Elucidation of the mechanisms of podocyte homeostasis and development of new therapeutic strategies against diabetic kidney disease

• Project/Area Number: 24591189
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: The University of Tokyo
• Principal Investigator: WADA Takehiko 東京大学, 医学部附属病院, 講師 (90447409)
• Co-Investigator(Kenkyū-buntansha): NANGAKU Masaomi 東京大学, 医学部附属病院, 教授 (90311620) ; INAGI Reiko 東京大学, 医学部附属病院, 准教授 (50232509) ; TANAKA Tetsuhiro 東京大学, 医学部附属病院, 講師 (90508079) ; OHSE Takamoto 東京大学, 医学部附属病院, その他 (10568447)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 糸球体足細胞 / 小胞体ストレス / 細胞骨格 / 蛋白尿 / オートファジー

Outline of Final Research Achievements

We investigated how podocytes, which are critical players in glomerular filtration barrier, maintain their homeostasis against various stresses. In this study, we focused on the role of NAD+-dependent deacetylase SIRT1 in the podocyte homeostasis, on the basis of the finding that actin cytoskeleton was deranged in response to oxidative stress. After the induction of experimental nephritis, podocyte-specific SIRT1 deficient mice showed more severe renal injury compared with wild-type mice. Enhanced actin cytoskeleton derangement was observed in the podocytes with downregulated SIRT1 activities. Interestingly, we found that intracellular localization of cortactin, which is associated with actin polymerization, was altered in association with its deacetylation. Our data suggested that deacetylation of cortactin by SIRT1 might play an important role in the maintenance of podocyte cytoskeleton.

Research Products

• [Journal Article] Sirtuin1 Maintains Actin Cytoskeleton by Deacetylation of Cortactin in Injured Podocytes. (2015)
  • Author(s): Motonishi S, Nangaku M, Wada T, Ishimoto Y, Ohse T, Matsusaka T, Kubota N, Shimizu A, Kadowaki T, Tobe K, Inagi R
  • Journal Title: Journal of American Society of Nephrology Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Inflammation and hypoxia linked to renal injury by CCAAT/enhancer-binding protein δ (2015)
  • Author(s): Yamaguchi J, Tanaka T, Eto N, Nangaku M.
  • Journal Title: Kidney International Volume: 印刷中 Issue: 2 Pages: 262-75
  • DOI: 10.1038/ki.2015.21
  • Peer Reviewed / Open Access
• [Journal Article] Anti-inflammatory role of DPP-4 inhibitors in a nondiabetic model of glomerular injury. (2015)
  • Author(s): Higashijima Y, Tanaka T, Yamaguchi J, Tanaka S, Nangaku M.
  • Journal Title: American Journal of Physiology Renal Physiology Volume: 308
  • Peer Reviewed
• [Journal Article] Role of Uremic Toxins in Erythropoiesis-Stimulating Agent Resistance in Chronic Kidney Disease and Dialysis Patients. (2015)
  • Author(s): Nangaku M, Mimura I, Yamaguchi J, Higashijima Y, Wada T, Tanaka T.
  • Journal Title: Journal of Renal Nutrition Volume: 25 Issue: 2 Pages: 160-163
  • DOI: 10.1053/j.jrn.2014.10.011
  • Peer Reviewed
• [Journal Article] Hypoxia and fibrosis in chronic kidney disease: crossing at pericytes. (2014)
  • Author(s): Kawakami T, Mimura I, Shoji K, Tanaka T, Nangaku M.
  • Journal Title: Kidney International Supplement Volume: 4 Pages: 107-112
  • Peer Reviewed
• [Journal Article] Hypoxia as a key player in the AKI-to-CKD transition. (2014)
  • Author(s): Tanaka S, Tanaka T, Nangaku M.
  • Journal Title: Am J Phyisol Renal Physiol Volume: 307 Issue: 11 Pages: F1187-F1195
  • DOI: 10.1152/ajprenal.00425.2014
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The potential for renoprotection with incretin-based drugs (2014)
  • Author(s): Tanaka T, Higashijima Y, Wada T, Nangaku M
  • Journal Title: Kidney Int Volume: 86 Issue: 4 Pages: 701-711
  • DOI: 10.1038/ki.2014.236
  • Peer Reviewed
• [Journal Article] Proteostasis in endoplasmic reticulum--new mechanisms in kidney disease. (2014)
  • Author(s): Inagi R, Ishimoto Y, Nangaku M.
  • Journal Title: Nature Reviews Nephrology Volume: 10 Issue: 7 Pages: 369-78
  • DOI: 10.1038/nrneph.2014.67
  • Peer Reviewed
• [Journal Article] ANO1: an additional key player in cyst growth. (2014)
  • Author(s): Tanaka T, Nangaku M
  • Journal Title: Kidney International Volume: 85 Issue: 5 Pages: 1007-9
  • DOI: 10.1038/ki.2013.436
  • Peer Reviewed
• [Journal Article] Glyoxalase I reduces glycative and oxidative stress and prevents age-related endothelial dysfunction through modulation of endothelial nitric oxide synthase phosphorylation. (2014)
  • Author(s): Jo-Watanabe A, Ohse T, Nishimatsu H, Takahashi M, Ikeda Y, Wada T, Shirakawa J, Nagai R, Miyata T, Nagano T, Hirata Y, Inagi R, Nangaku M.
  • Journal Title: Aging Cell Volume: Epub ahead of print Issue: 3 Pages: 519-28
  • DOI: 10.1111/acel.12204
  • Peer Reviewed / Open Access
• [Journal Article] 原発性巣状分節性糸球体硬化症の液性因子に関する最近の動向 (2014)
  • Author(s): 和田健彦、南学正臣
  • Journal Title: 日本腎臓学会誌 Volume: 56 Pages: 478-85
• [Journal Article] A multicenter cross-sectional study of circulating soluble urokinase receptor in Japanese patients with glomerular disease (2014)
  • Author(s): Wada T, Nangaku M, Maruyama S, Imai E, Shoji K, Kato S, Endo T, Muso E, Kamata K, Yokoyama H, Fujimoto K, Obata Y, Nishino T, Kato H, Uchida S, Sasatomi Y, Saito T, Matsuo S.
  • Journal Title: Kidney Int Volume: 85 Issue: 3 Pages: 641-8
  • DOI: 10.1038/ki.2013.544
  • Peer Reviewed / Open Access
• [Journal Article] 利尿薬の基本 種類と作用機序、量の調整、電解質バランスの維持 (2014)
  • Author(s): 和田健彦
  • Journal Title: レジデントノート Volume: 15 Pages: 2898-904
• [Journal Article] 補体異常とMPGN、DDD、C3GN (2014)
  • Author(s): 和田健彦
  • Journal Title: 腎と透析 Volume: 76 Pages: 13-7
• [Journal Article] Sperm-associated antigen 4, a novel hypoxia-inducible factor 1 target, regulates eytokinesis, and its expression correlates with the prognosis of renal cell earcinoma. (2013)
  • Author(s): Shoji K, Mimura I, Murayama T, Wada T, Kume H, Goto A, Ohse T, Tanaka T, Inagi R, van der Hoorn FA, Manabe I, Homma Y, Fukayama M, Sakurai T, Hasegawa T, Aburatani H, Kodama T, Nangaku M.
  • Journal Title: American Journal of Pathology Volume: 182 Issue: 6 Pages: 2191-2203
  • DOI: 10.1016/j.ajpath.2013.02.024
  • Peer Reviewed
• [Journal Article] Novel roles of complement in renal diseases and their therapeutic consequences. (2013)
  • Author(s): Wada T, Nangaku M.
  • Journal Title: Kidney Int Volume: 84 Issue: 3 Pages: 441-50
  • DOI: 10.1038/ki.2013.134
  • Peer Reviewed
• [Journal Article] 【検査値を読む2013】 腎機能検査 ペントシジン (2013)
  • Author(s): 和田健彦
  • Journal Title: 内科 Volume: 111 Pages: 1260-1260
• [Journal Article] 膜性腎症と巣状分節性糸球体硬化症 (2013)
  • Author(s): 和田健彦
  • Journal Title: BIO Clinica Volume: 28 Pages: 726-31
• [Journal Article] TMA 疾患概念と病因分類 (2013)
  • Author(s): 平川陽亮、和田健彦、南学正臣
  • Journal Title: 腎と透析 Volume: 74 Pages: 1045-9
• [Journal Article] 近年明らかになったネフローゼ症候群をきたす液性因子 (2013)
  • Author(s): 和田健彦
  • Journal Title: 内科 Volume: 112 Pages: 767-70
• [Journal Article] Novel roles of complement in renal diseases and their therapeutic consequences. (2013)
  • Author(s): Wada T, Nangaku M
  • Journal Title: Kidney International Volume: XX
  • Peer Reviewed
• [Journal Article] Downregulation of miR-205 modulates cell susceptibility to oxidative and endoplasmic reticulum stresses in renal tubular cells. (2012)
  • Author(s): Muratsu-Ikeda S, Nangaku M, Ikeda Y,Tanaka T, Wada T, Inagi R.
  • Journal Title: PLoS One. Volume: 7(7) Issue: 7 Pages: e41462-e41462
  • DOI: 10.1371/journal.pone.0041462
  • Peer Reviewed
• [Presentation] 飽和脂肪酸(パルミンチン酸)は小胞体ストレスを介して腎EPO産生細胞の機能破綻を招く (2015)
  • Author(s): Anusornvongchai Thitinun、本西秀太、鈴木教郎、山本雅之、南学正臣、稲城玲子
  • Organizer: 第58回日本腎臓学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-06-05 – 2015-06-07
• [Presentation] ラットThy-1腎炎モデルにおけるDPP-4阻害薬の腎保護効果に関する検討 (2015)
  • Author(s): 東島佳毅、田中哲洋、山口純奈、田中真司、南学正臣
  • Organizer: 第58回日本腎臓学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-06-05 – 2015-06-07
• [Presentation] SIRT1 maintains actin cytoskeleton by deacetylation of cortactin in podocytes (2014)
  • Author(s): Motonishi S, Nangaku M, Wada T, Ishimoto Y, Matsusaka T, Shimizu A, Inagi R
  • Organizer: Kidney Week 2014
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2014-11-13 – 2014-11-16
• [Presentation] 糸球体疾患の最近の進歩 FSGSとaHUS (2014)
  • Author(s): 南学正臣、和田健彦、加藤秀樹.
  • Organizer: 第44回日本腎臓学会東部学術大会
  • Place of Presentation: ベルサール新宿グランド（東京都新宿区）
  • Year and Date: 2014-10-24 – 2014-10-25
  • Invited
• [Presentation] SIRT1はpodocyteにおいてcortactinを脱アセチル化しアクチン細胞骨格を防御する (2014)
  • Author(s): 本西秀太、南学正臣、和田健彦、石本遊、松阪泰二、清水章、稲城玲子
  • Organizer: 第57回日本腎臓学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-07-04 – 2014-07-06
• [Presentation] 糸球体疾患の最近の進歩：可溶性ウロキナーゼ受容体（suPAR）は巣状分節性糸球体硬化症の液性因子か？ (2014)
  • Author(s): 和田健彦
  • Organizer: 第57回日本腎臓学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-07-04 – 2014-07-06
• [Presentation] SIRT1 Maintains Podocyte Homeostasis via Regulation of Actin Fiber Formation (2013)
  • Author(s): Shuta Motonishi, Reiko Inagi, Takehiko Wada, Takamoto Ohse, Akira Shimizu, Masaomi Nangaku
  • Organizer: American Society of Nephrology Annual Meeting
  • Place of Presentation: Georgia World Congress Center（米国・アトランタ）
• [Presentation] Circulating suPAR in Japanese Patients with Glomerular Diseases: A Multicenter Cross-Sectional Study (2013)
  • Author(s): Takehiko Wada, Masaomi Nangaku, Shoichi Maruyama, Enyu Imai, Kumi Shoji, Sawako Kato, Tomomi Endo, Eri Muso, Kouju Kamata, Hitoshi Yokoyama, Keiji Fujimoto, Yoko Obata, Tomoya Nishino, Hideki Kato, Shunya Uchida, Yoshie Sasatomi, Takao Saito, Seiichi Matsuo
  • Organizer: American Society of Nephrology Annual Meeting
  • Place of Presentation: Georgia World Congress Center（米国・アトランタ）
• [Presentation] Glyoxalase I Prevents Age-Related Endothelial Dysfunction through Modulation of eNOS Phosphorylation (2013)
  • Author(s): Airi Jo, Takamoto Ohse, Hiroaki Nishimatsu, Masao Takahashi, Satoshi Unuma, Takehiko Wada, Yoichiro Ikeda, Toshio Miyata, Yasunobu Hirata, Reiko Inagi, Masaomi Nangaku
  • Organizer: American Society of Nephrology Annual Meeting
  • Place of Presentation: Georgia World Congress Center（米国・アトランタ）
• [Presentation] Glyoxalase Iによる血管内皮の糖化抑制とeNOSの活性制御を介した内皮機能障害の軽減と血管老化の進行抑制 (2013)
  • Author(s): 城 愛理, 大瀬 貴元, 稲城 玲子, 鵜沼 智, 池田 洋一郎, 和田 健彦, 宮田 敏男, 高橋 政夫, 西松 寛明, 平田 恭信, 南学 正臣
  • Organizer: 日本臨床分子医学会学術総会
  • Place of Presentation: 東京国際フォーラム（東京）
• [Presentation] 新規HIF-1ターゲット分子SPAG4は細胞質分裂を調節し、腎細胞癌の進行に重要な役割を果たす (2013)
  • Author(s): 正路 久美, 村山 尚, 三村 維真理, 和田 健彦, 久米 春喜, 後藤 明輝, 大瀬 貴元, 田中 哲洋, 稲城 玲子, 油谷 浩幸, 児玉 龍彦, 南学 正臣
  • Organizer: 日本臨床分子医学会学術総会
  • Place of Presentation: 東京国際フォーラム（東京）
• [Presentation] 輸液療法の基本 (2013)
  • Author(s): 和田 健彦
  • Organizer: 日本腎臓学会学術総会
  • Place of Presentation: 東京国際フォーラム（東京）
  • Invited
• [Presentation] ネフローゼ症候群に関連する新規液性因子に対するアフェレシス療法の展望 (2013)
  • Author(s): 和田 健彦
  • Organizer: 日本アフェレシス学会
  • Place of Presentation: 軽井沢プリンスホテル（長野）
  • Invited
• [Presentation] 小胞体ストレスシグナル(unfolded protein response)による低酸素応答性エリスロポエチン産生機構の破綻 (2012)
  • Author(s): Chiang Chih-Kang, 南学 正臣, 田中 哲洋, 和田 健彦, 大瀬 貴元, 藤田 敏郎, 稲城 玲子
  • Organizer: 第５５回日本腎臓学会学術総会
  • Place of Presentation: 横浜
• [Presentation] microRNAによるprolyl hydroxylase domain 1(PHD1)の転写後制御を介した腎尿細管細胞のストレス応答調節機構 (2012)
  • Author(s): 村津 四葉, 南学 正臣, 田中 哲洋, 池田 洋一郎, 和田 健彦, 大瀬 貴元, 藤田 敏郎, 稲城 玲子
  • Organizer: 第５５回日本腎臓学会学術総会
  • Place of Presentation: 横浜
• [Presentation] 新規HIF-1ターゲット分子SPAG4は尿細管の細胞質分裂を調節する (2012)
  • Author(s): 正路 久美, 村山 尚, 三村 維真理, 和田 健彦, 久米 春喜, 後藤 明輝, 大瀬 貴元, 田中 哲洋, 稲城 玲子, 油谷 浩幸, 児玉 龍彦, 南学 正臣, 藤田 敏郎
  • Organizer: 第５５回日本腎臓学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Identification of a Novel Hypoxia-Inducible Factor 1 (HIF-1) Regulator, CCAAT/Enhancer-Binding Protein Delta (CEBPD) in Kidney Disease (2012)
  • Author(s): Junna Yamaguchi, Tetsuhiro Tanaka, Nobuaki Eto, Takamoto Ohse, Takehiko Wada, MD, Reiko Inagi, Masaomi Nangaku
  • Organizer: American Society of Nephrology Annual Meeting
  • Place of Presentation: San Diego, CA, USA
• [Presentation] Downregulation of miR-205 Modulates Cell Susceptibility to Oxidative and Endoplasmic Reticulum Stresses in Renal Tubular Cells (2012)
  • Author(s): Shiyo Muratsu, Masaomi Nangaku, Yoichiro Ikeda, Tetsuhiro Tanaka, Takehiko Wada, Reiko Inagi
  • Organizer: American Society of Nephrology Annual Meeting
  • Place of Presentation: San Diego, CA, USA
• [Presentation] Identification and Characterization of a Novel HIF-1 Target that Regulates Cytokinesis as a Defensive Mechanism against Polyploidy (2012)
  • Author(s): Kumi Shoji, Imari Mimura, Takashi Murayama, Takehiko Wada, Tetsuhiro Tanaka, Takamoto Ohse, Reiko Inagi, Hiroyuki Aburatani, Tatsuhiko Kodama, Masaomi Nangaku
  • Organizer: American Society of Nephrology Annual Meeting
  • Place of Presentation: San Diego, CA, USA
• [Presentation] SIRT1 はアクチン線維形成の制御を介して糸球体足細胞の恒常性を維持する
  • Author(s): 本西 秀太、南学 正臣、和田 健彦、石本 遊、清水 章、稲城 玲子
  • Organizer: 第４回腎不全研究会
  • Place of Presentation: 全社協・灘尾ホール（東京）
• [Book] 内科学 (2015)
  • Author(s): 和田健彦
  • Publisher: 朝倉書店
• [Book] Annual Review 腎臓 (2014)
  • Author(s): 岡田啓、和田健彦、南学正臣
  • Total Pages: 7
  • Publisher: 中外医学社
• [Book] CKDブックー慢性腎臓病管理の手引ー (2013)
  • Author(s): 南学正臣、和田健彦、花房規男（翻訳）他
  • Total Pages: 640
  • Publisher: メディカル・サイエンス・インターナショナル
• [Book] 他科専門医にきく 糖尿病腎症患者のための22の質問 (2013)
  • Author(s): 大西由希子、和田健彦
  • Total Pages: 120
  • Publisher: SCICUS
• [Remarks] 東京大学大学院医学系研究科 慢性腎臓病病態生理学講座
  • URL: http://www.todai-ckd.com
• [Remarks] 東京大学医学部附属病院腎臓・内分泌内科：腎分子病態研究グループ
  • URL: http://www.todai-jinnai.com/kenkyu/g_nephrology/g01_nephrology
• [Remarks] 東京大学医学部附属病院腎臓・内分泌内科：腎分子病態研究グループ
  • URL: http://www.todai-jinnai.com/kenkyu/g_nephrology/g01_nephrology