Identification and functional analysis of regulatory factors for fibroblast growth factor 23/klotho/inorganic sensor system

2010 Fiscal Year Final Research Report

• Project/Area Number: 20390236
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Kidney internal medicine
• 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): SEGAWA Hiroko 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 講師 (70325257) ; 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)
• Project Period (FY): 2008 – 2010
• Keywords: リン / 腎臓 / トランスポーター / 副甲状腺ホルモン / 骨 / 低リン血症 / クル病

Research Abstract

In the present study, we investigated inorganic phosphate (Pi) metabolism in the type IIa and type IIc sodium-dependent Pi cotransporter gene knockout mice (Npt2a^<-/->Npt2c>^<-/-> DKO mice). To clarify the relative importance of Npt2a and Npt2c, we studied DKO mice These mice exhibited severe hypophosphatemia, hypercalciuria, and rickets. This phenotype is similar to that seen inhereditary hypophosphatemic rickts with hypercalciuria (HHRH) which is characterized by hypophosphate, short stature, rickets, and/or osteomalacia, with secondary absorptive hypercalciuria. Studies of the DKO animals showed that the expansion of the late hypertrophic zone in the bone, which is a characteristic feature of rickets, might be secondary to the impaired apoptosis of these cells. In the analysis of DNA microarray in the kidney of DKO mice, we identified the clone encode calcium activated chloride channel 6 (CLCA6) and analyzed its function in Xenopus oocytes and renal epithelial cells. The present study indicates that CLCA6 modulates the activity of type III renal sodium-dependent Pi cotransporter PiT2 in DKO mice.

Research Products

• [Journal Article] Sodium-dependent phosphate cotransporters : Lessons from gene knockout and mutation studies. (2011)
  • Author(s): Miyamoto KI, Haito-Sugino S, Kuwahara S, Ohi A, Nomura K, Ito M, Kuwahata M, Kido S, Tatsumi S, Kaneko I, Segawa H.
  • Journal Title: J Pharm Sci. doi:10.1002/jps.22614.
  • Peer Reviewed
• [Journal Article] Transgenic overexpression of the extra-large Gsα variant XL αs enhances Gsα-mediated responses in the mouse renal proximal tubule in vivo. (2011)
  • Author(s): Liu Z, Segawa H, Aydin C, Reyes M, Erben RG, Weinstein LS, Chen M, Marshansky V, Frohlich LF, Bastepe M.
  • Journal Title: Endocrinology. 152(4) Pages: 1222-33
  • Peer Reviewed
• [Journal Article] Source matters : from phosphorus load to bioavailability. (2011)
  • Author(s): Fukagawa M, Komaba H, Miyamoto K.
  • Journal Title: Clin J Am Soc Nephrol. 6(2) Pages: 239-240
  • Peer Reviewed
• [Journal Article] Hypophosphatemia in vitamin D receptor null mice : effect of rescue diet on the developmental changes in renal Na+ -dependent phosphate cotransporters. (2011)
  • Author(s): Kaneko I, Segawa H, Furutani J, Kuwahara S, Aranami F, Hanabusa E, Tominaga R, Giral H, Caldas Y, Levi M, Kato S, Miyamoto K.
  • Journal Title: Pflugers Arch. 461(1) Pages: 77-90
  • Peer Reviewed
• [Journal Article] Acute down-regulation of sodium-dependent phosphate transporter NPT2a involves predominantly the cAMP/PKA pathway as revealed by signaling-selective parathyroid hormone analogs. (2011)
  • Author(s): Nagai S, Okazaki M, Segawa H, Bergwitz C, Dean T, Potts JT Jr, Mahon MJ, Gardella TJ, Juppner H.
  • Journal Title: J Biol Chem. 286(2) Pages: 1618-1626
  • Peer Reviewed
• [Journal Article] An apical expression signal of the renal type IIc Na+-dependent phosphate cotransporter in renal epithelial cells. (2010)
  • Author(s): 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 KI.
  • Journal Title: Am J Phisiol Renal Phisiol. 299(1) Pages: F243-254
  • 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 F, Furutani J, Kuwahara S, Tatsumi S, Matsumoto M, Ito M, Miyamoto KI.
  • Journal Title: Am J Physiol Renal Physiol. 298(6) Pages: F1341-1350
  • Peer Reviewed
• [Journal Article] Fibroblast growth factor 23 mediates the phosphaturic actions of cadmium. (2010)
  • Author(s): Aranami F, Segawa H, Furutani J, Kuwahara S, Tominaga R, Hanabusa E, Tatsumi S, Kido S, Ito M, Miyamoto KI.
  • Journal Title: J Med Invest. 57(1-2) Pages: 95-108
  • Peer Reviewed
• [Journal Article] Regulation of renal sodium-dependent phosphate cotransporter genes (Npt2a and Npt2c) by all-trans-retinoic acid and its receptors. (2010)
  • Author(s): Masuda M, Yamamoto H, Kozai M, Tanaka S, Ishiguro M, Takei Y, Nakahashi O, Ikeda S, Uebanso T, Taketani Y, Segawa H, Miyamoto KI, Takeda E.
  • Journal Title: Biochem J. 429(3) Pages: 583-592
  • Peer Reviewed
• [Journal Article] Immunohistochemical analyses of parathyroid hormone-dependent downregulation of renal type II Na-Pi cotransporters by cryobiopsy. (2010)
  • Author(s): Matsumoto N, Hemmi A, Yamato H, Ohnishi R, Segawa H, Ohno S, Miyamoto K.
  • Journal Title: J Med Invest. 57(1-2) Pages: 138-145
  • Peer Reviewed
• [Journal Article] Thyroid hormones regulate phosphate homoeostasis through transcriptional control of the renal type IIa sodium-dependent phosphate co-transporter (Npt2a) gene. (2010)
  • Author(s): Ishiguro M, Yamamoto H, Masuda M, Kozai M, Takei Y, Tanaka S, Sato T, Segawa H, Taketani Y, Arai H, Miyamoto K, Takeda E.
  • Journal Title: Biochem J. 427(1) Pages: 161-169
  • Peer Reviewed
• [Journal Article] Mutant FGF23 Prevents the Progression Chronic Kidney Disease but Aggravates Renal Osteodystrophy in Uremic Rats. (2009)
  • Author(s): Kusano K, Saito H, Segawa H, Fukushima N, Miyamoto K.
  • Journal Title: J Nutr Sci Vitaminol 55 Pages: 99-105
  • Peer Reviewed
• [Journal Article] Npt2a 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: F671-678
  • 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, Sutherland E, Caldas Y, Blaine JT, Segawa H, Miyamoto K, Barry NP, Levi M.
  • Journal Title: Am J Physiol Renal Physiol. 297(2) Pages: F350-361
  • 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: S2-S7
  • Peer Reviewed
• [Journal Article] Type 11c 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] Polypyrimidine tract-binding protein is involved in regulation of albumin synthesis in response to food intake. (2008)
  • Author(s): Kuwahata M, Kuramoto Y, Sawai Y, Amano S, Tomoe Y, Segawa H, Tatsumi S, Ito M, Kobayashi Y, Kido Y, Oka T, Miyamoto K.
  • Journal Title: J Nutr Sci Vitaminol. 54(2) Pages: 142-147
  • Peer Reviewed
• [Journal Article] Role of low protein and low phosphorus diet in the progression of chronic kidney disease in uremic rats. (2008)
  • Author(s): Kusano K, Segawa H, Ohnishi R, Fukushima N, Miyamoto K
  • Journal Title: J Nutr Sci Vitaminol. 54 Pages: 237-243
  • Peer Reviewed
• [Presentation] Phosphate Homeostasis in Osteocyte-Ablated Mice. (2010)
  • Author(s): Tatsumi S, Yamaguchi S,Kamatani T, Shiozaki Y, Nomura K, Saito Y, Kido S, Segawa H, Miyamoto K.
  • Organizer: The American Society of Nephrology. Colorado Convention Center
  • Place of Presentation: Denver, CO, USA.
  • Year and Date: 2010-11-18
• [Presentation] PTH-Dependent Regulation of Npt2a and Npt2c Expression Appears To Involve Predominantly cAMP/PKA-Dependent Mechanisms. (2010)
  • Author(s): Segawa H, Maeda A, Thomas J, Gardella, Miyamoto K, Harald J.
  • Organizer: The American Society of Nephrology. Colorado Convention Center
  • Place of Presentation: Denver, CO, USA.
  • Year and Date: 2010-11-18
• [Presentation] Inorganic Phosphate Homeostasis in the Type 1 Na/Pi-transporter(NPT1)Null Mice. (2009)
  • Author(s): Segawa H, Sawai Y, Tominaga R, Hanabusa E,Kuwahara S, Aranami F, Furutani J, Kaneko I, Kuroiwa Y, Kisuhara H,Sugiyama Y, Miyamoto K.
  • Organizer: The American Society of Nephrology. San Diego Convention Center.
  • Place of Presentation: San Diego, CA, USA.
  • Year and Date: 2009-10-30
• [Presentation] Deficiency of Vitamin D Receptor Prevents the Development of Renal Pi Reabsorption. (2009)
  • Author(s): Kaneko I, Segawa H, Hanabusa E, Miyamoto K.
  • Organizer: The American Society of Nephrology. San Diego Convention Center
  • Place of Presentation: San Diego, CA, USA.
  • Year and Date: 2009-10-30
• [Presentation] klotho Modulates the Activity of Type 11c Na+-Dependent Phosphate Cotransporter (NaPi-11c) in Renal Epithelial Cells. (2009)
  • Author(s): Nishiyama T, Ito M, Ohi A,Sugino S, Kaneko I,Sakata M,Kamahara A, Kido S, Tatsumi S, Segawa H, Miyamoto K.
  • Organizer: The American Society of Nephrology. San Diego Convention Center.
  • Place of Presentation: San Diego, CA, USA.
  • Year and Date: 2009-10-30
• [Presentation] Characterization of Phosphate Metabolism in the NaPi-11b Hetero Knockout Mice. (2009)
  • Author(s): Hanabusa E, Ueda O, Segawa H, Kaneko I, Kuwahara S, Tatsumi S, Ohtomo S, Horiba N, Tachibe T, Wada N, Kawase Y, Jishage K, Fukushima N, Miyamoto K
  • Organizer: The American Society of Nephrology San Diego Convention Center
  • Place of Presentation: San Diego, CA, USA.
  • Year and Date: 2009-10-30
• [Presentation] The American Society of Nephrology. (2008)
  • Author(s): Miyamoto K, Klotho, Minerals, Aging.
  • Organizer: Pennsylvania Convention Center
  • Place of Presentation: Philadelphia, Pennsylvania, USA.
  • Year and Date: 20081104-20081109
• [Presentation] The Synergistic Role of Npt2a and Npt2c in Inorganic Phoshate Metabolism of Mice. (2008)
  • Author(s): Segawa H, Tomoe Y, Furutani J, Kaneko I, Aranami F, Kuwahara S, Ito M, Miyamoto K.
  • Organizer: The American Society for Bone and Mineral Research. alais des congres de Montreal Montreal
  • Place of Presentation: Quebec, Canada.
  • Year and Date: 20080912-20080916
• [Presentation] Mutation of Type IIc Na+- Dependent Phosphate Cotransporter (NaPi-IIc) and Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) The American Society of Nephrology. (2008)
  • Author(s): Ito M, Sakurai A, Ohi A, Hayashi K, Nishiyama T, Kangawa N, Sugino S, Tatsumi S, Segawa H, Miyamoto K.
  • Organizer: Pennsylvania Convention Center
  • Place of Presentation: Philadelphia, Pennsylvania, USA.
  • Year and Date: 2008-11-07
• [Presentation] 1.25 (OH) 2Vitamin D3 Modulates The Expression of the Humman Type IIcSodium-Dependent Phosphate Cotranspoter (NaPi-IIc) Gene in Renal Osteoblast Cells. (2008)
  • Author(s): Tatsumi S, Fukushima Y, Shimamura S, Ito M, Segawa H, Miyamoto K.
  • Organizer: The American Society of Nephrology. Pennsylvania ConventionCenter
  • Place of Presentation: Philadelphia Pennsylvania, USA.
  • Year and Date: 2008-11-07
• [Presentation] Effect of Fibroblast Growth Factor (FGF) 23 on Npt2a, Npt2c Double-Knockout (WKO) Mice. (2008)
  • Author(s): Tomoe Y, Segawa H,Kaneko I, Furutani J, Aranami F, Kuwahara S, Tominaga R, Hanabusa E, Ito M, Miyamoto K.
  • Organizer: The American Society of Nephrology. Pennsylvania Convention Center
  • Place of Presentation: Philadelphia, Pennsylvania, USA.
  • Year and Date: 2008-11-07
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