{"insert":{"type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/118209","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/37164731","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=397418","label":"url"}],"paper_title":{"en":"Effects of EOS789, a novel pan-phosphate transporter inhibitor, on phosphate metabolism : Comparison with a conventional phosphate binder","ja":"Effects of EOS789, a novel pan-phosphate transporter inhibitor, on phosphate metabolism : Comparison with a conventional phosphate binder"},"authors":{"en":[{"name":"Tanifuji Kazuya"},{"name":"Shiozaki Yuji"},{"name":"Koike Megumi"},{"name":"Uga Minori"},{"name":"Miura Mizuki"},{"name":"Higashi Ayami"},{"name":"Shimohata Takaaki"},{"name":"Takahashi Akira"},{"name":"Hayashi Hisayoshi"},{"name":"Ishizuka Noriko"},{"name":"Ichida Yasuhiro"},{"name":"Ohtomo Shuichi"},{"name":"Horiba Naoshi"},{"name":"Miyamoto Ken-ichi"},{"name":"Segawa Hiroko"}],"ja":[{"name":"谷藤 和也"},{"name":"塩﨑 雄治"},{"name":"小池 萌"},{"name":"宇賀 穂"},{"name":"三浦 美月"},{"name":"東 彩生"},{"name":"下畑 隆明"},{"name":"髙橋 章"},{"name":"Hayashi Hisayoshi"},{"name":"Ishizuka Noriko"},{"name":"Ichida Yasuhiro"},{"name":"Ohtomo Shuichi"},{"name":"Horiba Naoshi"},{"name":"宮本 賢一"},{"name":"瀬川 博子"}]},"description":{"en":"Inorganic phosphate (Pi) binders are the only pharmacologic treatment approved for hyperphosphatemia. However, Pi binders induce the expression of intestinal Pi transporters and have limited effects on the inhibition of Pi transport. EOS789, a novel pan-Pi transporter inhibitor, reportedly has potent efficacy in treating hyperphosphatemia. We investigated the properties of EOS789 with comparison to a conventional Pi binder. Protein and mRNA expression levels of Pi transporters were measured in intestinal and kidney tissues from male Wistar rats fed diets supplemented with EOS789 or lanthanum carbonate (LC). 32Pi permeability was measured in intestinal tissues from normal rats using a chamber. Increased protein levels of NaPi-2b, an intestinal Pi transporter, and luminal Pi removal were observed in rats treated with LC but not in rats treated with EOS789. EOS789 but not LC suppressed intestinal protein levels of the Pi transporter Pit-1 and sodium/hydrogen exchanger isoform 3. 32Pi flux experiments using small intestine tissues from rats demonstrated that EOS789 may affect transcellular Pi transport in addition to paracellular Pi transport. EOS789 has differing regulatory effects on Pi metabolism compared to LC. The properties of EOS789 may compensate for the limitations of LC therapy. The combined or selective use of EOS789 and conventional Pi binders may allow tighter control of hyperphosphatemia. J. Med. Invest. 70 : 260-270, February, 2023.","ja":"Inorganic phosphate (Pi) binders are the only pharmacologic treatment approved for hyperphosphatemia. However, Pi binders induce the expression of intestinal Pi transporters and have limited effects on the inhibition of Pi transport. EOS789, a novel pan-Pi transporter inhibitor, reportedly has potent efficacy in treating hyperphosphatemia. We investigated the properties of EOS789 with comparison to a conventional Pi binder. Protein and mRNA expression levels of Pi transporters were measured in intestinal and kidney tissues from male Wistar rats fed diets supplemented with EOS789 or lanthanum carbonate (LC). 32Pi permeability was measured in intestinal tissues from normal rats using a chamber. Increased protein levels of NaPi-2b, an intestinal Pi transporter, and luminal Pi removal were observed in rats treated with LC but not in rats treated with EOS789. EOS789 but not LC suppressed intestinal protein levels of the Pi transporter Pit-1 and sodium/hydrogen exchanger isoform 3. 32Pi flux experiments using small intestine tissues from rats demonstrated that EOS789 may affect transcellular Pi transport in addition to paracellular Pi transport. EOS789 has differing regulatory effects on Pi metabolism compared to LC. The properties of EOS789 may compensate for the limitations of LC therapy. The combined or selective use of EOS789 and conventional Pi binders may allow tighter control of hyperphosphatemia. J. Med. Invest. 70 : 260-270, February, 2023."},"publication_date":"2023","publication_name":{"en":"The Journal of Medical Investigation : JMI","ja":"The Journal of Medical Investigation : JMI"},"volume":"Vol.70","number":"No.1,2","starting_page":"260","ending_page":"270","languages":["eng"],"referee":true,"identifiers":{"doi":["10.2152/jmi.70.260"],"issn":["1349-6867"]},"published_paper_type":"scientific_journal"}}
{"insert":{"type":"published_papers"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/35428804","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=387857","label":"url"}],"paper_title":{"en":"Tmem174, a regulator of phosphate transporter prevents hyperphosphatemia.","ja":"Tmem174, a regulator of phosphate transporter prevents hyperphosphatemia."},"authors":{"en":[{"name":"Sasaki Sumire"},{"name":"Shiozaki Yuji"},{"name":"Hanazaki Ai"},{"name":"Koike Megumi"},{"name":"Tanifuji Kazuya"},{"name":"Uga Minori"},{"name":"Kawahara Kota"},{"name":"Kaneko Ichiro"},{"name":"Kawamoto Yasuharu"},{"name":"Wiriyasermkul Pattama"},{"name":"Hasegawa Tomoka"},{"name":"Amizuka Norio"},{"name":"Miyamoto Ken-ichi"},{"name":"Nagamori Shushi"},{"name":"Kanai Yoshikatsu"},{"name":"Segawa Hiroko"}],"ja":[{"name":"佐々木 すみれ"},{"name":"塩﨑 雄治"},{"name":"花崎 愛"},{"name":"小池 萌"},{"name":"谷藤 和也"},{"name":"宇賀 穂"},{"name":"Kawahara Kota"},{"name":"金子 一郎"},{"name":"Kawamoto Yasuharu"},{"name":"Wiriyasermkul Pattama"},{"name":"Hasegawa Tomoka"},{"name":"Amizuka Norio"},{"name":"宮本 賢一"},{"name":"Nagamori Shushi"},{"name":"Kanai Yoshikatsu"},{"name":"瀬川 博子"}]},"description":{"en":"Renal type II sodium-dependent inorganic phosphate (Pi) transporters NaPi2a and NaPi2c cooperate with other organs to strictly regulate the plasma Pi concentration. A high Pi load induces expression and secretion of the phosphaturic hormones parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) that enhance urinary Pi excretion and prevent the onset of hyperphosphatemia. How FGF23 secretion from bone is increased by a high Pi load and the setpoint of the plasma Pi concentration, however, are unclear. Here, we investigated the role of Transmembrane protein 174 (Tmem174) and observed evidence for gene co-expression networks in NaPi2a and NaPi2c function. Tmem174 is localized in the renal proximal tubules and interacts with NaPi2a, but not NaPi2c. In Tmem174-knockout (KO) mice, the serum FGF23 concentration was markedly increased but increased Pi excretion and hypophosphatemia were not observed. In addition, Tmem174-KO mice exhibit reduced NaPi2a responsiveness to FGF23 and PTH administration. Furthermore, a dietary Pi load causes marked hyperphosphatemia and abnormal NaPi2a regulation in Tmem174-KO mice. Thus, Tmem174 is thought to be associated with FGF23 induction in bones and the regulation of NaPi2a to prevent an increase in the plasma Pi concentration due to a high Pi load and kidney injury.","ja":"Renal type II sodium-dependent inorganic phosphate (Pi) transporters NaPi2a and NaPi2c cooperate with other organs to strictly regulate the plasma Pi concentration. A high Pi load induces expression and secretion of the phosphaturic hormones parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) that enhance urinary Pi excretion and prevent the onset of hyperphosphatemia. How FGF23 secretion from bone is increased by a high Pi load and the setpoint of the plasma Pi concentration, however, are unclear. Here, we investigated the role of Transmembrane protein 174 (Tmem174) and observed evidence for gene co-expression networks in NaPi2a and NaPi2c function. Tmem174 is localized in the renal proximal tubules and interacts with NaPi2a, but not NaPi2c. In Tmem174-knockout (KO) mice, the serum FGF23 concentration was markedly increased but increased Pi excretion and hypophosphatemia were not observed. In addition, Tmem174-KO mice exhibit reduced NaPi2a responsiveness to FGF23 and PTH administration. Furthermore, a dietary Pi load causes marked hyperphosphatemia and abnormal NaPi2a regulation in Tmem174-KO mice. Thus, Tmem174 is thought to be associated with FGF23 induction in bones and the regulation of NaPi2a to prevent an increase in the plasma Pi concentration due to a high Pi load and kidney injury."},"publication_date":"2022-04-15","publication_name":{"en":"Scientific Reports","ja":"Scientific Reports"},"volume":"Vol.12","number":"No.1","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1038/s41598-022-10409-3"],"issn":["2045-2322"]},"published_paper_type":"scientific_journal"}}
{"insert":{"type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/117148","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/36244766","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85139886601&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=387841","label":"url"}],"paper_title":{"en":"Dietary polyphosphate has a greater effect on renal damage and FGF23 secretion than dietary monophosphate","ja":"Dietary polyphosphate has a greater effect on renal damage and FGF23 secretion than dietary monophosphate"},"authors":{"en":[{"name":"Sasaki Sumire"},{"name":"Koike Megumi"},{"name":"Tanifuji Kazuya"},{"name":"Uga Minori"},{"name":"Kawahara Kota"},{"name":"Komiya Aoi"},{"name":"Miura Mizuki"},{"name":"Harada Yamato"},{"name":"Hamaguchi Yuki"},{"name":"Sasaki Shohei"},{"name":"Shiozaki Yuji"},{"name":"Kaneko Ichiro"},{"name":"Miyamoto Ken-ichi"},{"name":"Segawa Hiroko"}],"ja":[{"name":"佐々木 すみれ"},{"name":"小池 萌"},{"name":"谷藤 和也"},{"name":"宇賀 穂"},{"name":"川原 滉太"},{"name":"小宮 蒼"},{"name":"三浦 美月"},{"name":"原田 和"},{"name":"濵口 ゆき"},{"name":"佐々木 祥平"},{"name":"塩﨑 雄治"},{"name":"金子 一郎"},{"name":"宮本 賢一"},{"name":"瀬川 博子"}]},"description":{"en":"Phosphate (Pi)-containing food additives are used in several forms. Polyphosphate (PPi) salt has more harmful effects than monophosphate (MPi) salt on bone physiology and renal function. This study aimed to analyze the levels of parathyroid hormone PTH and fibroblast growth factor 23 (FGF23) and the expression of renal / intestinal Pi transport-related molecules in mice fed with an MPi or PPi diet. There were no significant differences in plasma Pi concentration and fecal Pi excretion levels between mice fed with the high-MPi and PPi diet. However, more severe tubular dilatation, interstitial fibrosis, and calcification were observed in the kidneys of mice fed with the high PPi diet versus the MPi diet. Furthermore, there was a significant increase in serum FGF23 levels and a decrease in renal phosphate transporter protein expression in mice fed with the PPi diet versus the MPi diet. Furthermore, the high MPi diet was associated with significantly suppressed expression and activity of intestinal alkaline phosphatase protein. In summary, PPi has a more severe effect on renal damage than MPi, as well as induces more FGF23 secretion. Excess FGF23 may be more involved in inflammation, fibrosis, and calcification in the kidney. J. Med. Invest. 69 : 173-179, August, 2022.","ja":"Phosphate (Pi)-containing food additives are used in several forms. Polyphosphate (PPi) salt has more harmful effects than monophosphate (MPi) salt on bone physiology and renal function. This study aimed to analyze the levels of parathyroid hormone PTH and fibroblast growth factor 23 (FGF23) and the expression of renal / intestinal Pi transport-related molecules in mice fed with an MPi or PPi diet. There were no significant differences in plasma Pi concentration and fecal Pi excretion levels between mice fed with the high-MPi and PPi diet. However, more severe tubular dilatation, interstitial fibrosis, and calcification were observed in the kidneys of mice fed with the high PPi diet versus the MPi diet. Furthermore, there was a significant increase in serum FGF23 levels and a decrease in renal phosphate transporter protein expression in mice fed with the PPi diet versus the MPi diet. Furthermore, the high MPi diet was associated with significantly suppressed expression and activity of intestinal alkaline phosphatase protein. In summary, PPi has a more severe effect on renal damage than MPi, as well as induces more FGF23 secretion. Excess FGF23 may be more involved in inflammation, fibrosis, and calcification in the kidney. J. Med. Invest. 69 : 173-179, August, 2022."},"publication_date":"2022","publication_name":{"en":"The Journal of Medical Investigation : JMI","ja":"The Journal of Medical Investigation : JMI"},"volume":"Vol.69","number":"No.3","starting_page":"173","ending_page":"179","languages":["eng"],"referee":true,"identifiers":{"doi":["10.2152/jmi.69.173"],"issn":["1349-6867"]},"published_paper_type":"scientific_journal"}}
{"insert":{"type":"published_papers"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/118681","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=387844","label":"url"}],"paper_title":{"en":"最前線 慢性腎臓病の合併症とlipotoxicity","ja":"最前線 慢性腎臓病の合併症とlipotoxicity"},"authors":{"en":[{"name":"Masuda Masashi"},{"name":"Shiozaki Yuji"},{"name":"Taketani Yutaka"},{"name":"宮崎 淳"}],"ja":[{"name":"増田 真志"},{"name":"塩﨑 雄治"},{"name":"竹谷 豊"},{"name":"宮崎 淳"}]},"publication_date":"2022-04-01","publication_name":{"en":"Farumashia","ja":"ファルマシア"},"volume":"Vol.58","number":"No.4","starting_page":"329","ending_page":"333","languages":["jpn"],"identifiers":{"doi":["10.14894/faruawpsj.58.4_329"],"issn":["2189-7026"]},"published_paper_type":"research_institution"}}
{"insert":{"type":"published_papers"},"force":{"see_also":[{"@id":"https://cir.nii.ac.jp/crid/1390574047045835904/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=387834","label":"url"}],"paper_title":{"en":"The physiological function of vitamin D which maintains phosphate homeostasis","ja":"生体内リン恒常性を維持するビタミンD作用"},"authors":{"en":[{"name":"金子 一郎"},{"name":"宇賀 穂"},{"name":"Shiozaki Yuji"},{"name":"Miyamoto Ken-ichi"},{"name":"Segawa Hiroko"}],"ja":[{"name":"金子 一郎"},{"name":"宇賀 穂"},{"name":"塩﨑 雄治"},{"name":"宮本 賢一"},{"name":"瀬川 博子"}]},"description":{"en":"Inorganic phosphate (Pi) plays essential roles in many biological processes. Blood Pi level should be maintained at a constant range because hypophosphatemia causes rickets/osteomalacia, whereas hyperphosphatemia causes cardiovascular events in chronic kidney disease (CKD) or hemodialysis patients. As a phosphaturic hormone, parathyroid hormone (PTH) or fibroblast growth factor (FGF) 23 strongly suppresses Pi reabsorption. 1,25-Dihydroxyvitamin D[1,25(OH) 2D] up-regulates Pi absorption in intestines, and regulates urinary Pi excretion through PTH or FGF23.
Activated FGF23 signal leads urinary Pi excretion, and hypophosphatemic rickets (FGF23-related hypophosphatemic rickets). Rickets characterized as vitamin D deficiency also associates with impaired renal Pi reabsorption in juvenile stage in addition to low Pi absorption in intestines. Now, burosumab (FGF23 neutralizing antibody) has a beneficent effect on FGF23-related hypophosphatemic rickets/osteomalacia. The antibody increases renal Pi reabsorption and 1,25(OH) 2D production. On the other hand, treatment with vitamin D alone in an animal model of X-linked hypophosphatemic rickets can potentially increase renal Pi reabsorption, despite of excess FGF23, and improve hypophosphatemia and bone phenotypes.
CKD patients often accompany with mineral bone disorder (CKD-MBD) such as hyperparathyroidism, cardiovascular calcification, and osteodystrophy. Prevention and treatment for hyperphosphatemia or hypovitaminosis D would improve their QOL or mortality.
Thus, renal Pi reabsorption is important for bone and mineral homeostasis. We focus on the metabolism of Pi and vitamin D to understand the molecular mechanism for the onset and prevention of diseases associated with Pi and vitamin D.","ja":"無機リン酸(リン)は生体内で多くの生化学反応に必要であるため,血中リン濃度は一定範囲内に維持されている.低リン血症はくる病/骨軟化症の原因となり,高リン血症は慢性腎臓病(CKD)や透析患者において心血管疾患発症のリスクファクターとなる.副甲状腺ホルモン(PTH)や線維芽細胞増殖因子23(FGF23)は,腎臓でのリン再吸収を抑制することでリン利尿ホルモンとして機能している.活性型ビタミンD[1,25(OH) 2D]は小腸でのリン吸収を促進することに加え,PTHやFGF23の産生調節も行い,生体内リン恒常性を保っている.
FGF23シグナル活性化は,尿中リン排泄を亢進させ,低リン血症性くる病を引き起こす(FGF23関連低リン血症性くる病).また,ビタミンD依存性くる病では,小腸でのリン吸収抑制に加えて,成長期における尿中リン排泄の亢進が低リン血症の原因となる.近年,FGF23中和抗体(Burosumab)が開発され,腎臓リン再吸収と1,25(OH) 2D産生を改善することでくる病患者に有益な効果を示し,欧米及び日本でFGF23関連低リン血症性くる病・骨軟化症の治療薬として承認されている.一方,X連鎖性低リン血症性くる病モデル動物を用いた実験では,ビタミンD製剤単独投与でも低リン血症性くる病の症状を改善できることが示された.この作用の特徴は,FGF23が高値を示すにも関わらずリン再吸収の改善がみとめられることである.
CKD患者では,しばしば副甲状腺機能亢進や心血管疾患,骨異栄養症など骨ミネラル代謝異常(CKD-MBD: 慢性腎臓病に伴う骨ミネラル代謝異常)が出現する.CKDにおける高リン血症および1,25(OH) 2D低下を予防・治療することで患者のQOLや予後を改善することが報告されている.
このように腎臓でのリン再吸収調節は骨ミネラル代謝に極めて重要である.我々は,リンとビタミンD代謝に注目し,疾患の発症および予防を分子レベルで理解することに努めている."},"publication_date":"2021-06-25","publication_name":{"en":"Vitamins","ja":"ビタミン"},"volume":"Vol.95","number":"No.56","starting_page":"280","ending_page":"285","languages":["jpn"],"identifiers":{"doi":["10.20632/vso.95.5-6_280"],"issn":["0006-386X"]},"published_paper_type":"research_institution"}}