新たな腎臓膜輸送体制御法の開発

2013 年度 研究成果報告書

• 研究課題/領域番号: 22249032
• 研究種目: 基盤研究(A)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 腎臓内科学
• 研究機関: 東京医科歯科大学
• 研究代表者: 佐々木 成 東京医科歯科大学, 医歯(薬)学総合研究科, 教授 (60170677)
• 研究期間 (年度): 2010-04-01 – 2014-03-31
• キーワード: 水・電解質代謝学 / 塩分感受性高血圧 / 遺伝子改変マウス

研究概要

対象とする輸送体分子（AQP水チャネル、CLCクロライドチャネル、SLC12A輸送体）のさらなる制御機構の解明と病態への関与を明らかにし、それに基づいた新たな膜輸送体制御機構を確立することを目的として本研究は開始された。その結果、AQP研究においては近位尿細管小胞体に存在するAQP11の欠損が嚢胞腎原因遺伝子PC-1の糖化と細胞膜局在を障害することで嚢胞腎を引き起こすという新たな分子機構を解明し、CLC研究においては変異バーチンの小胞体係留を軽減する薬剤を同定し、WNK研究ではWNKキナーゼ系阻害薬の単離に成功した。

研究成果

• [雑誌論文] Immunolocalization and translocation of aquaporin-5 water channel in sweat glands (2013)
  • 著者名/発表者名: Inoue R, Sohara E, Rai T, Satoh T, Yokozeki H, Sasaki S, Uchida S
  • 雑誌名: J Dermatol Sci 巻: 70 ページ: 26-33
  • 査読あり
• [雑誌論文] Development of enzyme-linked immunosorbent assays for urinary thiazide-sensitive Na-Cl cotransporter (NCC) measurement (2013)
  • 著者名/発表者名: Isobe K, Mori T, Asano T, Kawaguchi H, Nonoyama S, Kumagai N, Kamada F, Morimoto T, Hayashi M, Sohara E, Rai T, Sasaki S, Uchida S
  • 雑誌名: Am J Physiol Renal Physiol 巻: 305 ページ: F1374-F1381
  • 査読あり
• [雑誌論文] Chemical library screening for WNK signalling inhibitors using fluorescence correlation spectroscopy (2013)
  • 著者名/発表者名: Mori T, Kikuchi E, Watanabe Y, Fujii S, Ishigami-Yuasa M, Kagechika H, Sohara E, Rai T, Sasaki S, Uchida S
  • 雑誌名: Biochem J 巻: 455 ページ: 339-345
  • 査読あり
• [雑誌論文] Decrease of WNK4 ubiquitination by disease-causing mutations of KLHL3 through different molecular mechanisms (2013)
  • 著者名/発表者名: Mori Y, Wakabayashi M, Mori T, Araki Y, Sohara E, Rai T, Sasaki S, Uchida S
  • 雑誌名: Biochem Biophys Res Commun 巻: 439 ページ: 30-34
  • 査読あり
• [雑誌論文] Treatment with 17-allylamino-17-demethoxygeldanamycin ameliorated symptoms of Bartter syndrome type caused by mutated Bsnd in mice (2013)
  • 著者名/発表者名: Nomura N, Kamiya K, Ikeda K, Yui N, Chiga M, Sohara E, Rai T, Sasaki S, Uchida S
  • 雑誌名: Biochem Biophys Res Commun 巻: 441 ページ: 544-549
  • 査読あり
• [雑誌論文] Hereditary nephrogenic diabetes insipidus in Japanese patients : analysis of 78 families and report of 22 new mutations in AVPR2 and AQP2 (2013)
  • 著者名/発表者名: Sasaki S, Chiga M, Kikuchi E, Rai T, Uchida S
  • 雑誌名: Clin Exp Nephrol 巻: 17 ページ: 338-344
  • 査読あり
• [雑誌論文] KLHL2 interacts with and ubiquitinates WNK kinases (2013)
  • 著者名/発表者名: Takahashi D, Mori T, Wakabayashi M, Mori Y, Susa K, Zeniya M, Sohara E, Rai T, Sasaki S, Uchida S
  • 雑誌名: Biochem Biophys Res Commun 巻: 437 ページ: 457-462
  • 査読あり
• [雑誌論文] Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension (2013)
  • 著者名/発表者名: Wakabayashi M, Mori T, Isobe K, Sohara E, Susa K, Araki Y, Chiga M, Kikuchi E, Nomura N, Mori Y, Matsuo H, Murata T, Nomura S, Asano T, Kawaguchi H, Nonoyama S, Rai T, Sasaki S, Uchida S
  • 雑誌名: Cell Rep 巻: 3 ページ: 858-868
  • 査読あり
• [雑誌論文] Dietary salt intake regulates WNK3-SPAK-NKCC1 phosphorylation cascade in mouse aorta through angiotensin II (2013)
  • 著者名/発表者名: Zeniya M, Sohara E, Kita S, Iwamoto T, Susa K, Mori T, Oi K, Chiga M, Takahashi D, Yang SS, Lin SH, Rai T, Sasaki S, Uchida S
  • 雑誌名: Hypertension 巻: 62 ページ: 872-878
  • 査読あり
• [雑誌論文] Phosphorylation of Na-Cl cotransporter by OSR1 and SPAK kinases regulates its ubiquitination (2012)
  • 著者名/発表者名: Hossain Khan MZ, Sohara E, Ohta A, Chiga M, Inoue Y, Isobe K, Wakabayashi M, Oi K, Rai T, Sasaki S, Uchida S
  • 雑誌名: Biochem. Biophys. Res. Commun 巻: 425 ページ: 456-461
  • 査読あり
• [雑誌論文] Phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in hyperinsulinemic db/db mice (2012)
  • 著者名/発表者名: Nishida H, Sohara E, Nomura N, Chiga M, Alessi DR, Rai T, Sasaki S, Uchida S
  • 雑誌名: Hypertension 巻: 60 ページ: 981-990
  • 査読あり
• [雑誌論文] A minor role of WNK3 in regulating phosphorylation of renal NKCC2 and NCC co-transporters in vivo (2012)
  • 著者名/発表者名: Oi K, Sohara E, Rai T, Misawa M, Chiga M, Alessi DR, Sasaki S, Uchida S
  • 雑誌名: Biol.Open 巻: 1 ページ: 120-127
  • 査読あり
• [雑誌論文] Effect of heterozygous deletion of WNK1 on the WNK-OSR1/ SPAK-NCC/NKCC1/NKCC2 signal cascade in the kidney and blood vessels (2012)
  • 著者名/発表者名: Susa K, Kita S, Iwamoto T, Yang SS, Lin SH, Ohta A, Sohara E, Rai T, Sasaki S, Alessi DR, Uchida S
  • 雑誌名: Clin. Exp. Nephrol 巻: 16 ページ: 530-538
  • 査読あり
• [雑誌論文] WNK-OSR1/SPAK-NCC signal cascade has circadian rhythm dependent on aldosterone (2012)
  • 著者名/発表者名: Susa K, Sohara E, Isobe K, Chiga M, Rai T, Sasaki S, Uchida S
  • 雑誌名: Biochem. Biophys. Res. Commun 巻: 427 ページ: 743-747
  • 査読あり
• [雑誌論文] Does a β 2-adrenergic receptor-WNK4-Na-Cl co-transporter signal cascade exist in the in vivo kidney? (2012)
  • 著者名/発表者名: Uchida S, Chiga M, Sohara E, Rai T, Sasaki S
  • 雑誌名: Nat. Med 巻: 18 ページ: 1324-1325
  • 査読あり
• [雑誌論文] Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A missense mutation are dependent on the WNK-OSR1/SPAK kinase cascade (2011)
  • 著者名/発表者名: Chiga M, Rafiqi FH, Alessi DR, Sohara E, Ohta A, Rai T, Sasaki S, Uchida S
  • 雑誌名: J. Cell Sci 巻: 124 ページ: 1391-1395
  • 査読あり
• [雑誌論文] Regulation of WNK1 kinase by extracellular potassium (2011)
  • 著者名/発表者名: Naito S, Ohta A, Sohara E, Ohta E, Rai T, Sasaki S, Uchida S
  • 雑誌名: Clin. Exp. Nephrol 巻: 15 ページ: 195-202
  • 査読あり
• [雑誌論文] Generation and analyses of R8L barttin knockin mouse (2011)
  • 著者名/発表者名: Nomura N, Tajima M, Sugawara N, Morimoto T, Kondo Y, Ohno M, Uchida K, Mutig K, Bachmann S, Soleimani M, Ohta E, Ohta A, Sohara E, Okado T, Rai T, Jentsch TJ, Sasaki S, Uchida S
  • 雑誌名: Am. J. Physiol. Renal. Physiol 巻: 301 ページ: F297-307
  • 査読あり
• [雑誌論文] Immunolocalization of WNK4 in mouse kidney (2011)
  • 著者名/発表者名: Ohno M, Uchida K, Ohashi T, Nitta K, Ohta A, Chiga M, Sasaki S, Uchida S
  • 雑誌名: Histochem. Cell Biol 巻: 136 ページ: 25-35
  • 査読あり
• [雑誌論文] Acute insulin stimulation induces phosphorylation of the Na-Cl cotransporter in cultured distal mpkDCT cells and mouse kidney (2011)
  • 著者名/発表者名: Sohara E, Rai T, Yang SS, Ohta A, Naito S, Chiga M, Nomura N, Lin SH, Vandewalle A, Ohta E, Sasaki S, Uchida S
  • 雑誌名: PLoS One 巻: 6 ページ: e24277
  • 査読あり
• [雑誌論文] Phosphorylation of aquaporin-2 regulates its water permeability (2010)
  • 著者名/発表者名: Eto K, Noda Y, Horikawa S, Uchida S, Sasaki S
  • 雑誌名: J. Biol. Chem 巻: 285 ページ: 40777-40784
  • 査読あり
• [雑誌論文] Effect of angiotensin II on the WNK-OSR1/SPAK-NCC phosphorylation cascade in cultured mpkDCT cells and in vivo mouse kidney (2010)
  • 著者名/発表者名: Talati G, Ohta A, Rai T, Sohara E, Naito S, Vandewalle A, Sasaki S, Uchida S
  • 雑誌名: Biochem. Biophys. Res. Commun 巻: 393 ページ: 844-848
  • 査読あり
• [雑誌論文] Mechanisms for hypercalciuria in pseudohypoaldosteronism type II-causing WNK4 knock-in mice (2010)
  • 著者名/発表者名: Yang SS, Hsu YJ, Chiga M, Rai T, Sasaki S, Uchida S, Lin SH
  • 雑誌名: Endocrinology 巻: 151 ページ: 1829-1836
  • 査読あり
• [学会発表] Analyses of KLHL3 mutants that cause Pseudohypoaldosteronism type II (2013)
  • 著者名/発表者名: Mori Y, Wakabayashi M, Mori T, Araki Y, Sohara E, Rai T, Sasaki S, Uchida S
  • 学会等名: The 46^<th> Annual Meeting of American Society of Nephrology
  • 発表場所: Atlanta
  • 年月日: 2013-11-09
• [学会発表] KLHL2 interacts with and ubiquitinates WNK kinases (2013)
  • 著者名/発表者名: Takahashi D, Mori T, Wakabayashi M, Mori Y, Susa K, Zeniya M, Sohara E, Rai T, Sasaki S, Uchida S
  • 学会等名: The 46^<th> Annual Meeting of American Society of Nephrology
  • 発表場所: Atlanta
  • 年月日: 2013-11-09
• [学会発表] Impaired KLHL3-mediated ubiquitination of WNK4 activates OSR1 and SPAK kinases-NaCl cotransporter (NCC) signaling and causes hypertension (2013)
  • 著者名/発表者名: Wakabayashi M, Mori T, Isobe K, Sohara E, Susa K, Araki Y, Chiga M, Kikuchi E, Nomura N, Mori Y, Rai T, Sasaki S, Uchida S
  • 学会等名: The 46^<st> Annual Meeting of American Society of Nephrology
  • 発表場所: Atlanta
  • 年月日: 2013-11-09
• [学会発表] WNK3 Regulates Blood Pressure Through the Regulation of Vascular OSR1/SPAK-NKCC1 Phosphorylation Cascade (2013)
  • 著者名/発表者名: Zeniya M, Sohara E, Kita S, Iwamoto T, Susa K, Mori T, Oi K, Chiga M, Takahashi D, Yang SS, Lin SH, Rai T, Sasaki S, Uchida S
  • 学会等名: The 46^<th> Annual Meeting of American Society of Nephrology
  • 発表場所: Atlanta
  • 年月日: 2013-11-09
• [学会発表] Aberrant Glycosylation and Localization of Polycystin-1 Cause Polycystic Kidney in AQP11-Knockout Mice (2013)
  • 著者名/発表者名: Inoue Y, Sohara E, Kobayashi K, Rai T, Ishibashi K, Horie S, Su X, Zhou J, Sasaki S, Uchida S
  • 学会等名: The 46^<th> Annual Meeting of American Society of Nephrology
  • 発表場所: Atlanta
  • 年月日: 2013-11-07
• [学会発表] Clinical Significance of Urinary Thiazide-Sensitive Na-Cl Cotransporter (NCC) Measurement by Newly Development Enzyme-Linked Immunosorbent Assays (2013)
  • 著者名/発表者名: Isobe K, Mori T, Sohara E, Rai T, Sasaki S, Uchida S
  • 学会等名: The 46^<th> Annual meeting of American Society of Nephrology
  • 発表場所: Atlanta
  • 年月日: 2013-11-07
• [学会発表] Chemical library screening for WNK signaling inhibitors by using fluorescent correlation spectroscopy (2013)
  • 著者名/発表者名: Mori T, Eriko K, Sohara E, Rai T, Sasaki S, Uchida S
  • 学会等名: The 46^<th> Annual Meeting of American Society of Nephrology
  • 発表場所: Atlanta
  • 年月日: 2013-11-07
• [学会発表] Low salt intake decreased transcription and protein level of KLHL3 in mouse kidney (2013)
  • 著者名/発表者名: Susa K, Sohara E, Zeniya M, Rai T, Sasaki S, Uchida S
  • 学会等名: The 46^<th> Annual Meeting of American Society of Nephrology
  • 発表場所: Atlanta
  • 年月日: 2013-11-07
• [学会発表] Ser-261 phosphorylation is an endocytic signal of aquaporin-2 water channel (2013)
  • 著者名/発表者名: Yui N, Uchida S, Sasaki S
  • 学会等名: The 46^<th> Annual Meeting of American Society of Nephrology
  • 発表場所: Atlanta, USA
  • 年月日: 2013-11-07
• [学会発表] Hereditary nephrogenic diabetes insipidus (NDI) in Japanese patients : Analysis of 73 families (2012)
  • 著者名/発表者名: Sasaki S, Chiga M, Kikuchi E, Uchida S
  • 学会等名: The 45th Annual Meeting of American Society of Nephrology
  • 発表場所: San Diego (USA)
  • 年月日: 2012-11-02
• [学会発表] WNK4-OSR1/SPAK-NCC signal cascade has circadian rhythm dependent on aldosterone (2012)
  • 著者名/発表者名: Susa K, Sohara E, Isobe K, Chiga M, Rai T, Sasaki S, Uchida S
  • 学会等名: The 45th Annual Meeting of American Society of Nephrology
  • 発表場所: San Diego (USA)
  • 年月日: 2012-11-02
• [学会発表] Chemical library screening for direct SPAK inhibitors by a newly developed ELISA system (2012)
  • 著者名/発表者名: Kikuchi E, Mori T, Isobe K, Sohara E, Rai T, Sasaki S, Uchida S
  • 学会等名: The 45th Annual Meeting of American Society of Nephrology
  • 発表場所: San Diego (USA)
  • 年月日: 2012-11-01
• [学会発表] Generation and analysis of WT-WNK4 transgenic mice revealed the physiological role of WNK4 (2012)
  • 著者名/発表者名: Mori T, Sohara E, Rai T, Sasaki S, Uchida S
  • 学会等名: The 45th Annual Meeting of American Society of Nephrology
  • 発表場所: San Diego (USA)
  • 年月日: 2012-11-01
• [学会発表] Generation and analyses of AQP11 BAC transgenic mice (2011)
  • 著者名/発表者名: Inoue Y, Sohara E, Kobayashi K, Rai T, Ishibashi K, Sasaki S, Uchida S
  • 学会等名: The 44th Annual Meeting of American Society of Nephrology
  • 発表場所: Philadelphia (USA)
  • 年月日: 2011-11-12
• [学会発表] High throughput screening of drugs that inhibit WNK-OSR1/SPAK signaling cascade (2011)
  • 著者名/発表者名: Mori T, Ohta A, Sohara E, Rai T, Sasaki S, Uchida S
  • 学会等名: The 44th Annual Meeting of American Society of Nephrology
  • 発表場所: Philadelphia (USA)
  • 年月日: 2011-11-12
• [学会発表] Renal phenotype of WNK3 knockout mouse (2011)
  • 著者名/発表者名: Oi K, Sohara E, Rai T, Chiga M, Alessi DR, Sasaki S, Uchida S
  • 学会等名: The 44th Annual Meeting of American Society of Nephrology
  • 発表場所: Philadelphia (USA)
  • 年月日: 2011-11-12
• [学会発表] Chemical library screening for drugs to correct intracellular mislocalization of R8L mutant barttin (2011)
  • 著者名/発表者名: Nomura N, Naito S, Sohara E, Rai T, Sasaki S, Uchida S
  • 学会等名: The 44th Annual Meeting of American Society of Nephrology
  • 発表場所: Philadelphia (USA)
  • 年月日: 2011-11-11
• [学会発表] Treatment of Bartter syndrome type IV caused by R8L barttin mutation (2010)
  • 著者名/発表者名: Nomura N, Masato T, Ohta E, Ohta A, Sohara E, Rai T, Sasaki S, Uchida S
  • 学会等名: The 43nd Annual Meeting of American Society of Nephrology
  • 発表場所: Denver (USA)
  • 年月日: 2010-11-10
• [備考] 東京医科歯科大学腎臓内科学ホームページ
  • URL: http://www.tmd.ac.jp/grad/kid/kid-J.htm