Molecular mechanisms of proximal tubule cell endocytosis and its pathological roles in the development of chronic kidney disease

2011 Fiscal Year Final Research Report

• Project/Area Number: 21591023
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Niigata University
• Principal Investigator: SAITO Akihiko 新潟大学, 大学院・医歯学総合研究科, 特任教授 (80293207)
• Co-Investigator(Kenkyū-buntansha): SATO Hiroyoshi 新潟大学, 大学院・医歯学総合研究科, 特任助教 (30413610) ; IINO Noriaki 新潟大学, 医歯学総合病院, 助教 (10420308) ; TAKEDA Tetsuro 獨協医科大学, 医学部, 教授 (10361924)
• Co-Investigator(Renkei-kenkyūsha): NISHIYAMA Akira 香川大学, 医学部, 教授 (10325334) ; ICHIHARA Atsuhiro 東京女子医科大学, 医学部, 教授 (60203105)
• Project Period (FY): 2009 – 2011
• Keywords: メガリン / 近位尿細管 / エンドサイトーシス / 慢性腎臓病 / レニン-アンジオテンシン系 / バイオマーカー

Research Abstract

We analyzed molecular mechanisms of functions of megalin, an endocytic receptor in proximal tubule cells. We also established a novel megalin-related method for evaluating chronic kidney disease and investigated megalin-mediated mechanisms of the development of chronic kidney disease.
1) We found that megalin and nonmuscle myosin heavy chain IIA interact with the adaptor protein Disabled-2 in proximal tubule cells(Kidney Int 2009).
2) Endotoxins are increased in the serum of patients with type 2 diabetes and metabolic syndrome. We found that megalin is downregulated via LPS-TNF-α-ERK1/2 signaling pathway in proximal tubule cells(BBRC 2011).
3) We established ELISA systems to measure human megalin and showed that urinary megalin excretion is a useful biomarker for early diagnosis and evaluation of the severity of diabetic nephropathy and for analyzing cardiovascular risks(Diabetes Care 2012).
4) We found that liver-derived angiotensinogen is involved in the activation of the renin-angiotensin system(generation of angiotensin II) in the kidney and that glomerular-filtered angiotensinogen is taken up by megalin in proximal tubule cells(JASN 2012).

Research Products

• [Journal Article] Liver angiotensinogen is the primary source of renal angiotensin II (2012)
  • Author(s): Matsusaka T, Niimura F, Shimizu A, Pastan I, Saito A, Kobori H, Nishiyama A, Ichikawa I
  • Journal Title: J Am Soc Nephrol. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Significance of urinary full-length and ectodomain forms of megalin in patients with type 2 diabetes (2012)
  • Author(s): Ogasawara S, Hosojima M, Kaseda R, Kabasawa H, Yamamoto-Kabasawa K, Kurosawa H, Sato H, Iino N, Takeda T, Suzuki Y, Narita I, Yamagata K, Tomino Y, Gejyo F, Hirayama Y, Sekine S, Saito A
  • Journal Title: Diabetes Care. Volume: Vol.35 Pages: 1112-1118
  • DOI: doi:10.2337/dc11-1684
  • Peer Reviewed
• [Journal Article] 慢性腎臓病と透析医療?研究の歩みから腎の再生医療に向けて (2012)
  • Author(s): 成田一衛, 斉藤亮彦, 下条文武
  • Journal Title: 再生医療 Volume: 11(1) Pages: 35-50
  • Peer Reviewed
• [Journal Article] 慢性腎臓病と急性腎傷害におけるバイオマーカー (2012)
  • Author(s): 斉藤亮彦
  • Journal Title: 日本臨床検査自動化学会誌 Volume: 37(1) Pages: 3-9
  • Peer Reviewed
• [Journal Article] Analysis of different complexes of type IIa sodium-dependent phosphate transporter in rat renal cortex using blue-native polyacrylamide gel electrophoresis (2011)
  • Author(s): Tanimura A, Yamada F, Saito A, Ito M, Kimura T, Anzai N, Horie D, Yamamoto H, Miyamoto K, Taketani Y, Takeda E
  • Journal Title: J Med Invest. Volume: Vol.58(1, 2) Pages: 140-147
  • Peer Reviewed
• [Journal Article] β2-ミクログロブリンの近位尿細管における再吸収・代謝機構-エンドサイトーシス受容体メガリンの構造,機能,分子間相互作用 (2010)
  • Author(s): 忰田亮平, 斉藤亮彦
  • Journal Title: 臨床検査 Pages: 37-49
• [Journal Article] Proximal tubule cell hypothesis for cardiorenal syndrome in diabetes (2010)
  • Author(s): Saito A, Kaseda R, Hosojima M, Sato H
  • Journal Title: Int J Nephrol Volume: Vol.2011
  • DOI: doi:10.4061/2011/957164
  • Peer Reviewed
• [Journal Article] 腎障害とメガリン (2010)
  • Author(s): 斉藤亮彦
  • Journal Title: 臨床検査 Volume: 38巻 Pages: 733-734
• [Journal Article] Molecular mechanisms of receptor-Mediated endocytosis in the renal proximal tubular epithelium (2009)
  • Author(s): Saito A, Sato H, Iino N, Takeda T
  • Journal Title: J Biomed Biotechnol Volume: Vol.2010
  • DOI: doi:10.1155/2010/403272
  • Peer Reviewed
• [Journal Article] Megalin and nonmuscle myosin heavy chain IIA interact with the adaptor protein Disabled-2 in proximal tubule (2009)
  • Author(s): Hosaka K, Takeda T, Iino N, Hosojima M, Sato H, Kaseda R, Yamamoto K, Kobayashi S, Gejyo F, Saito A
  • Journal Title: Kidney International Volume: Vol.75 Pages: 1308-1315
  • DOI: doi:10.1038/ki.2009.85
  • Peer Reviewed
• [Journal Article] Megalin is downregulated via LPS-TNF-α-ERK1/2 signaling pathway in proximal tubule cells
  • Author(s): Takeyama A, Sato H, Soma-Nagae T, Kabasawa H, Suzuki A, Yamamoto-Kabasawa K, Hosojima M, Kaneko R, Higuchi F, Kaseda R, Ogasawara S, Narita I, Saito A
  • Journal Title: Biochem Biophys Res Commun Volume: Vol.407(1) Pages: 108-112
  • DOI: doi:10.1016/j.bbrc.2011.02.118
  • Peer Reviewed
• [Presentation] 糖尿病性腎症における尿中メガリン排泄量の測定意義 (2011)
  • Author(s): 細島康宏,小笠原真也,黒澤寛之,鈴木芳樹,富野康日己,山縣邦弘,成田一衛,平山吉朗,関根盛,斉藤亮彦
  • Organizer: 第23回日本糖尿病性腎症研究会
  • Place of Presentation: 東京
  • Year and Date: 20111203-04
• [Presentation] Regulation of megalin expression proximal tubule cells by angiotensin II-, inslin-and LPSTNF-α-mediated signaling cross-talk (2011)
  • Author(s): Hosojima M, Kabasawa H, Takeyama A, Sato H, Yamamoto-Kabasawa K, Kaseda R, Narita I, Saito A
  • Organizer: 2011 Forefronts Symposium-Forefronts in Nephrology
  • Place of Presentation: Aahus Denmark
  • Year and Date: 20110922-25
• [Presentation] Significance of urinary full-length and ectodomain forms of megalin in patients with type 2 diabetes (2011)
  • Author(s): Ogasawara S, Hosojima M, Kabasawa H, Kaseda R, Yamamoto-Kabasawa K, Sato H, Takeda T, Suzuki Y, Narita I, Yamagata K, Tomino Y, Gejyo F, Hirayama Y, Sekine S, Saito A
  • Organizer: 2011 Forefronts Symposium-Forefronts in Nephrology
  • Place of Presentation: Aahus Denmark
  • Year and Date: 20110922-25
• [Presentation] 2型糖尿病における尿中全長型および細胞外領域型メガリンの測定の意義 (2011)
  • Author(s): 斉藤亮彦,小笠原真也,細島康宏,忰田亮平,蒲澤秀門,山本-蒲澤佳子,佐藤博慶,黒澤寛之,竹田徹朗,鈴木芳樹,成田一衛,山縣邦弘,富野康日己,下条文武,平山吉朗,関根盛
  • Organizer: 日本プロテオーム学会2011年会
  • Place of Presentation: 新潟
  • Year and Date: 20110728-30
• [Presentation] 培養近位尿細管上皮細胞におけるLPS-TNFα-ERK1/2シグナル経路を介したメガリンの発現調節機構 (2011)
  • Author(s): 佐藤博慶,竹山綾,蒲澤秀門,長江多恵子,金子麗華,樋口文恵,鈴木哲世,山本佳子,細島康宏,竹田徹朗,鈴木芳樹,成田一衛,斉藤亮彦
  • Organizer: 第54回日本腎臓学会学術総会
  • Place of Presentation: 神奈川横浜市
  • Year and Date: 20110615-17
• [Presentation] 低タンパク血症にもかかわらず軽度タンパク尿を呈したネフローゼ症候群患者のmegalin発現の検討 (2011)
  • Author(s): 小椋雅夫,亀井宏一,佐藤舞,藤丸拓也,石川智朗,宇田川智宏,松岡健太郎,斉藤亮彦,伊藤秀一
  • Organizer: 第54回日本腎臓学会学術総会
  • Place of Presentation: 神奈川横浜市
  • Year and Date: 20110615-17
• [Presentation] 生活習慣改善プログラムによる尿中アルブミン排泄量の減少効果 (2011)
  • Author(s): 山本佳子,細島康宏,蒲澤秀門,飯野則昭,竹田徹朗,鈴木芳樹,成田一衛,荒川正昭,斉藤亮彦
  • Organizer: 第54回日本腎臓学会学術総会
  • Place of Presentation: 神奈川横浜市
  • Year and Date: 20110615-17
• [Presentation] CKDの病態把握と予後推定における尿中メガリン測定の意義 (2011)
  • Author(s): 小笠原真也,忰田亮平,蒲澤秀門,竹田徹朗,鈴木芳樹,成田一衛,平山吉朗,関根盛,斉藤亮彦
  • Organizer: 第54回日本腎臓学会学術総会
  • Place of Presentation: 神奈川横浜市
  • Year and Date: 20110615-17
• [Presentation] 第54回日本糖尿病学会年次学術集会 (2011)
  • Author(s): 斉藤亮彦,竹山綾,佐藤博慶,蒲澤秀門,長江多恵子,金子麗華,樋口文恵,鈴木哲世,山本佳子,細島康宏,忰田亮平,飯野則昭,竹田徹朗,鈴木芳樹,成田一衛
  • Organizer: 培養近位尿細管細胞におけるLPS-TNFα-ERK1/2シグナル経路を介したメガリンの発現調節機構
  • Place of Presentation: 北海道
  • Year and Date: 20110519-21
• [Presentation] Urinary full-length form of megalin is a novel biomarker for diabetic nephropathy (2011)
  • Author(s): Saito A, Ogasawara S, Kabasawa H, Hosojima M, Kaseda R, Takeda T, Suzuki Y, Narita I, Hirayama Y, Sekine S
  • Organizer: 7th International Congress on Uremia Research and Toxicity
  • Place of Presentation: Nagoya
  • Year and Date: 20110512-14
• [Presentation] Effect of rice protein on the progression of diabetic nephropathy (2011)
  • Author(s): Watanabe R, Kubota M, Saito A, Kumagai T, Kadowaki M
  • Organizer: International Symposium Dietary Protein for Human Health
  • Place of Presentation: Auckland, New Zealand
  • Year and Date: 20110327-30
• [Presentation] メタボリックシンドローム関連腎症の発症・進展機序におけるメガリンの関与 (2010)
  • Author(s): 佐藤博慶,笹川泰司,蒲澤秀門,飯野則昭,鈴木哲世,金子麗華,青木弘行,樋口文恵,鈴木芳樹,成田一衛,斉藤亮彦
  • Organizer: 第22回日本糖尿病性腎症研究会
  • Place of Presentation: 東京
  • Year and Date: 20101204-05
• [Presentation] 近位尿細管におけるメガリンを介するエンドサイトーシス機構のイメージング解析 (2010)
  • Author(s): 斉藤亮彦
  • Organizer: 第42回日本臨床分子形態学会総会・学術
  • Place of Presentation: 静岡
  • Year and Date: 20100924-25
• [Presentation] Blue Native-PAGE法を用いたメガリンをめぐる分子間相互作用の検討 (2010)
  • Author(s): 佐藤博慶,塩田友也,保坂聖子,蒲澤秀門,山本佳子,鈴木哲世,相馬多恵子,飯野則昭,竹田徹朗,成田一衛,斉藤亮彦
  • Organizer: 第53回日本腎臓学会学術総会
  • Place of Presentation: 兵庫
  • Year and Date: 20100616-18
• [Presentation] 原正則:尿中PCX測定系の構築と臨床的意義 (2010)
  • Author(s): 黒澤寛之,小笠原真也,淺沼克彦,富野康日己,山縣邦弘,斉藤亮彦,平山吉朗,関根盛
  • Organizer: 第53回日本腎臓学会学術総会
  • Place of Presentation: 兵庫
  • Year and Date: 20100616-18
• [Presentation] 尿中メガリンELISA測定系の構築とCKD評価における有用性 (2010)
  • Author(s): 小笠原真也,黒澤寛之,竹田徹朗,飯野則昭,佐藤博慶,鈴木芳樹,淺沼克彦,富野康日己,山縣邦弘,成田一衛,下条文武,平山吉郎,関根盛,斉藤亮彦
  • Organizer: 第53回日本腎臓学会学術総会
  • Place of Presentation: 兵庫
  • Year and Date: 20100616-18
• [Presentation] Urinary shedding forms of megalin as novel biomarkers of proximal tubular injury, ISN Nexus-The Kidney and the Vascular System : Emerging Culprits in Pathogenesis and Advances in Therapy (2010)
  • Author(s): Saito A, Ogasawara S, Kurosawa H, Takeda T, Iino N, Sato H, Suzuki Y, Asanuma K, Tomino Y, Narita I, Gejyo F, Hirayama Y, Sekine S
  • Place of Presentation: Kyoto
  • Year and Date: 20100415-18
• [Presentation] メタボリックシンドローム腎症におけるエンドサイトーシス受容体メガリンの病的役割とオートファジーとの関連 (2010)
  • Author(s): 斉藤亮彦
  • Organizer: 平成22年度「オートファジー研究会」
  • Place of Presentation: 静岡
  • Year and Date: 20100112-14
• [Presentation] Calorie diet reduces albuminuria in proportion to the improvement in serum leptin level and fractional excretion of uric acid in obese men (2009)
  • Author(s): Takeda T, Yamamoto K, Iino N, Narita I, Saito A
  • Organizer: Renal Week 2009
  • Place of Presentation: San Diego CA US
  • Year and Date: 20091027-1101
• [Presentation] Establishment of ELISA system to evaluate ectodomain and full-length forms of megalin shed in human urine (2009)
  • Author(s): Ogasawara S, Kurosawa H, Takeda T, Iino N, Sato H, Suzuki Y, Asanuma K, Tomino Y, Yamagata K, Narita I, Gejyo F, Hirayama Y, Sekine S and Saito A
  • Organizer: Renal Week 2009
  • Place of Presentation: San Diego CA US
  • Year and Date: 20091027-1101
• [Presentation] LPSによる培養近位尿細管細胞におけるmegalinの発現調節 (2009)
  • Author(s): 竹山綾,佐藤博慶,相馬多恵子,蒲澤秀門,山本佳子,笹川泰司,飯野則昭,竹田徹朗,鈴木芳樹,下条文武,斉藤亮彦
  • Organizer: 第52回日本腎臓学会学術総会
  • Place of Presentation: 神奈川
  • Year and Date: 20090603-05
• [Presentation] マウス近位尿細管におけるMegalinを介したタンパク取り込みのin vivoイメージング (2009)
  • Author(s): 生山健児,蒲澤秀門,佐藤博慶,山本佳子,竹山綾,笹川泰司,細島康宏,飯野則昭,竹田徹朗,鈴木芳樹,追手巍,下条文武,斉藤亮彦
  • Organizer: 第52回日本腎臓学会学術総会
  • Place of Presentation: 神奈川
  • Year and Date: 20090603-05
• [Presentation] Megalin, Cubilin, Amnionless遺伝子安定発現MDCK細胞の樹立 (2009)
  • Author(s): 鈴木哲世,竹田徹朗,佐藤博慶,笹川泰司,蒲澤秀門,竹山綾,山本佳子,細島康宏,相馬多恵子,飯野則昭,鈴木芳樹,下条文武,斉藤亮彦
  • Organizer: 第52回日本腎臓学会学術総会
  • Place of Presentation: 神奈川
  • Year and Date: 20090603-05
• [Presentation] 培養近位尿細管上皮細胞におけるGlucose, Insulin, EGF, Ang IIによるMegalinの発現調節機構 (2009)
  • Author(s): 佐藤博慶,山本佳子,細島康宏,相馬多恵子,鈴木哲世,蒲澤秀門,竹山綾,笹川泰司,生山健児,塩田友也,飯野則昭,竹田徹朗,鈴木芳樹,下条文武,斉藤亮彦
  • Organizer: 第52回日本腎臓学会学術総会
  • Place of Presentation: 神奈川
  • Year and Date: 20090603-05
• [Presentation] Effects of lifestyle modification with combibnes aerobic and resistance exercise on urinary albmin excretion in the population with metabolic syndrome (2009)
  • Author(s): Yamamoto K, Hosojima M, Saito M, Tanaka J, Hashiba M, Iino N, Takeda T, Suzuki Y Gejyo F, Arakawa M, Saito A
  • Organizer: 3rd International Congress on Prediabetes and the Metabolic Syndrome
  • Place of Presentation: Nice France
  • Year and Date: 20090401-04
• [Presentation] The efficacy of pioglitazone on the plasma asiponectin level and glucose control in patients with steroid-induced diabetes (2009)
  • Author(s): Kaseda R, Hosojima M, Yamamoto K, Iino N, Takeda T, Suzuki Y, Saito A
  • Organizer: 3rd International Congress on Prediabetes and the Metabolic Syndrome
  • Place of Presentation: Nice France
  • Year and Date: 20090401-04
• [Book] actions and interactions in proximal tubule cells associated with the development of chronic kidney disease. In : Basic and Clinical Endocrinology Up-to-Date, ISBN 978-953-307-340-8, Edited by Fulya Akin (2011)
  • Author(s): Saito A, Hosojima M, Sato H
  • Publisher: InTech
• [Book] 糖尿病における微量アルブミン尿の機序-糸球体・血管系と尿細管系の相互的関係の観点から-「腎臓」 (2011)
  • Author(s): 細島康宏,蒲澤秀門,佐藤博慶,斉藤亮彦
  • Total Pages: 176-182
  • Publisher: Annual Review 2011
• [Book] Physiology and pathophysiology of megalin-mediated endocytosis in renal proximal tubule cells. In : Advances in Medicine and Biology Research(Leon V. Berhardt) (2010)
  • Author(s): Saito A, Sato H, Iino N, Takeda T
  • Publisher: Nova Science Publishers
• [Remarks]
  • URL: http://www.med.niigata-u.ac.jp/amm/
• [Patent(Industrial Property Rights)] 急性腎障害の検査方法 (2012)
  • Inventor(s): 斉藤亮彦,黒澤寛之,平山吉朗
  • Industrial Property Rights Holder: 国立大学法人新潟大学,デンカ生研株式会社
  • Industrial Property Number: 特許、特願2012-045844
  • Filing Date: 2012-03-01
• [Patent(Industrial Property Rights)] URINE PRETREATMENT AGENT FOR URINARY PROTEIN QUANTITATION, URINE PRETREATMENT METHOD, AND URINARY PROTEIN QUANTITATION METHOD (2012)
  • Inventor(s): Hara M, Saito A, Ogasawara S, Hirayama Y, Kurosawa H
  • Industrial Property Rights Holder: Niigata University, Hara M, Denka Seiken Co., Ltd.
  • Industrial Property Number: 特許、US 8, 105, 840
  • Acquisition Date: 2012-01-31
  • Overseas
• [Patent(Industrial Property Rights)] ヒトメガリンの測定方法 (2011)
  • Inventor(s): 斉藤亮彦,黒澤寛之,平山吉朗
  • Industrial Property Rights Holder: 国立大学法人新潟大学,デンカ生研株式会社
  • Industrial Property Number: 特許、特許第486537号
  • Acquisition Date: 2011-11-18
• [Patent(Industrial Property Rights)] METHOD FOR MEASURING HUMAN MEGALIN (2011)
  • Inventor(s): Saito A, Takeda T, Ogasawara S, Miura S
  • Industrial Property Rights Holder: Niigata University, Denka Seiken Co., Ltd.
  • Industrial Property Number: 特許、US 7, 955, 809
  • Acquisition Date: 2011-06-07
  • Overseas
• [Patent(Industrial Property Rights)] 腎疾患の検査方法 (2010)
  • Inventor(s): 原正則,斉藤亮彦,富野康日己,淺沼克彦,黒澤寛之,小笠原真也,平山吉朗
  • Industrial Property Rights Holder: 原正則,国立大学法人新潟大学,学校法人順天堂大学,デンカ生研株式会社
  • Industrial Property Number: 特許、特願2009-139187, PCT/JP2010/003836
  • Filing Date: 2010-06-10
• [Patent(Industrial Property Rights)] 糖尿病性腎症の検査方法 (2010)
  • Inventor(s): 原正則,斉藤亮彦,富野康日己,淺沼克彦,黒澤寛之,小笠原真也,平山吉朗
  • Industrial Property Rights Holder: 原正則,国立大学法人新潟大学,学校法人順天堂大学,デンカ生研株式会社
  • Industrial Property Number: 特許、特願2009-139188, PCT/JP2010/003837
  • Filing Date: 2010-06-10
• [Patent(Industrial Property Rights)] 尿中ヒトメガリンを測定する事を含む腎疾患検出方法 (2010)
  • Inventor(s): 斉藤亮彦,富野康日己,淺沼克彦,小笠原真也,黒澤寛之,平山吉朗
  • Industrial Property Rights Holder: 国立大学法人新潟大学,学校法人順天堂,デンカ生研株式会社
  • Industrial Property Number: 特許、特願2009-108498, PCT/JP2010/057465
  • Filing Date: 2010-04-27
• [Patent(Industrial Property Rights)] 腎障害の検出用マーカーとしての尿中メガリンおよびその使用 (2010)
  • Inventor(s): 斉藤亮彦,富野康日己,淺沼克彦,小笠原真也,黒澤寛之,平山吉朗
  • Industrial Property Rights Holder: 国立大学法人新潟大学,学校法人順天堂,デンカ生研株式会社
  • Industrial Property Number: 特許、特願2011-511418, PCT/JP2010/057490
  • Filing Date: 2010-04-27
• [Patent(Industrial Property Rights)] メガリンタンパク切断阻害剤 (2010)
  • Inventor(s): 岩田博司,原田英里,三井彰,斉藤亮彦
  • Industrial Property Rights Holder: 味の素株式会社
  • Industrial Property Number: 特許、特願2011-503880
  • Filing Date: 2010-03-12