Inorganic phosphate transportsome and human disease

2009 Fiscal Year Final Research Report

• Project/Area Number: 17081013
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokushima
• Principal Investigator: MIYAMOTO Kenichi The University of Tokushima, 大学院・ヘルスバイオサイエンス研究部, 教授 (70174208)
• Co-Investigator(Kenkyū-buntansha): TAKETANI Yutaka 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 准教授 (30263825) ; TATSUMI Sawako 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 助教 (80420545) ; SEGAWA Hiroko 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 助教 (70325257) ; ITOH Mikiko 兵庫県立大学, 環境人間学部, 准教授 (50314852)
• Project Period (FY): 2005 – 2009
• Keywords: 無機リン酸 / 腎臓 / ナトリウム依存性 / 輸送体 / リン利尿因子Inorganic phosphate / Kidney / Sodium-dependent / transporter / phosphaturic factor

Research Abstract

The maintenance of constant circulating levels of Pi depends on the activity of the kidney. Two types of Na/Pi co-transporters (Npt2a, Npt2c) have been identified in the kidney. The abundance of Npt2a and Npt2c in the apical membrane of the renal epithelial cells is a major determinant for Pi homeostasis. Npt2a knockout (KO) mice exhibit increased urinary Pi excretion, a 50% to 70% decrease in renal BBM vesicle Na/Pi cotransport, and hypophosphatemia. Npt2a KO mice also overexpress Npt2c, which may support residual renal Pi reabsorption function. Laboratory and bone abnormalities are more profound in Npt2a^<-/->Npt2c^<-/->double knockout (DKO) mice than in animals with ablation of only one transporter (Npt2a or Npt2c), indicating that both molecules have similar non-redundant roles in Pi homeostasis in rodents and humans. In addition, we found that the mutations of human Npt2c cause hereditary hypophosphatemie rickets with hypercalciuria (ITHRH)
After correct targeting and insertion into the plasma membrane of epithelial cells, specific protein-protein interactions may be required to stabilize the final localization of membrane proteins. Classical yeast two-hybrid screens performed against the C-terminus of NaPi-ll (Npt2a and Npt2c) revealed interactions of this cotransporter with several PDZ domain containing proteins that may contribute to the stabilization of NaPi-ll at the apical membrane. NaPi-He (Npt2c) was shown to interact with NHERF1 and NHERF4. The consequences of these interactions for apical positioning and regulation of NaPi-llc remain to be clarified. In this study, we discovered new aspect of the regulation of the Pi transportsome in the kidney.

Research Products

• [Journal Article] An apical expression signal of the renal type II Na+-dependent phosphate cotransporter in renal prithelial cells. (2010)
  • Author(s): Ito M, Sakurai A, Hayashi K, Ohi A, Kangawa N, Nishiyama T, Sugino S, Uehata Y, Kamahara A, Sakata Tatsumi S, Kuwahata M, Taketani Y, Segawa H, Miyamoto K.
  • Journal Title: Am J Physiol Renal Physiol.
  • Peer Reviewed
• [Journal Article] Phosphaturic action of fibroblast growth factor 23 in Npt2 null mice. (2010)
  • Author(s): Tomoe Y, Segawa H, Shiozawa K, Kaneko I, Tominaga R, Hanabusa E, Aranami H, Furutani J, Kuwahara S, Tatsumi S, Matsumoto M, Ito M, Miyamoto K.
  • Journal Title: Am J Physicl Renal Physiol. 298(6) Pages: F1341-50
  • Peer Reviewed
• [Journal Article] Thyroid hormones regulate phosphate homoeostasis through transcriptional control of the renal type IIa sodium-dependent. (2010)
  • Author(s): Ishiguro M, Yamamoto H, Masuda M, Kozai NI, Takei Y, Tanaka S, Sato T, Segawa H, Taketani Y, Arai H, Miyamoto K, Takeda E.
  • Journal Title: Biochem J. 427(1) Pages: 161-9
  • Peer Reviewed
• [Journal Article] Not2a and Npt2c in mice play distinct and synergistic roles in inorganic phosphate metabolism and skeletal development. (2009)
  • Author(s): Segawa H, Onitsuka A, Furutani J, Kaneko I, Aranami F, Matsumoto N, Tomoe Y, Kuwahata M, Ito M, Matsumoto M, Li M, Amizuka N, Miyamoto K.
  • Journal Title: Am J Physiol Renal Physiol. 297(3) Pages: F671-8
  • Peer Reviewed
• [Journal Article] Differential regulation of the renal sodium-phosphate cotransporters NaPi-IIa, NaPi-IIc, and PiT-2 in dietary potassium deficiency. (2009)
  • Author(s): Breusegem SY, Takahashi H, Giral-Arnal H, Wang X, Jiang T, Verlander JW, Wilson P, Miyazaki-Anzai S, Sutherl, E, Caldas Y, Blaine JT, Segawa H, Miyamoto K, Barry NP, Levi M.
  • Journal Title: Am J Physiol Renal Physiol. 297(2) Pages: F350-61
  • Peer Reviewed
• [Journal Article] The roles of Na/Pi-II transporters in phosphate metabolism. (2009)
  • Author(s): Segawa H, Aranami H, Kaneko I, Tomoe Y, Miyamoto K.
  • Journal Title: Bone. Vol.45 Pages: 52-57
  • Peer Reviewed
• [Journal Article] Type llc sodium- dependent phosphate transporter regulates calcium metabolism. (2009)
  • Author(s): Segawa H, Onitsuka A, Kuwahata M, Hanabusa E, Furutani J, Kaneko I, Tomoe Y, Aranami H, Matsumoto M, Li M, Amizuka N, Miyamoto K.
  • Journal Title: J Am Nephrol 20(1) Pages: 104-113
  • Peer Reviewed
• [Journal Article] Hereditary hypophosphatemic rickets with hypercalciuria: a study for the phosphate transporter gene type IIc and osteoblastic function. (2007)
  • Author(s): Yamamoto T, Michigami T, Aranami F, Segawa H, Yoh K, Nakajima S, Miyamoto K, Ozono K.
  • Journal Title: J Bone Miner Metab. 25(6) Pages: 407-13
  • Peer Reviewed
• [Journal Article] New aspect of renal phosphate reabsorption: the type IIc sodium-dependent phosphate transporter. (2007)
  • Author(s): Miyamoto K, Ito M, Tatsumi S, Kuwahata Segawa H.
  • Journal Title: Am J Nephrol 27(5) Pages: 503-15
  • Peer Reviewed
• [Journal Article] Cavelin-1 in extracellular matrix vesicles secreted from osteoblasts. (2007)
  • Author(s): Sawada N, Taketani Y, Amizuka N, Ichikawa M, Ogawa C, Nomoto K, Nashiki K, Sato T, Arai H, Isshiki M, Segawa H, Yamamoto H, Miyamoto K, Takeda E.
  • Journal Title: Bone 41(1) Pages: 52-8
  • Peer Reviewed
• [Journal Article] Parathyroid hormone-dependent endocytosis of renal type IIc Na-Pi cotransporter. (2007)
  • Author(s): Segawa H, Yamanaka S, Onitsuka A, Tomoe Y, Kuwahata M, Ito M, Taketani Y, Miyamoto K.
  • Journal Title: Am J Physiol Renal Physiol. 292(1) Pages: F395-403
  • Peer Reviewed
• [Journal Article] Correlation between hyperphosphatemia and type II Na/Pi cotransporter activity in klotho mice. (2007)
  • Author(s): 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 K.
  • Journal Title: Am J Physiol Renal Physiol. 292(2) Pages: F769-79
  • Peer Reviewed
• [Journal Article] Unique uptake and efflux systems of inorganic phosphate in osteoclast-like cells. (2007)
  • Author(s): Ito M, Haito S, Furumoto M, Uehata Y, Sakurai A, Segawa H, Tatsumi S, Kuwahata Miyamoto K.
  • Journal Title: Am J Physiol Cell Physiol 292(1) Pages: C526-34
  • Peer Reviewed
• [Journal Article] Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. (2007)
  • Author(s): Tatsumi S, Ishii K, Amizuka N, Li M, Kobayashi T, Kohno K, Ito M, Takeshita S, Ikeda K.
  • Journal Title: Cell Metab. 5(6) Pages: 464-75
  • Peer Reviewed
• [Journal Article] Inhibitory effect of JTP-59557, a new triazole derivative, on intestinal phosphate transport in vitro and in vivo. (2005)
  • Author(s): Matsuo A, Negoro T, Seo T, Kitao Y, Shindo M, Segawa H, Miyamoto K.
  • Journal Title: Eur J Pharmacol 517(1-2) Pages: 111-119
  • Peer Reviewed
• [Journal Article] Role of the vitamin D receptor in FGF23 action on phosphate metabolism. (2005)
  • Author(s): Inoue Y, Segawa H, Kaneko I, Yamanaka S, Kusano K, Kawakami E, Furutani J, Ito M, Kuwahata M, Saito H, Fukushima N, Kato S, Kanayama HO, Miyamoto K.
  • Journal Title: Biochem J. 390 Pages: 325-31
  • Peer Reviewed
• [Journal Article] Vitamin D and phosphate regulate fibroblast groeth factor-23 in K-562 cells. (2005)
  • Author(s): Ito M, Sakai Y, Furumoto M, Segawa H, Haiso S, Yamanaka S, Nakamura R, Kuwahata Miyamoto K.
  • Journal Title: Am J Physiol Endocrinol Metab 288(6) Pages: E1101-9
  • Peer Reviewed
• [Journal Article] Characterization of inorganic phosphate transport in osteoclast like cells. (2005)
  • Author(s): Ito M, Matsuka N, Izuka M, Haito S, Sakai Y, Nakamura R, Segawall, Kuwahata M, Yamamoto H, Wesley J. Pike, Miyamoto K.
  • Journal Title: Am J Physiol. 288(4) Pages: C921-31
  • Peer Reviewed
• [Journal Article] Internalization of renal type IIc Na-Pi cotransporter in response to a high-phosphate diet. (2005)
  • Author(s): Segawa H, Yamanaka S, Ito M, Kuwahata M, Shono ht Yamamoto T, Miyamoto K.
  • Journal Title: Am J Physiol Renal Physiol. 288(3) Pages: F587-96
  • Peer Reviewed
• [Journal Article] Circulating FGF-23 is regulated by lalpha, 25-dihydroxyvitamiq D3 and phosphorus in vivo. (2005)
  • Author(s): Saito H, Maeda A, Ohtomo S, Hirata M, Kusano K, Kato S, Ogata E, Segawa H, Miyamoto K, Fukushima N.
  • Journal Title: J Biol Chem. 280(4) Pages: 2543-9
  • Peer Reviewed
• [Journal Article] Role of membrane microdomains in PTH-mediated down-regulation of NaPi-IIa in opossum kidney cells. (2005)
  • Author(s): Nashiki K, Taketani Y, Takeichi T, Sawada N, Yamamoto H, Ichikawa M, Arai H, Miyamoto K, Takeda E.
  • Journal Title: Kidney Int. 68(3) Pages: 1137-47
  • Peer Reviewed