Identification of renal transportsomes by analyzing disease-causing mutants of transporters and their regulators.

2009 Fiscal Year Final Research Report

• Project/Area Number: 17081009
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: UCHIDA Shinichi Tokyo Medical and Dental University, 大学院・医歯学総合研究科, 准教授 (50262184)
• Co-Investigator(Kenkyū-buntansha): SASAKI Sei 東京医科歯科大学, 医歯学総合研究科, 准教授
• Project Period (FY): 2005 – 2009
• Keywords: 水チャネル / クロライドチャネル / WNKキナーゼ

Research Abstract

The aim of this study was to identify functionally important proteincomplexes regulating AQP water channels, CLC chloride channels and Na-Cl cotransporter(NCC), by focusing on the naturally occurring mutations of these genes. We found that thebinding of tropomyosin 5b to phosphorylated AQP2 was necessary for AQP2's apical sortingby vasopressin. We also found a novel phosphorylation cascade (WNK-OSR1/SPAK-NCC)in the kidney that is important for blood pressure regulation.

Research Products

• [Journal Article] Targeted disruption of the Wnk4 gene decreases phosphorylation of Na-Cl cotransporter, increases Na excretion and lowers blood pressure. (2009)
  • Author(s): Ohta A, Rai T, Yui N, Chiga M, Yang SS, Lin SH, Sohara E, Sasaki S, Uchida S.
  • Journal Title: Hum. Mol. Genet. 18 Pages: 3978-86
• [Journal Article] Pancreas-specific aquaporin 12 null mice showed increased susceptibility to caerulein-induced acute pancreatitis. (2009)
  • Author(s): Ohta E, Itoh T, Nemoto T, Kumagai J, Ko SB, Ishibashi K, Ohno M, Uchida K, Ohta A, Sohara E, Uchida S, Sasaki S, Rai T.
  • Journal Title: Am. J. Physiol. Cell Physiol. 297 Pages: 1368-78
• [Journal Article] FAPP2 is required for aquaporin-2 apical sorting at trans-Golgi network in polarized MDCK cells. (2009)
  • Author(s): Yui N, Okutsu R, Sohara E, Rai T, Ohta A, Noda Y, Sasaki S, Uchida S.
  • Journal Title: Am. J. Physiol. Cell Physiol. 297 Pages: 1389-1396
• [Journal Article] Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone. (2008)
  • Author(s): Chiga M, Rai T, Yang S-S, Ohta A, Takizawa T, Sasaki S, Uchida S.
  • Journal Title: Kidney Int. 74 Pages: 1403-1409
• [Journal Article] Reciprocal interaction with G-actin and tropomyosin is essential for aquaporin-2 trafficking. (2008)
  • Author(s): Noda Y, Horikawa S, Kanda E, Yamashita M, Meng H, Eto E, Li Y, Kuwahara M, Hirai K, Pack C, Kinjo M, Okabe S, Sasaki S.
  • Journal Title: J. Cell Biol. 182 Pages: 587-601
• [Journal Article] Molecular pathogenesis of pseudohypoaldosteronism type II: generation and analysis of a Wnk4 D561A/+ knock-in mouse model. (2007)
  • Author(s): Yang SS, Morimoto T, Rai T, Chiga M, Sohara E, Ohno M, Uchida K, Lin S-H, Moriguchi T, Shibuya H, Kondo Y, Sasaki S, Uchida S.
  • Journal Title: Cell Metab 5 Pages: 331-344
• [Journal Article] The polarized trafficking of the aquaporin-3 water channel is mediated by an N-Terminal Sorting Signal. (2006)
  • Author(s): Rai T, Sasaki S, Uchida S.
  • Journal Title: Am J Physiol Cell Physiol. 290(1) Pages: C298-304
• [Journal Article] Pathogenesis and treatment of autosomal-dominant nephrogenic diabetes insipidus caused by an aquaporin 2 mutation. (2006)
  • Author(s): Sohara E, Rai T, Yang SS, Uchida K, Nitta K, Horita S, Ohno M, Harada A, Sasaki S, Uchida S.
  • Journal Title: Proc Natl Acad Sci U S A. 103 Pages: 14217-14222
• [Journal Article] Progressive adipocyte hypertrophy in aquaporin-7 deficient mice: Adipocyte glycerol permeability as a novel regulator of fat accumulation. (2005)
  • Author(s): Hara-Chikuma M, Sohara E, Rai T, Ikawa M, Okabe M, Sasaki S, Uchida S, Verkman AS.
  • Journal Title: J Biol Chem. 280(16) Pages: 15493-15496
• [Journal Article] Disruption of aquaporin-11 produces polycystic kidneys following vacuolization of the proximal tubule. (2005)
  • Author(s): Morishita Y, Matsuzaki T, Hara-Chikuma M, Ando A, Shimono M, Matsuki A, Kobayashi K, Ikeda M, Yamamoto T, Verkman A, Kusano E, Ookawara S, Takata K, Sasaki S, Ishibashi K.
  • Journal Title: Mol Cell Biol. 25 Pages: 7770-7779
• [Journal Article] Identification of a multiprotein "motor" complex binding to water channel aquaporin-2. (2005)
  • Author(s): Noda Y, Horikawa S, Katayama Y, Sasaki S.
  • Journal Title: Biochem Biophys Res Commun. 330 Pages: 1041-1047
• [Journal Article] Defective water and glycerol transport in the proximal tubules of AQP7 knockout mice. (2005)
  • Author(s): Sohara E, Rai T, Miyazaki J, Verkman AS, Sasaki S, Uchida S.
  • Journal Title: Am J Physiol Renal Physiol. 289(6) Pages: F1195-1200
• [Presentation] Molecular pathogenesis of Bartter syndrome caused by R8L barttin mutation. (2009)
  • Author(s): Uchida S, Nomura N, Sugawara N, Morimoto T, Kondo Y, Naito S, Yui N, Oi K, Talat G, KMZ Hossain, Wakabayashi M, Nishida H, Ohta E, Ohta A, Sohara E, Rai T, Sasaki S.
  • Organizer: 40th NIPS International Symposium & Physiology of anion transport and cell volume regulation (PAT-CVR 2009)
  • Place of Presentation: Okazaki
  • Year and Date: 20090800
• [Presentation] Epithelial transport: bridges between molecules and function. WNK kinases and cation-chloride cotransporters, novel transportsomes regulating blood pressure (2009)
  • Author(s): Uchida S. Symposium.
  • Organizer: The 36th International Congress of Physiological Sciences (IUPS2009)
  • Place of Presentation: Kyoto
  • Year and Date: 20090700
• [Presentation] Basic and Clinical Science Symposium, "Transport regulation by phosphorylation" Phosphorylation-dependent regulation of NCC by WNKs. (2008)
  • Author(s): Uchida S.
  • Organizer: The 41st Annual meeting of American Society of Nephrology
  • Place of Presentation: Philadelphia
  • Year and Date: 20081100
• [Presentation] Generation and analysis of Wnk4D561A/+ knock-in mice. (2007)
  • Author(s): Yang S, Morimoto T, Rai T, Chiga M, Sohara E, Ohno M, Uchida K, Lin S, Moriguchi T, Shibuya H, Kondo Y, Sasaki S, Uchida S.
  • Organizer: ISN- Nature Genetics Forefronts Symposium on Nephrogenetics: from Development to Physiology
  • Place of Presentation: Danvers, USA
  • Year and Date: 20070300
• [Presentation] Identification of protein complex isolated with a mutant AQP2 that causes autosominal dominant nephrogenic diabetes insipidus. (2006)
  • Author(s): Araki Y, Sohara E, Rai T, Sasaki S, Uchida S.
  • Organizer: The 39th Annual Meeting of American Society of Nephrology
  • Place of Presentation: San Diego
  • Year and Date: 20061100
• [Presentation] Defective water and glycerol transport in the proximal tubules of AQP7 knockout mice. (2005)
  • Author(s): Sohara E, Rai T, Verkman AS, Sasaki S, Uchida S.
  • Organizer: 4th International Conference on Aquaporins
  • Place of Presentation: Brussels
  • Year and Date: 20050900
• [Book] 水とアクアポリンの生物学 (2008)
  • Author(s): 佐々木成編
  • Publisher: 中山書店
• [Book] からだと水の事典 (2008)
  • Author(s): 佐々木成、石橋賢一編
  • Publisher: 朝倉書店
• [Book] ずみずしい体のしくみ (2005)
  • Author(s): 佐々木成
  • Publisher: クバプロ
• [Remarks]
  • URL: http://www.tmd.ac.jp/grad/kid/aquaporin/index.html