内皮細胞オートファジー不全が糖尿病腎線維化において演じる分子機構の解明

2017 Fiscal Year Research-status Report

• Project/Area Number: 16K15472
• Research Institution: Kanazawa Medical University
• Principal Investigator: 古家 大祐 金沢医科大学, 医学部, 教授 (70242980)
• Co-Investigator(Kenkyū-buntansha): 金崎 啓造 金沢医科大学, 医学部, 准教授 (60589919)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: オートファジー / 内皮・間葉化 / IL-6 / 腎線維化 / 心線維化 / 膵島

Outline of Annual Research Achievements

我々は予備的検討でオートファジー不全(Atg5 siRNA過剰投与)が、内皮間葉化を惹起する事を見出した。オートファジー不全誘導EndMTは予想に反して線維性増殖疾患で中心的役割を演じるtransforming growth factor(TGF)ベータ非依存的であり、分子機構を解明することが目的である。結果として、Atg5 siRNA処理した内皮細胞において、IL-6が内皮間葉化を惹起することを明らかにした。内皮細胞特異的Atg5ノックアウトマウス（Atg5 endo)において、内皮間葉化を介する腎線維化と血漿および腎のIL-6は高値であることを見出した。それらは1型糖尿病誘発および高脂肪食負荷マウスにおいて増悪した。IL-6中和抗体の投与によって、高脂肪食負荷Atg5 endoの腎線維化は改善した。さらに、高脂肪食負荷Atg5 endoマウスは血圧の上昇、高インスリン血漿、耐糖能障害がおこり、腎と同様に心臓においても血管周囲の線維化が認められた。これら変化も、IL-6中和抗体によて改善した。興味あることに、Atg5 endoマウスにおける膵島の委縮が、IL-6中和抗体によって改善していた。

Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

内皮・間葉化を惹起する因子として、IL-6を同定したことにより、飛躍的な結果が得られている。

Strategy for Future Research Activity

今回見出した内皮間葉化のターゲットであったIL-6が、Atg5 endoマウスにおいてどのような機構で上昇するのかを最終年度に解明する。

Research Products

• [Journal Article] A Low-Protein Diet for Diabetic Kidney Disease: Its Effect and Molecular Mechanism, an Approach from Animal Studies (2018)
  • Author(s): Kitada M, Ogura Y, Monno I, Koya D.
  • Journal Title: Nutrients Volume: 10 Pages: -
  • DOI: 10.3390/nu10050544.
  • Peer Reviewed
• [Journal Article] A ketogenic amino acid rich diet benefits mitochondrial homeostasis by altering the AKT/4EBP1 and autophagy signaling pathways in the gastrocnemius and soleus. (2018)
  • Author(s): Li J, Kanasaki M, Xu L, Kitada M, Nagao K, Adachi Y, Jinzu H, Noguchi Y, Kohno M, Kanasaki K, Koya D
  • Journal Title: Biochim Biophys Acta Volume: S0304-4165 Pages: 30075-8
  • DOI: 10.1016/j.bbagen.2018.03.013.
  • Peer Reviewed
• [Journal Article] FGFR1 is essential for N-acetyl-seryl-aspartyl-lysyl-proline regulation of mitochondrial dynamics by upregulating microRNA let-7b-5p (2018)
  • Author(s): Hu Q, Li J, Nitta K, Kitada M, Nagai T, Kanasaki K, Koya D.
  • Journal Title: Biochem Biophys Res Commun Volume: 495 Pages: 2214-2220
  • DOI: 10.1016/j.bbrc.2017.12.089.
  • Peer Reviewed
• [Journal Article] The Effect of Piceatannol from Passion Fruit (Passiflora edulis) Seeds on Metabolic Health in Humans. (2018)
  • Author(s): Kitada M, Ogura Y, Maruki-Uchida H, Sai M, Suzuki T, Kanasaki K, Hara Y, Seto H, Kuroshima Y, Monno I, Koya D
  • Journal Title: Nutrients. Volume: 9 Pages: -
  • DOI: 10.3390/nu9101142
  • Peer Reviewed
• [Journal Article] Eplerenone prevented obesity-induced inflammasome activation and glucose intolerance (2017)
  • Author(s): Wada T, Ishikawa A, Watanabe E, Nakamura Y, Aruga Y, Hasegawa H, Onogi Y, Honda H, Nagai Y, Takatsu K, Ishii Y, Sasahara M, Koya D, Tsuneki H, Sasaoka T
  • Journal Title: J Endocrinol. Volume: 235 Pages: 179-191
  • DOI: 10.1530/JOE-17-0351.
  • Peer Reviewed
• [Journal Article] Cyclic and intermittent very low-protein diet can have beneficial effects against advanced diabetic nephropathy in Wistar fatty (fa/fa) rats, an animal model of type 2 diabetes and obesity. (2017)
  • Author(s): Kitada M, Ogura Y, Suzuki T, Monnno I, Kanasaki K, Watanabe A, Koya D.
  • Journal Title: Nephrology (Carlton). Volume: 22 Pages: 1030-1034
  • DOI: 10.1111/nep.13152.
  • Peer Reviewed
• [Journal Article] Deficiency in catechol-o-methyltransferase is linked to a disruption of glucose homeostasis in mice. (2017)
  • Author(s): Kanasaki M, Srivastava SP, Yang F, Xu L, Kudoh S, Kitada M, Ueki N, Kim H, Li J, Takeda S, Kanasaki K, Koya D.
  • Journal Title: Sci Rep Volume: 7 Pages: -
  • DOI: 10.1038/s41598-017-08513-w.
  • Peer Reviewed
• [Journal Article] FGFR1 is critical for the anti-endothelial mesenchymal transition effect of N-acetyl-seryl-aspartyl-lysyl-proline via induction of the MAP4K4 pathway (2017)
  • Author(s): Li J, Shi S, Srivastava SP, Kitada M, Nagai T, Nitta K, Kohno M, Kanasaki K, Koya D
  • Journal Title: Cell Death Dis. Volume: 8 Pages: -
  • DOI: 10.1038/cddis.2017.353.
  • Peer Reviewed
• [Journal Article] Anagliptin ameliorates albuminuria and urinary liver-type fatty acid-binding protein excretion in patients with type 2 diabetes with nephropathy in a glucose-lowering-independent manner. (2017)
  • Author(s): Kitada M, Tsuda SI, Konishi K, Takeda-Watanabe A, Fujii M, Kanasaki K, Nishizawa M, Nakagawa A, Koya D
  • Journal Title: BMJ Open Diabetes Res Care. Volume: 5 Pages: -
  • DOI: 10.1136/bmjdrc-2017-000391.
  • Peer Reviewed
• [Journal Article] Regulating Autophagy as a Therapeutic Target for Diabetic Nephropathy (2017)
  • Author(s): Kitada M, Ogura Y, Monno I, Koya D.
  • Journal Title: Curr Diab Rep Volume: 17 Pages: -
  • DOI: 10.1007/s11892-017-0879-y
  • Peer Reviewed
• [Journal Article] Catechol-O-Methyltransferase Deficiency Leads to Hypersensitivity of the Pressor Response Against Angiotensin II. (2017)
  • Author(s): Ueki N, Kanasaki K, Kanasaki M, Takeda S, Koya D
  • Journal Title: Hypertension Volume: 69 Pages: 1156-1164
  • DOI: 10.1161/HYPERTENSIONAHA.117.09247.
  • Peer Reviewed
• [Journal Article] PDGFRβ Regulates Adipose Tissue Expansion and Glucose Metabolism via Vascular Remodeling in Diet-Induced Obesity (2017)
  • Author(s): Onogi Y, Wada T, Kamiya C, Inata K, Matsuzawa T, Inaba Y, Kimura K, Inoue H, Yamamoto S, Ishii Y, Koya D, Tsuneki H, Sasahara M, Sasaoka T
  • Journal Title: Diabates Volume: 66 Pages: 1008-1021.
  • DOI: 10.2337/db16-0881
  • Peer Reviewed
• [Journal Article] Impact of empagliflozin on diabetic kidney disease. (2017)
  • Author(s): Koya D
  • Journal Title: J Diabetes Investig. Volume: 8 Pages: 658-660
  • DOI: 10.1111/jdi.12615.
  • Peer Reviewed
• [Remarks] 金沢医科大学 糖尿病・内分泌内科学
  • URL: http://www.kanazawa-med.ac.jp/~endocrin/