Downregulation of cPLA2 suppress diabetic nephropathy in diabetic mouse models

2019 Fiscal Year Annual Research Report

• Project/Area Number: 17K09835
• Research Institution: Kumamoto University
• Principal Investigator: 松村 剛 熊本大学, 大学院生命科学研究部(医), 准教授 (20398192)
• Co-Investigator(Kenkyū-buntansha): 瀬ノ口 隆文 熊本大学, 大学院生命科学研究部(医), 助教 (00530320) ; 石井 規夫 熊本大学, 病院, 特任助教 (10599111)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 糖尿病性腎症 / 炎症 / マクロファージ / cPLA2

Outline of Annual Research Achievements

研究の目的：糖尿病腎症の発症・進展阻止は、我が国の重要な命題である。近年申請者は、阻害剤やノックアウト(KO)マウスを用いた検討で、細胞内アラキドン酸カスケードに関与する分子であるcPLA2の発現抑制が、マクロファージや大動脈において抗炎症作用・抗動脈硬化作用を発揮することを見出した。一方、糖尿病腎症の発症にはPKCとその下流に位置するcPLA2の関与が示唆されているが、糖尿病腎症に対して、このcPLA2抑制の治療的効果や有用性は確立していない。本研究では、STZを用いて糖尿病を導入したWTマウスとcPLA2欠損マウスを用い、糖尿病腎症発症・進展に対するcPLA2阻害療法の有用性を検討することで、糖尿病腎症発症・進展の新規機序の解明と新たな治療法開発の可能性を見出すことを目的とする。
研究の成果：①ヒト腎糸球体内皮細胞に対しAACOCF3存在下、非存在下で30mMグルコース刺激を行ったところ、TNF-α、IL-1β、IL-6、MCP-1、TGF-β、ICAM-1、VCAM-1mRNA産生はAACOCF3で有意に抑制された。さらにcaspase-3発現量の誘導もAACOCF3で有意に抑制された。②ヒト腎メサンギウム細胞に対しても同様の刺激によるTGF-β、IV型コラーゲン、フィブロネクチン、TNF-α、IL-1β、IL-6、MCP-1、TGF-βのmRNA発現量がAACOCF3で有意に抑制された。③マウス腹腔マクロファージに対しても同様の刺激によるTNF-α、IL-1β、IL-6、MCP-1、TGF-βのmRNA発現は、AACOCF3で有意に抑制された。
以上の結果より、STZ誘導糖尿病モデルマウスにおける腎症発症進展抑制効果において、腎糸球体内皮細胞、腎メサンギウム細胞、マクロファージへの抗炎症効果が関与する可能性が示唆された。

Research Products

• [Journal Article] Inhibition of inflammation-mediated DPP-4 expression by linagliptin increases M2 macrophages in atherosclerotic lesions (2020)
  • Author(s): Nishida S, Matsumura T, Senokuchi T, Murakami-Nishida S, Ishii N, Morita Y, Yagi Y, Motoshima H, Kondo T, Araki E
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 524(1) Pages: 8-15
  • DOI: 10.1016/j.bbrc.2020.01.027.
  • Peer Reviewed / Open Access
• [Journal Article] Hyperemesis gravidarum followed by refeeding syndrome causes electrolyte abnormalities induced rhabdomyolysis and diabetes insipidus. (2019)
  • Author(s): Kondo T, Nakamura M, Kawashima J, Matsumura T, Ohba T, Yamaguchi M, Katabuchi H, Araki E.
  • Journal Title: Endocrine Journal Volume: 66(3) Pages: 253-258
  • DOI: 10.1507/endocrj.EJ18-0496.
  • Peer Reviewed / Open Access
• [Journal Article] Mineralocorticoid Receptor May Regulate Glucose Homeostasis through the Induction of Interleukin-6 and Glucagon-Like peptide-1 in Pancreatic Islets (2019)
  • Author(s): Goto R, Kondo T, Ono K, Kitano S, Miyakawa N, Watanabe T, Sakaguchi M, Sato M, Igata M, Kawashima J, Motoshima H, Matsumura T, Shimoda S, Araki E
  • Journal Title: Journal of Clinical Medicine Volume: 8(5) Pages: 674
  • DOI: 10.3390/jcm8050674.
  • Peer Reviewed / Open Access
• [Journal Article] Pioglitazone suppresses macrophage proliferation in apolipoprotein-E deficient mice by activating PPARγ (2019)
  • Author(s): Murakami-Nishida S, Matsumura T, Senokuchi T, Ishii N, Kinoshita H, Yamada S, Morita Y, Nishida S, Motoshima H, Kondo T, Komohara Y, Araki E
  • Journal Title: Atherosclerosis Volume: 286 Pages: 30-39
  • DOI: 10.1016/j.atherosclerosis.2019.04.229.
  • Peer Reviewed / Open Access
• [Journal Article] Differential Predictive Factors for Cardiovascular Events in Patients with or without Cancer History (2019)
  • Author(s): Sueta D, Tabata N, Ikeda S, Saito Y, Ozaki K, Sakata K, Matsumura T, Yamamoto-Ibusuki M, Murakami Y, Jodai T, Fukushima S, Yoshida N, Kamba T, Araki E, Iwase H, Fujii K, Ihn H, Kobayashi Y, Minamino T, Yamagishi M, Maemura K, Baba H, Matsui K, Tsujita K
  • Journal Title: Medicine Volume: 98(44) Pages: e17602
  • DOI: 10.1097/MD.0000000000017602.
  • Peer Reviewed / Open Access
• [Presentation] Effects of linagliptin on macrophages and on progression of atherosclerosis in high fat-fed apoE-deficient mice (2019)
  • Author(s): Nishida S, Matsumura T, Senokuchi T, Ishii N, Murakami-Nishida S, Yamada S, Morita Y, Wada T, Motoshima H, Kondo T, Araki E
  • Organizer: The 11th Scientific Meeting of the Asian Association for the Study of Diabetes
  • Int'l Joint Research
• [Presentation] The Hepatic Role of Heat Shock Protein 72 in the Pathogenesis of Type 2 Diabetes (2019)
  • Author(s): Kondo T, Kitano S, Miyakawa N, Watanabe T, Goto R, Ono K, Igata M, Kawashima J, Motoshima H, Matsumura T, Araki E
  • Organizer: The 79th ADA Scientific Meetng
  • Int'l Joint Research
• [Presentation] Pioglitazone Suppresses Macrophage Proliferation in Apolipoprotein-e Deficient Mice by Activating PPARγ (2019)
  • Author(s): Murakami-Nishida S, Matsumura T, Nishida S, Senokuchi T, Ishi N, Yamada S, Morita Y, Wada T, Motoshima H, Kondo T, Araki E
  • Organizer: The 79th ADA Scientific Meetng
  • Int'l Joint Research
• [Presentation] Linagliptin induces M2 macrophage polarization and suppresses progression of atherosclerosis in high fat-fed apoE-deficient mice (2019)
  • Author(s): Nishida S, Matsumura T, Senokuchi T, Ishii N, Murakami-Nishida S, Yamada S, Morita Y, Wada T, Motoshima H, Kondo T, Araki E
  • Organizer: The 79th ADA Scientific Meeting
  • Int'l Joint Research
• [Presentation] Pioglitazone suppresses macrophage proliferation in apolipoprotein-E deficient mice by activating PPARγ (2019)
  • Author(s): Matsumura T, Murakami-Nishida S, Nishida S, Senokuchi T, Ishii N, Morita Y, Wada T, Motoshima H, Kondo T, Arak E
  • Organizer: 55th Annual Meetng of the European Association of the Study of Diabetes
  • Int'l Joint Research
• [Presentation] The organ cross talk in the regulation of glucose homeostasis through heat shock protein 72 expression (2019)
  • Author(s): Kondo T, Kitano S, Miyakawa N, Watanabe T, Goto R, Igata M, Kawashima J, Motoshima H, Matsumura T, Araki E
  • Organizer: 55th Annual Meetng of the European Association of the Study of Diabetes
  • Int'l Joint Research
• [Presentation] Inhibition of DPP-4 suppresses atherosclerotic lesion formation through the regulation of M2 macrophage polarization (2019)
  • Author(s): Yagi Y, Matsumura T, Nishida S, Senokuchi T, Ishii N, Murakami-Nishida S, Morita Y, Wada T, Motoshima H, Kondo T, Araki E
  • Organizer: IDF Congress 2019
  • Int'l Joint Research
• [Presentation] Role of Tissue Macrophages Proliferation in Insulin Resistance in the Liver and Adipose tissue (2019)
  • Author(s): Wada T, Senokuchi T, Yamada S, Morita Y, Furusho T, Motoshima H, Ishi N, Matsumura T, Araki E
  • Organizer: IDF Congress 2019
  • Int'l Joint Research
• [Presentation] 糖尿病患者における肝細胞癌発生の実態調査 (2019)
  • Author(s): 松村剛，瀬ノ口隆文，建石良介，窪田直人，小池和彦，荒木栄一
  • Organizer: 第62回日本糖尿病学会年次学術集会
• [Presentation] ピオグリタゾンによるマクロファージ増殖抑制効果を介した糖尿病大血管合併症進展抑制効果 (2019)
  • Author(s): 松村剛，西田彩子，瀬ノ口隆文，石井規夫，山田沙梨恵，守田雄太郎，西田周平，和田敏明, 佐藤美希，本島寛之，近藤龍也，荒木栄一
  • Organizer: 第62回日本糖尿病学会年次学術集会