturic Factor in the Liver-Kidney Axis 査読

Kengo Nomura, Sawako Tatsumi, Atsumi Miyagawa, Yuji Shiozaki, Shohei Sasaki, Ichiro Kaneko, Mikiko Ito, Shinsuke Kido, Hiroko Segawa, Mitsue Sano, Tsutomu Fukuwatari, Katsumi Shibata, Ken-ichi Miyamoto

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 25 ( 4 ) 761 - 772 2014年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

Effect of dietary components on renal inorganic phosphate (Pi) excretion induced by a Pi-depleted diet. 国際誌

Ohnishi R, Segawa H, Ohmoto T, Sasaki S, Hanazaki A, Mori A, Ikuta K, Furutani J, Kawakami E, Tatsumi S, Hamada Y, Miyamoto K.

J Med Invest. 61 ( 1.2 ) 162 - 170 2014年2月

[Sodium-dependent inorganic phosphate transporters and biomineralization]. 査読

Tatsumi S, Fujii O, Miyagawa A, Miyamoto K

Clinical calcium 24 ( 2 ) 249 - 255 2014年2月

Effect of dietary components on renal inorganic phosphate (Pi) excretion induced by a Pi-depleted diet 査読

Ritsuko Ohnishi, Hiroko Segawa, Tomoyo Ohmoto, Shohei Sasaki, Ai Hanazaki, Ayaka Mori, Kayo Ikuta, Junya Furutani, Eri Kawakami, Sawako Tatsumi, Yasuhiro Hamada, Ken-Ichi Miyamoto

Journal of Medical Investigation 61 ( 1-2 ) 162 - 170 2014年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

Vitamin D and type II sodium-dependent phosphate cotransporters. 招待国際誌

Kido S, Kaneko I, Tatsumi S, Segawa H, Miyamoto K.

Contrib Nephrol. 180 86 - 97 2013年5月

Histological examination on osteoblastic activities in the alveolar bone of transgenic mice with induced ablation of osteocytes. 国際誌

Li M, Hasegawa T, Hogo H, Tatsumi S, Liu Z, Guo Y, Sasaki M, Tabata C, Yamamoto T, Ikeda K, Amizuka N.

Histol Histopathol. 28 ( 3 ) 327 - 335 2013年3月

Histological examination on osteoblastic activities in the alveolar bone of transgenic mice with induced ablation of osteocytes 査読

Minqi Li, Tomoka Hasegawa, Hiromi Hogo, Sawako Tatsumi, Zhusheng Liu, Ying Guo, Muneteru Sasaki, Chihiro Tabata, Tsuneyuki Yamamoto, Kyoji Ikeda, Norio Amizuka

HISTOLOGY AND HISTOPATHOLOGY 28 ( 3 ) 327 - 335 2013年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

Vitamin D and Type II Sodium-Dependent Phosphate Cotransporters 査読

Shinsuke Kido, Ichiro Kaneko, Sawako Tatsumi, Hiroko Segawa, Ken-ichi Miyamoto

PHOSPHATE AND VITAMIN D IN CHRONIC KIDNEY DISEASE 180 86 - 97 2013年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

[Information about phosphorus additives and nutritional counseling]. 査読

Kido S, Nomura K, Sasaki S, Shiozaki Y, Segawa H, Tatsumi S

Clinical calcium 22 ( 10 ) 1583 - 1591 2012年10月

[The roles of intestinal and renal sodium dependent phosphate transporters in phosphate homeostasis]. 査読

Segawa H, Sasaki S, Mukai T, Manabe M, Kido S, Tatsumi S, Miyamoto K

Clinical calcium 22 ( 10 ) 1469 - 1476 2012年10月

[Phosphate sensing and intestine]. 査読

Tatsumi S, Nomura K, Miyagawa A, Kido S, Segawa H

Clinical calcium 22 ( 10 ) 1537 - 1541 2012年10月

Processing and stability of type IIc sodium-dependent phosphate cotransporter mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria. 国際誌

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.

Am J Physiol Cell Physiol. 302 ( 9 ) C1316 - C1330 2012年5月

Processing and stability of type IIc sodium-dependent phosphate cotransporter mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria 査読

Sakiko Haito-Sugino, Mikiko Ito, Akiko Ohi, Yuji Shiozaki, Natsumi Kangawa, Takashi Nishiyama, Fumito Aranami, Shohei Sasaki, Ayaka Mori, Shinsuke Kido, Sawako Tatsumi, Hiroko Segawa, Ken-ichi Miyamoto

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY 302 ( 9 ) C1316 - C1330 2012年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

Identification and functional analysis of a splice variant of mouse sodium-dependent phosphate transporter Npt2c. 国際誌

Kuwahara S, Aranami F, Segawa H, Onitsuka A, Honda N, Tominaga R, Hanabusa E, Kaneko I, Yamanaka S, Sasaki S, Ohi A, Nomura K, Tatsumi S, Kido S, Ito M, Miyamoto K.

J Med Invest. 59 ( 1,2 ) 116 - 126 2012年2月

Identification and functional analysis of a splice variant of mouse sodium-dependent phosphate transporter Npt2c 査読

Shoji Kuwahara, Fumito Aranami, Hiroko Segawa, Akemi Onitsuka, Naoko Honda, Rieko Tominaga, Etsuyo Hanabusa, Ichiro Kaneko, Setsuko Yamanaka, Shohei Sasaki, Akiko Ohi, Kengo Nomura, Sawako Tatsumi, Shinsuke Kido, Mikiko Ito, Ken-Ichi Miyamoto

Journal of Medical Investigation 59 ( 1-2 ) 116 - 126 2012年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

[Fibroblast growth factor 23 mediates the phosphaturic actions of cadmium]. 査読

Kido S, Fujihara M, Nomura K, Sasaki S, Shiozaki Y, Segawa H, Tatsumi S, Miyamoto K

Nihon eiseigaku zasshi. Japanese journal of hygiene 67 ( 4 ) 464 - 471 2012年

Inorganic phosphate homeostasis in sodium-dependent phosphate cotransporter Npt2b⁺/⁻ mice. 国際誌

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.

Am J Physiol Renal Physiol. 301 ( 5 ) F1105 - F1113 2011年11月

Inorganic phosphate homeostasis in sodium-dependent phosphate cotransporter npt2b +/-mice 査読

Akiko Ohi, Etsuyo Hanabusa, Otoya Ueda, Hiroko Segawa, Naoshi Horiba, Ichiro Kaneko, Shoji Kuwahara, Tomo Mukai, Shohei Sasaki, Rieko Tominaga, Junya Furutani, Fumito Aranami, Shuichi Ohtomo, Yumiko Oikawa, Yousuke Kawase, Naoko A. Wada, Takanori Tachibe, Mami Kakefuda, Hiromi Tateishi, Kaoru Matsumoto, Sawako Tatsumi, Shinsuke Kido, Naoshi Fukushima, Kou-ichi Jishage, Ken-ichi Miyamoto

American Journal of Physiology - Renal Physiology 301 ( 5 ) F1105 - F1113 2011年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

Inorganic phosphate homeostasis in sodium-dependent phosphate cotransporter Npt2b⁺/⁻ mice. 査読

American journal of physiology. Renal physiology 301 ( 5 ) F1105 - F1113 2011年11月

Sodium-dependent phosphate cotransporters: lessons from gene knockout and mutation studies. 招待国際誌

Miyamoto K, Haito-Sugino S, Kuwahara S, Ohi A, Nomura K, Ito M, Kuwahata M, Kido S, Tatsumi S, Kaneko I, Segawa H.

J Pharm Sci. 100 ( 9 ) 3719 - 3730 2011年9月

Sodium-Dependent Phosphate Cotransporters: Lessons from Gene Knockout and Mutation Studies 査読

Ken-Ichi Miyamoto, Sakiko Haito-Sugino, Shoji Kuwahara, Akiko Ohi, Kengo Nomura, Mikiko Ito, Masashi Kuwahata, Shinsuke Kido, Sawako Tatsumi, Ichiro Kaneko, Hiroko Segawa

JOURNAL OF PHARMACEUTICAL SCIENCES 100 ( 9 ) 3719 - 3730 2011年9月

記述言語：英語出版者・発行元：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

高カルシウム尿を伴う遺伝性低リン血症性クル病の原因遺伝子リン酸トランスポーターNPT2cの変異体解析

塩崎雄治, 杉野さきこ, 大井彰子, 辰巳佐和子, 伊藤美紀子, 宮本賢一

日本腎臓学会誌 53 ( 3 ) 366 - 366 2011年5月

リン代謝における骨細胞の役割

山口誠一, 辰巳佐和子, 釜谷達哉, 塩崎雄治, 野村憲吾, 齋藤友紀子, 木戸慎介, 宮本賢一

腎と骨代謝 23 ( 4 ) 343 - 343 2010年10月

An apical expression signal of the renal type IIc Na+-dependent phosphate cotransporter in renal epithelial cells. 国際誌

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.

Am J Physiol Renal Physiol. 299 ( 1 ) F243 - F254 2010年7月

An apical expression signal of the renal type IIc Na+-dependent phosphate cotransporter in renal epithelial cells 査読

Mikiko Ito, Aya Sakurai, Keiji Hayashi, Akiko Ohi, Natsumi Kangawa, Takashi Nishiyama, Sakiko Sugino, Yoko Uehata, Akihiro Kamahara, Masae Sakata, Sawako Tatsumi, Masashi Kuwahata, Yutaka Taketani, Hiroko Segawa, Ken-Ichi Miyamoto

American Journal of Physiology - Renal Physiology 299 ( 1 ) F243 - F254 2010年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

An apical expression signal of the renal type IIc Na+-dependent phosphate cotransporter in renal epithelial cells 査読

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY 299 ( 1 ) F243 - F254 2010年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

Phosphaturic action of fibroblast growth factor 23 in Npt2 null mice. 国際誌

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.

Am J Physiol Renal Physiol. 298 ( 6 ) F1341 - F1350 2010年6月

Phosphaturic action of fibroblast growth factor 23 in Npt2 null mice 査読

Yuka Tomoe, Hiroko Segawa, Kazuyo Shiozawa, Ichiro Kaneko, Rieko Tominaga, Etsuyo Hanabusa, Fumito Aranami, Junya Furutani, Shoji Kuwahara, Sawako Tatsumi, Mitsutu Matsumoto, Mikiko Ito, Ken-ichi Miyamoto

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY 298 ( 6 ) F1341 - F1350 2010年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

Phosphaturic action of fibroblast growth factor 23 in Npt2 null mice 査読

American Journal of Physiology - Renal Physiology 298 ( 6 ) F1341 - F1350 2010年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

新規リン利尿因子の探索

野村憲吾, 辰巳佐和子, 菊井聡子, 齋藤友紀子, 塩崎雄治, 山口誠一, 木戸慎介, 宮本賢一

日本栄養・食糧学会大会講演要旨集 64回 105 - 105 2010年5月

Fibroblast growth factor 23 mediates the phosphaturic actions of cadmium. 国際誌

Aranami F, Segawa H, Furutani J, Kuwahara S, Tominaga R, Hanabusa E, Tatsumi S, Kido S, Ito M, Miyamoto K.

J Med Invest. 57 ( 1,2 ) 95 - 108 2010年2月

Fibroblast growth factor 23 mediates the phosphaturic actions of cadmium 査読

Fumito Aranami, Hiroko Segawa, Junya Furutani, Shoji Kuwahara, Rieko Tominaga, Etsuyo Hanabusa, Sawako Tatsumi, Shinsuke Kido, Mikiko Ito, Ken-Ichi Miyamoto

Journal of Medical Investigation 57 ( 1-2 ) 95 - 108 2010年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

Localization of polypyrimidine-tract-binding protein is involved in the regulation of albumin synthesis by branched-chain amino acids in HepG2 cells. 国際誌

Kuwahata M, Yoshimura T, Sawai Y, Amano S, Tomoe Y, Segawa H, Tatsumi S, Ito M, Ishizaki S, Ijichi C, Sonaka I, Oka T, Miyamoto K.

J Nutr Biochem. 19 ( 7 ) 438 - 447 2008年7月

Localization of polypyrimidine-tract-binding protein is involved in the regulation of albumin synthesis by branched-chain amino acids in HepG2 cells 査読

Masashi Kuwahata, Tomoyo Yoshimura, Yukiko Sawai, Saki Amano, Yuka Tomoe, Hiroko Segawa, Sawako Tatsumi, Mikiko Ito, Sonoko Ishizaki, Chiori Ijichi, Ichiro Sonaka, Tatsuzo Oka, Ken-ichi Miyamoto

JOURNAL OF NUTRITIONAL BIOCHEMISTRY 19 ( 7 ) 438 - 447 2008年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

Polypyrimidine tract-binding protein is involved in regulation of albumin synthesis in response to food intake. 国際誌

Kuwahata M, Kuramoto Y, Sawai Y, Amano S, Tomoe Y, Segawa H, Tatsumi S, Ito M, Kobayashi Y, Kido Y, Oka T, Miyamoto K.

J Nutr Sci Vitaminol (Tokyo). 54 ( 2 ) 142 - 147 2008年4月

Polypyrimidine tract-binding protein is involved in regulation of albumin synthesis in response to food intake 査読

Masashi Kuwahata, Yasuko Kuramoto, Yukiko Sawai, Saki Amano, Yuka Tomoe, Hiroko Segawa, Sawako Tatsumi, Mikiko Ito, Yukiko Koayashi, Yasuhiro Krdo, Tatsuzo Oka, Ken-Ichi Miyamoto

JOURNAL OF NUTRITIONAL SCIENCE AND VITAMINOLOGY 54 ( 2 ) 142 - 147 2008年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

Life-long caloric restriction reveals biphasic and dimorphic effects on bone metabolism in rodents. 国際誌

Tatsumi S*, Ito M, Asaba Y, Tsutsumi K, Ikeda K.

Endocrinology. 149 ( 2 ) 634 - 641 2008年2月

Life-long caloric restriction reveals biphasic and dimorphic effects on bone metabolism in rodents 査読

Sawako Tatsumi, Masako Ito, Yutaro Asaba, Kumi Tsutsumi, Kyoji Ikeda

ENDOCRINOLOGY 149 ( 2 ) 634 - 641 2008年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

[New aspect of renal phosphate reabsorption and phosphate metabolism]. 査読

Miyamoto K, Tatsumi S, Ito M, Segawa H

Clinical calcium 17 ( 10 ) 1485 - 1492 2007年10月

Control of phosphate appetite in young rats. 国際誌

Ohnishi R, Segawa H, Kawakami E, Furutani J, Ito M, Tatsumi S, Kuwahata M, Miyamoto K.

J Med Invest. 54 ( 3, 4 ) 366 - 369 2007年8月

New aspect of renal phosphate reabsorption: the type IIc sodium-dependent phosphate transporter. 招待国際誌

Miyamoto K, Ito M, Tatsumi S, Kuwahata M, Segawa H.

Am J Nephrol. 27 ( 5 ) 503 - 5015 2007年8月

Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. 国際誌

Tatsumi S, Ishii K, Amizuka N, Li M, Kobayashi T, Kohno K, Ito M, Takeshita S, Ikeda K.

Cell Metab. 5 ( 6 ) 464 - 475 2007年6月

Overexpression of gamma-glutamyltransferase in transgenic mice accelerates bone resorption and causes osteoporosis. 国際誌

Hiramatsu K, Asaba Y, Takeshita S, Nimura Y, Tatsumi S, Katagiri N, Niida S, Nakajima T, Tanaka S, Ito M, Karsenty G, Ikeda K.

Endocrinology. 148 ( 6 ) 2708 - 2715 2007年6月

Overexpression of gamma-glutamyltransferase in transgenic mice accelerates bone resorption and causes osteoporosis 査読

Kiyoshi Hiramatsu, Yutaro Asaba, Sunao Takeshita, Yuji Nimura, Sawako Tatsumi, Nobuyoshi Katagiri, Shumpei Niida, Toshihiro Nakajima, Sakae Tanaka, Masako Ito, Gerard Karsenty, Kyoji Ikeda

ENDOCRINOLOGY 148 ( 6 ) 2708 - 2715 2007年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

Targeted ablation of Osteocytes induces osteoporosis with defective mechanotransduction 査読

Sawako Tatsumi, Kiyoaki Ishii, Norio Amizuka, Minqi Li, Toshihiro Kobayashi, Kenji Kohno, Masako Ito, Sunao Takeshita, Kyoji Ikeda

CELL METABOLISM 5 ( 6 ) 464 - 475 2007年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

[alpha Klotho and inorganic phosphate metabolism]. 査読

Miyamoto K, Segawa H, Ito M, Tatsumi S

Clinical calcium 17 ( 5 ) 698 - 703 2007年5月

Characterization of the molecular mechanisms involved in the increased insulin secretion in rats with acute liver failure. 国際誌

Kuwahata M, Tomoe Y, Harada N, Amano S, Segawa H, Tatsumi S, Ito M, Oka T, Miyamoto K.

Biochim Biophys Acta. 1772 ( 1 ) 60 - 65 2007年1月

Unique uptake and efflux systems of inorganic phosphate in osteoclast-like cells. 国際誌

Ito M, Haito S, Furumoto M, Uehata Y, Sakurai A, Segawa H, Tatsumi S, Kuwahata M, Miyamoto K.

Am J Physiol Cell Physiol. 292 ( 1 ) C526 - C534 2007年1月

Characterization of the molecular mechanisms involved in the increased insulin secretion in rats with acute liver failure 査読

Masashi Kuwahata, Yuka Tomoe, Nagakatsu Harada, Saki Amano, Hiroko Segawa, Sawako Tatsumi, Mikiko Ito, Tatsuzo Oka, Ken-ichi Miyamoto

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE 1772 ( 1 ) 60 - 65 2007年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

Characterization of the molecular mechanisms involved in the increased insulin secretion in rats with acute liver failure. 査読

Kuwahata M, Tomoe Y, Harada N, Amano S, Segawa H, Tatsumi S, Ito M, Oka T, Miyamoto K

Biochimica et biophysica acta 1772 ( 1 ) 60 - 65 2007年1月

Unique uptake and efflux systems of inorganic phosphate in osteoclast-like cells 査読

Mikiko Ito, Sakiko Haito, Mari Furumoto, Yoko Uehata, Aya Sakurai, Hiroko Segawa, Sawako Tatsumi, Masashi Kuwahata, Ken-ichi Miyamoto

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY 292 ( 1 ) C526 - C534 2007年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

Control of phosphate appetite in young rats 査読

Ritsuko Ohnishi, Hiroko Segawa, Eri Kawakami, Junya Furutani, Mikiko Ito, Sawako Tatsumi, Masashi Kuwahata, Ken-Ichi Miyamoto

Journal of Medical Investigation 54 ( 3-4 ) 366 - 369 2007年

記述言語：英語掲載種別：研究論文（国際会議プロシーディングス）

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

Correlation between hyperphosphatemia and type II Na/Pi cotransporter activity in klotho mice. 査読

Segawa H, Yamanaka S, Ohno Y, Onitsuka A, Shiozawa K, Aranami F, Furutani J, Tomoe Y, Ito M, Kuwahata M, Tatsumi S, Imura A, Nabeshima Y, Miyamoto KI

Am J Physiol Renal Physiol 292 ( 2 ) F769-79 - F779 2007年

New aspect of renal phosphate reabsorption: The type IIc sodium-dependent phosphate transporter 査読

Ken-Ichi Miyamoto, Mikiko Ito, Sawako Tatsumi, Masashi Kuwahata, Hiroko Segawa

AMERICAN JOURNAL OF NEPHROLOGY 27 ( 5 ) 503 - 515 2007年

記述言語：英語出版者・発行元：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

Activation of pre-mRNA splicing by human RNPS1 is regulated by CK2 phosphorylation. 国際誌

Trembley JH, Tatsumi S, Sakashita E, Loyer P, Slaughter CA, Suzuki H, Endo H, Kidd VJ, Mayeda A.

Mol Cell Biol. 25 ( 4 ) 1446 - 1457 2005年2月

Activation of pre-mRNA splicing by human RNPS1 is regulated by CK2 phosphorylation 査読

JH Trembley, S Tatsumi, E Sakashita, P Loyer, CA Slaughter, H Suzuki, H Endo, VJ Kidd, A Mayeda

MOLECULAR AND CELLULAR BIOLOGY 25 ( 4 ) 1446 - 1457 2005年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC MICROBIOLOGY

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

Human RNPS1 and its associated factors: a versatile alternative pre-mRNA splicing regulator in vivo. 国際誌

Sakashita E, Tatsumi S, Werner D, Endo H, Mayeda A.

Mol Cell Biol. 24 ( 3 ) 1174 - 1187 2004年2月

Human RNPS1 and its associated factors: A versatile alternative pre-mRNA splicing regulator in vivo 査読

E Sakashita, S Tatsumi, D Werner, H Endo, A Mayeda

MOLECULAR AND CELLULAR BIOLOGY 24 ( 3 ) 1174 - 1187 2004年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC MICROBIOLOGY

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

Molecular mechanisms of mammalian inorganic phosphate homeostasis. 招待国際誌

Takeda E, Taketani Y, Morita K, Tatsumi S, Katai K, Nii T, Yamamoto H, Miyamoto K.

Advances in Enzyme Regulation 40 ( 1 ) 285 - 302 2002年6月

Growth-related renal type II Na/Pi cotransporter. 国際誌

Segawa H, Kaneko I, Takahashi A, Kuwahata M, Ito M, Ohkido I, Tatsumi S, Miyamoto K.

J Biol Chem. 277 ( 22 ) 19665 - 19672 2002年5月

Identification and functional analysis of three isoforms for the Na+-dependent phosphate co-transporter (NaPi-2) in rat kidney. 招待国際誌

Miyamoto K, Tatsumi S, Segawa H, Ohkido I, Takeda E.

Nephrol Dial Transplant. 15 ( Suppl 6 ) 31 - 33 2002年5月

Growth-related renal type IINa/P-i cotransporter 査読

H Segawa, Kaneko, I, A Takahashi, M Kuwahata, M Ito, Ohkido, I, S Tatsumi, K Miyamoto

JOURNAL OF BIOLOGICAL CHEMISTRY 277 ( 22 ) 19665 - 19672 2002年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

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

Identification and functional analysis of three isoforms for the Na+-dependent phosphate co-transporter (NaPi-2) in rat kidney 査読

K Miyamoto, S Tatsumi, H Segawa, Ohkido, I, E Takeda

NEPHROLOGY DIALYSIS TRANSPLANTATION 15 31 - 33 2000年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OXFORD UNIV PRESS

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.

Molecular mechanisms of mammalian inorganic phosphate homeostasis. 査読

Takeda E, Taketani Y, Morita K, Tatsumi S, Katai K, Nii T, Yamamoto H, Miyamoto K

Advances in enzyme regulation 40 285 - 302 2000年

Regulation of intestinal Na+-dependent phosphate co-transporters by a low-phosphate diet and 1,25-dihydroxyvitamin D3. 国際誌

Katai K, Miyamoto K, Kishida S, Segawa H, Nii T, Tanaka H, Tani Y, Arai H, Tatsumi S, Morita K, Taketani Y, Takeda E.

Biochem J. 343 ( Pt 3 ) 705 - 712 1999年11月

Regulation of intestinal Na+-dependent phosphate co-transporters by a low-phosphate diet and 1,25-dihydroxyvitamin D3. 査読

Katai K, Miyamoto K, Kishida S, Segawa H, Nii T, Tanaka H, Tani Y, Arai H, Tatsumi S, Morita K, Taketani Y, Takeda E

The Biochemical journal 343 Pt 3 705 - 712 1999年11月

Nicotinamide inhibits sodium-dependent phosphate cotransport activity in rat small intestine. 国際誌

Katai K, Tanaka H, Tatsumi S, Fukunaga Y, Genjida K, Morita K, Kuboyama N, Suzuki T, Akiba T, Miyamoto K, Takeda E.

Nephrol Dial Transplant. 14 ( 5 ) 195 - 201 1999年5月

Regulation of PiT-1, a sodium-dependent phosphate co-transporter in rat parathyroid glands. 招待国際誌

Miyamoto K, Tatsumi S, Segawa H, Morita K, Nii T, Fujioka A, Kitano M, Inoue Y, Takeda E.

Nephrol Dial Transplant. 14 ( Suppl 1 ) 73 - 75 1999年5月

Nicotinamide inhibits sodium-dependent phosphate cotransport activity in rat small intestine 査読

K Katai, H Tanaka, S Tatsumi, Y Fukunaga, K Genjida, K Morita, N Kuboyama, T Suzuki, T Akiba, K Miyamoto, E Takeda

NEPHROLOGY DIALYSIS TRANSPLANTATION 14 ( 5 ) 1195 - 1201 1999年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OXFORD UNIV PRESS

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.

Regulation of PiT-1, a sodium-dependent phosphate co-transporter in rat parathyroid glands 査読

K Miyamoto, S Tatsumi, H Segawa, K Morita, T Nii, A Fujioka, M Kitano, Y Inoue, E Takeda

NEPHROLOGY DIALYSIS TRANSPLANTATION 14 73 - 75 1999年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OXFORD UNIV PRESS

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.

Does the parathyroid 'see' phosphate? 国際誌

Miyamoto K, Tatsumi S, Morita K, Takeda E.

Nephrol Dial Transplant. 13 ( 11 ) 2727 - 2729 1998年11月

Identification of three isoforms for the Na+-dependent phosphate cotransporter (NaPi-2) in rat kidney. 国際誌

Tatsumi S, Miyamoto K, Kouda T, Motonaga K, Katai K, Ohkido I, Morita K, Segawa H, Tani Y, Yamamoto H, Taketani Y, Takeda E.

J Biol Chem. 273 ( 44 ) 28568 - 28575 1998年10月

Identification of three isoforms for the Na+-dependent phosphate cotransporter (NaPi-2) in rat kidney 査読

S Tatsumi, K Miyamoto, T Kouda, K Motonaga, K Katai, Ohkido, I, K Morita, H Segawa, Y Tani, H Yamamoto, Y Taketani, E Takeda

JOURNAL OF BIOLOGICAL CHEMISTRY 273 ( 44 ) 28568 - 28575 1998年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

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.

Effects of dietary Pi on the renal Na+-dependent Pi transporter NaPi-2 in thyroparathyroidectomized rats. 国際誌

Takahashi F, Morita K, Katai K, Segawa H, Fujioka A, Kouda T, Tatsumi S, Nii T, Taketani Y, Haga H, Hisano S, Fukui Y, Miyamoto KI, Takeda E.

Biochem J. 333 ( Pt1 ) 175 - 181 1998年7月

Effects of dietary Pi on the renal Na+-dependent Pi transporter NaPi-2 in thyroparathyroidectomized rats. 査読

Takahashi F, Morita K, Katai K, Segawa H, Fujioka A, Kouda T, Tatsumi S, Nii T, Taketani Y, Haga H, Hisano S, Fukui Y, Miyamoto KI, Takeda E

The Biochemical journal 333 ( Pt 1) 175 - 181 1998年7月

Regulation of type II renal Na+-dependent inorganic phosphate transporters by 1,25-dihydroxyvitamin D3. Identification of a vitamin D-responsive element in the human NAPi-3 gene. 国際誌

Taketani Y, Segawa H, Chikamori M, Morita K, Tanaka K, Kido S, Yamamoto H, Iemori Y, Tatsumi S, Tsugawa N, Okano T, Kobayashi T, Miyamoto K, Takeda E.

J Biol Chem. 273 ( 23 ) 14575 - 14581 1998年6月

Regulation of type II renal Na+-dependent inorganic phosphate transporters by 1,25-dihydroxyvitamin D-3 - Identification of a vitamin D-responsive element in the human NAPI-3 gene 査読

Y Taketani, H Segawa, M Chikamori, K Morita, K Tanaka, S Kido, H Yamamoto, Y Iemori, S Tatsumi, N Tsugawa, T Okano, T Kobayashi, K Miyamoto, E Takeda

JOURNAL OF BIOLOGICAL CHEMISTRY 273 ( 23 ) 14575 - 14581 1998年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

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

Characterization of the 5' flanking region of the human NPT-1 Na+/phosphate cotransporter gene. 国際誌

Taketani Y, Miyamoto K, Chikamori M, Tanaka K, Yamamoto H, Tatsumi S, Morita K, Takeda E.

Biochim Biophys Acta. 1396 ( 3 ) 267 - 272 1998年5月

Molecular cloning and hormonal regulation of PiT-1, a sodium-dependent phosphate cotransporter from rat parathyroid glands. 国際誌

Tatsumi S, Segawa H, Morita K, Haga H, Kouda T, Yamamoto H, Inoue Y, Nii T, Katai K, Taketani Y, Miyamoto KI, Takeda E.

Endocrinology. 139 ( 4 ) 1692 - 1699 1998年4月

Molecular cloning and hormonal regulation of PiT-1, a sodium-dependent phosphate cotransporter from rat parathyroid glands. 査読

Tatsumi S, Segawa H, Morita K, Haga H, Kouda T, Yamamoto H, Inoue Y, Nii T, Katai K, Taketani Y, Miyamoto KI, Takeda E

Endocrinology 139 ( 4 ) 1692 - 1699 1998年4月

Characterization of the 5 ' flanking region of the human NPT-1 Na+/phosphate cotransporter gene 査読

Y Taketani, K Miyamoto, M Chikamori, K Tanaka, H Yamamoto, S Tatsumi, K Morita, E Takeda

BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION 1396 ( 3 ) 267 - 272 1998年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE BV

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.

Characterization of the 5' flanking region of the human NPT-1 Na+/phosphate cotransporter gene. 査読

Taketani Y, Miyamoto K, Chikamori M, Tanaka K, Yamamoto H, Tatsumi S, Morita K, Takeda E

Biochimica et biophysica acta 1396 ( 3 ) 267 - 272 1998年3月

Cloning, functional expression and dietary regulation of the mouse neutral and basic amino acid transporter (NBAT). 査読

Segawa H, Miyamoto K, Ogura Y, Haga H, Morita K, Katai K, Tatsumi S, Nii T, Taketani Y, Takeda E

The Biochemical journal 328 ( Pt 2) 657 - 664 1997年12月

Relative contributions of Na+-dependent phosphate co-transporters to phosphate transport in mouse kidney: RNase H-mediated hybrid depletion analysis. 国際誌

Miyamoto K, Segawa H, Morita K, Nii T, Tatsumi S, Taketani Y, Takeda E.

Biochem J. 327 ( Pt3 ) 735 - 739 1997年11月

Relative contributions of Na+-dependent phosphate co-transporters to phosphate transport in mouse kidney: RNase H-mediated hybrid depletion analysis. 査読

Miyamoto K, Segawa H, Morita K, Nii T, Tatsumi S, Taketani Y, Takeda E

The Biochemical journal 327 ( Pt 3) 735 - 739 1997年11月

Immunohistochemical and RT-PCR detection of Na+-dependent inorganic phosphate cotransporter (NaPi-2) in rat brain. 国際誌

Hisano S, Haga H, Li Z, Tatsumi S, Miyamoto KI, Takeda E, Fukui Y.

Brain Res. 772 ( 1, 2 ) 149 - 155 1997年10月

Immunohistochemical and RT-PCR detection of Na+-dependent inorganic phosphate cotransporter (NaP(i)-2) in rat brain 査読

Setsuji Hisano, Hiromi Haga, Zhunan Li, Sawako Tatsumi, Ken-Ichi Miyamoto, Eiji Takeda, Yoshihiro Fukui

Brain Research 772 ( 1-2 ) 149 - 155 1997年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

Acute regulation by dietary phosphate of the sodium-dependent phosphate transporter (NaP(i)-2) in rat kidney. 査読

Cloning, functional expression and dietary regulation of the mouse neutral and basic amino acid transporter (NBAT) 国際誌

Segawa H, Miyamoto K, Ogura Y, Haga H, Morita K, Katai K, Tatsumi S, Nii T, Taketani Y, Takeda E

Biochem J. 328 ( Pt 2 ) 657 - 664 1997年10月

Structural organization of the human vitamin D receptor chromosomal gene and its promoter. 国際誌

Miyamoto K, Kesterson RA, Yamamoto H, Taketani Y, Nishiwaki E, Tatsumi S, Inoue Y, Morita K, Takeda E, Pike JW.

Mol Endocrinol. 11 ( 8 ) 1165 - 1179 1997年7月

Gene structure and functional analysis of the human Na+/phosphate co-transporter 国際誌

Taketani Y, Miyamoto Ki, Tanaka K, Katai K, Chikamori M, Tatsumi S, Segawa H, Yamamoto H, Morita K, Takeda E.

Biochem J. 324 ( Pt 3 ) 927 - 934 1997年6月

Gene structure and functional analysis of the human Na+/phosphate co-transporter. 査読

Taketani Y, Miyamoto Ki, Tanaka K, Katai K, Chikamori M, Tatsumi S, Segawa H, Yamamoto H, Morita K, Takeda E

The Biochemical journal 324 ( Pt 3) 927 - 934 1997年6月

Acute regulation by dietary phosphate of the sodium-dependent phosphate transporter (NaP(i)-2) in rat kidney. 国際誌

Katai K, Segawa H, Haga H, Morita K, Arai H, Tatsumi S, Taketani Y, Miyamoto K, Hisano S, Fukui Y, Takeda E.

J Biochem. 121 ( 1 ) 50 - 55 1997年1月

Katai K, Segawa H, Haga H, Morita K, Arai H, Tatsumi S, Taketani Y, Miyamoto K, Hisano S, Fukui Y, Takeda E

Journal of biochemistry 121 ( 1 ) 50 - 55 1997年1月

記述言語：英語出版者・発行元：The Japanese Biochemical Society

Alteration of the dietary intake of phosphate (Pi) leads to rapid changes in renal Pi 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-Pi (0. 02%) diet (CLP rats), the low-Pi diet followed by a high-P, (1. 2%) diet (AHP rats), or a normal (0. 6%) diet (control rats). Nat-dependent Pi 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 Pi transport in the AHP rats indicated that the reduction was accompanied by a decrease in the apparent Vmax, for Na+-dependent Pi uptake. Northern blot analysis showed no difference in the abundance of NaPi-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 NaPi-2 protein as compared with CLP rats. Immunoreactive signals for NaPi-2 were detected in lysosomal fractions of AHP and CLP rats. Immunohistochemical analysis showed that, NaPi-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-Pi-induced reduction of NaPi-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-Pi 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 Pi intake.

Effects of truncation of the COOH-terminal region of a Na+-independent neutral and basic amino acid transporter on amino acid transport in Xenopus oocytes. 国際誌

Miyamoto K, Segawa H, Tatsumi S, Katai K, Yamamoto H, Taketani Y, Haga H, Morita K, Takeda E.

J Biol Chem. 271 ( 28 ) 16758 - 16763 1996年7月

Role of rBAT gene products in cystinuria. 国際誌

Miyamoto K, Katai K, Tatsumi S, Sone K, Segawa H, Takada K, Yamamoto H, Taketani Y, Morita K, Kanayama H, Kagawa S, Takeda E.

Int J Urol. 3 ( 1 ) S92 - S94 1996年1月

Role of rBAT gene products in cystinuria 査読

Ken-ichi Miyamoto, Kanako Katai, Sawako Tatsumi, Kanako Sone, Hiroko Segawa, Kazumi Takada, Hironori Yamamoto, Yutaka Taketani, Kyoko Morita, Hiroomi Kanayama, Susumu Kagawa, Eiji Takeda

International Journal of Urology 3 ( 1 ) s92 - s94 1996年

記述言語：英語掲載種別：研究論文（学術雑誌）

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