The investigation of peptidase inhibition toward diabetic nephropathy and cardiomyopathy

2013 Fiscal Year Final Research Report

• Project/Area Number: 24790098
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: Kobe Pharmaceutical University
• Principal Investigator: NAKAYAMA Kazuhiko 神戸薬科大学, 薬学部, 助教 (70584738)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Keywords: エンドセリン変換酵素 / 糖尿病性腎症 / 糖尿病性心筋症

Research Abstract

We investigated the novel therapeutic mechanism of endothelin converting enzyme (ECE) inhibition toward diabetic concomitant diseases like nephropathy, cardiomyopathy, and limb ischemia by using genetically modified mice. Although ECE was known as synthetic enzyme for endothelin-1, this time, we proved the the potentiating vasodilative peptide as bradykinin, and also anti-inflammatory peptide as calcitonin gene related peptide by inhibiting their degradation. This study is the first investigation to confirm the new mechanism of ECE inhibition in diabetic complication.

Research Products

• [Journal Article] Inhibition of vascular endothelial growth factor receptor under hypoxia causes severe, human-like pulmonary arterial hypertension in mice : Potential roles of interleukin-6 and endothelin (2014)
  • Author(s): Hung Tran Van, Noriaki Emoto, Nicolas Vignon-Zellweger, Kazuhiko Nakayama, Keiko Yagi, Yoko Suzuki, Ken-ichi Hirata
  • Journal Title: Life Sci Volume: (in press) Pages: 0024-3205
• [Journal Article] エンドセリン受容体拮抗薬の臨床研究と今後の課題 (2013)
  • Author(s): 中山和彦、江本憲明
  • Journal Title: 心臓 Volume: 45(12) Pages: 1503-1511
• [Journal Article] Endothelin-converting enzyme-1 gene ablation attenuates pulmonary fibrosis via CGRP-cAMP/EPAC1 pathway (2013)
  • Author(s): Hartopo AB, Emoto N, Vignon-Zellweger N, Suzuki Y, Yagi K, Nakayama K, Hirata K
  • Journal Title: Am J Respir Cell Mol Biol Volume: 48 Pages: 465-76
• [Journal Article] Noninvasive and Simple Assessment of Cardiac Output and Pulmonary Vascular Resistance With Whole-Body Impedance Cardiography Is Useful for Monitoring Patients With Pulmonary Hypertension (2013)
  • Author(s): TaniguchiY, Emoto N, Miyagawa K, Nakayama K, Kinutani H, Tanaka H, Shinke T, Hirata KI
  • Journal Title: Circulation Journal Volume: 77 Pages: 2383-2389
• [Journal Article] Physiological relevance of hydrolysis of atrial natriuretic Peptide by endothelin-converting enzyme-1. Kobe (2012)
  • Author(s): Nakayama K, Emoto N, SuzukiY, Vignon-Zellweger N, Yagi K, Hirata K
  • Journal Title: J Med Sci Volume: 58 Pages: 12-18
• [Journal Article] ET-1 from endothelial cells is required for complete angiotensin II-induced cardiac fibrosis and hypertrophy (2012)
  • Author(s): Adiarto S, Heiden S, Vignon-Zellweger N, Nakayama K, Yagi K, Yanagisawa M, Emoto N
  • Journal Title: Life Science Volume: 15 Pages: 651-657
• [Journal Article] ET-1 deletion from endothelial cells protects the kidney during the extension phase of ischemia/reperfusion injury (2012)
  • Author(s): Arfian N, Emoto N, Vignon-Zellweger N, Nakayama K, Yagi K, Hirata K
  • Journal Title: Biochem Biophys Res Commun Volume: 425 Pages: 443-449
• [Presentation] The Potentiation of Calcitonin Gene-related Peptide Pathway by Suppressing Endothelin Converting Enzyme Attenuates Kidney Dysfunction in Type 1 Diabetic Mice (2014)
  • Author(s): Kazuhiko Nakayama , Yoko Suzuki, Takuya Okano, Kazuya Miyagawa, Keiko Yagi, Ken-ichi Hirata, Noriaki Emoto
  • Organizer: 第78回日本循環器学会総会
  • Place of Presentation: 東京
  • Year and Date: 20140300
• [Presentation] Possible Involvement of Estrogen on Endothelin-1 Transgenic Mice in the Hypoxia Induced Pulmonary Arterial Hypertension Model (2014)
  • Author(s): Muhammad G, N Emoto, K Nakayama, K Yagi, K Hirata
  • Organizer: 第78回日本循環器学会総会
  • Place of Presentation: 東京
  • Year and Date: 20140300
• [Presentation] Knockout of Endothelin-1 in Vascular Endothelial Cells Ameliorates Cardiac Remodelling induced by Cryoinfarction in Mice (2014)
  • Author(s): Muliawan HS, Emoto N, Nakayama K, Yagi K, Hirata K
  • Organizer: 第78回日本循環器学会総会
  • Place of Presentation: 東京
  • Year and Date: 20140300
• [Presentation] Endothelin-1 Derived Vascular Endothelial Cells Importance for Cardiac Remodeling Induced by Cryoinfarction (2014)
  • Author(s): Muliawan HS, Nakayama K, Yagi K, Miyagawa K Suzuki Y, Satwiko MG, Nugroho DB, Jeffilano AB, Emoto N
  • Organizer: 第43回日本心脈管作動物質学会年会
  • Place of Presentation: 神戸
  • Year and Date: 20140200
• [Presentation] エンドセリン変換酵素阻害によるカルシトニン遺伝子関連ペプチド賦活を介した糖尿病性腎症進展抑制効果の検討 (2014)
  • Author(s): 中山和彦、亀田真吾、中原大介、鈴木陽子、岡野卓也、宮川一也、八木敬子、江本憲昭、平田健一
  • Organizer: 第43回日本心脈管作動物質学会年会
  • Place of Presentation: 神戸
  • Year and Date: 20140200
• [Presentation] Role of Vascular Endothelial Cells Endothelin-1 in Cardiac Remodeling Induced by Cryoinfarction (2014)
  • Author(s): Muliawan HS, Emoto N, Nakayama K, Yagi K, Hirata K
  • Organizer: 10th Asia Pacific Congress of Hypertension (APCH2014)
  • Place of Presentation: Philippines Cebu
  • Year and Date: 20140200
• [Presentation] Harimurti Role of Bradykinin and Endothelin-Converting Enzyme-1 in Pulmonary Hypertension (2013)
  • Author(s): Sunu B. Raharjo, Noriaki Emoto, Yoga Yuniadi, Kazuhiko Nakayama, Ganesja M
  • Organizer: International conference of Endothelin (ET-13)
  • Place of Presentation: 東京
  • Year and Date: 20130900
• [Presentation] Absence of ETA receptors on podocytes is not antialbuminuric in diabetic mice (2013)
  • Author(s): Nicolas Vignon-Zellweger, Susi Heiden, Kazuhiko Nakayama, Keiko Yagi, Marc Iglarz, Masashi Yanagisawa, Noriaki Emoto
  • Organizer: International conference of Endothelin (ET-13)
  • Place of Presentation: 東京
  • Year and Date: 20130900
• [Presentation] Endothelin converting enzyme inhibition attenuates early albuminuria and late renal failure in streptozotocin induced diabetic mice (2013)
  • Author(s): Kazuhiko Nakayama, Nicolas Vignon-Zellweger, Susi Heiden, Yoko Suzuki, Takuya Okano, Kazuya Miyagawa, Keiko Yagi, Masashi Yanagisawa, Noriaki Emoto
  • Organizer: International conference of Endothelin (ET-13)
  • Place of Presentation: 東京
  • Year and Date: 20130900
• [Presentation] Endothelial Cells-derived Endothelin-1 Exaggerates Kidney Fibrosis Through ETAR Activation in Renal Interstitial Cells (2013)
  • Author(s): Nur Arfi an, Keiko Yagi, Kazuhiko Nakayama, Nicolas Vignon-Zellweger, Susi Heiden, Tran V. Hung, Hary S. Muliawan, Gahan Satwiko, Noriaki Emoto
  • Organizer: International conference of Endothelin (ET-13)
  • Place of Presentation: 東京
  • Year and Date: 20130900
• [Presentation] Analysis of ET-1 system in mild and severe pulmonary arterial hypertension in mice (2013)
  • Author(s): Hung Van Tran, Noriaki Emoto, Nicolas Vignon-Zellweger, Kazuhiko Nakayama, Keiko Yagi, Yoko Suzuki, Ken-ichi Hirata
  • Organizer: International conference of Endothelin (ET-13)
  • Place of Presentation: 東京
  • Year and Date: 20130900
• [Presentation] Serum Endothelin-1 and big endothelin-1 in patients with chronic thromboembolic pulmonary hypertension can be markers to predict hemodynamics after balloon pulmonary angioplasty (2013)
  • Author(s): Kazuya Miyagawa, Kazuhiko Nakayama, Yoko Suzuki, Yu Taniguchi, Hiroto Kinutani, Toshiro Shinke, Ken-ich Hirata, Noriaki Emoto
  • Organizer: International conference of Endothelin (ET-13)
  • Place of Presentation: 東京
  • Year and Date: 20130900
• [Presentation] Distinct expression of endothelin-1 and endothelin converting enzyme-1 in the lung of patients undergoing right heart bypass surgery (2013)
  • Author(s): Naoki Yoshimura, Tomonori Higuma, Masaya Aoki, Yoshinori Doki, Hideyuki Nagkaoka, Keiichirou Ibuki, Sayaka Ozawa, Keiichi Hirono, Fukiko Ichida, Kazuhiko Nakayama, Takuya Okano, Noriaki Emoto
  • Organizer: A preliminary study International conference of Endothelin (ET-13)
  • Place of Presentation: 東京
  • Year and Date: 20130900
• [Presentation] 肺高血圧・肺線維症に対する新たなエンドセリン研究-エンドセリン変換酵素阻害の可能性 (2013)
  • Author(s): 中山和彦, Anggoro B. Hartopo,鈴木陽子, Sunu Budhi Raharjo,江本憲昭
  • Organizer: 第2回日本肺循環学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 20130600
  • Invited
• [Presentation] Focusing right heart function for predicting the oral medical efficacy in pulmonary hypertension (2013)
  • Author(s): 中山和彦、江本憲昭、谷口悠、絹谷洋人、鈴木陽子、新家俊郎、平田健一
  • Organizer: 第2回日本肺循環学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 20130600
• [Presentation] 肺動脈性肺高血圧症患者に対するエンドセリン受容体拮抗薬およびPDE5阻害剤追加併用療法の長期効果の検討 (2013)
  • Author(s): 谷口悠、江本憲昭、絹谷洋人、中山和彦、新家俊郎、平田健一
  • Organizer: 第2回日本肺循環学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 20130600
• [Presentation] Impaired right heart function predicts the inefficacy of oral pulmonary vasodilators in the patients with pulmonary hypertension (2013)
  • Author(s): Kazuhiko Nakayama, Noriaki Emoto, Yu Taniguchi, Hiroto Kinutani, Yoko Suzuki, Toshiro Shinke, Ken-ichi Hirata
  • Organizer: 第77回日本循環器学会総会
  • Place of Presentation: 横浜
  • Year and Date: 20130300
• [Remarks] 神戸大学循環器内科 肺高血圧グループ
  • URL: http://www.med.kobe-u.ac.jp/im1/doctor/activity/basic/acti-03.html
• [Remarks] 神戸薬科大学 臨床薬学研究室
  • URL: http://www.kobepharma-u.ac.jp/~clinical/publications/index.html