The relationship between homeostatic inflammation and renin-angiotensin system in the progression of diabetic nephropathy

• Project/Area Number: 25860673
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: Kumamoto University (2014); Kyoto University (2013)
• Principal Investigator: KUWABARA Takashige 熊本大学, 生命科学研究部, 助教 (00393356)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 自然炎症 / 糖尿病性腎症 / レニン・アンジオテンシン系 / MRP8 / 細胞間クロストーク

Outline of Final Research Achievements

We have previously observed that the macrophages (Mf) infiltrated in glomeruli showed higher MRP8 positivity compared to those in interstitium in diabetic nehropathy. TLR4 deletion did not ameliorate the worsening of diabetic nephropathy nor glomerular MRP8 upregulation by angiotensin II infusion. Besides, MRP8 upregulation in Mf stimulated with mesangilal cell-cultured medium was not altered by TLR4 antagonist. Taken together, MRP8 could become a novel therapeutic target rather than blockade of TLR4 especially in the pathogenesis associated with intraglomerular cross talk.

Research Products

• [Journal Article] Reduction of Tubular Flow Rate as a Mechanism of Oliguria in the Early Phase of Endotoxemia Revealed by Intravital Imaging. (2015)
  • Author(s): Nakano D, Doi K, Kitamura H, Kuwabara T, Mori K, Mukoyama M, Nishiyama A.
  • Journal Title: J Am Soc Nephrol Volume: in press
  • Peer Reviewed
• [Journal Article] An AKI biomarker lipocalin 2 in the blood derives from the kidney in renal injury but from neutrophils in normal and infected conditions. (2015)
  • Author(s): Kanda J, Mori K, Kawabata H, Kuwabara T, Mori KP, Imamaki H, Kasahara M, Yokoi H, Mizumoto C, Thoennissen NH, Koeffler HP, Barasch J, Takaori-Kondo A, Mukoyama M, Nakao K.
  • Journal Title: Clin Exp Nephrol. Volume: 19 Issue: 1 Pages: 99-106
  • DOI: 10.1007/s10157-014-0952-7
  • NAID: 120005678175
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Predictive significance of kidney myeloid-related protein 8 expression in patients with obesity- or type 2 diabetes-associated kidney diseases (2014)
  • Author(s): Kuwabara T, Mori K, Kasahara M, Yokoi H, Imamaki H, Ishii A, Koga K, Sugawara A, Yasuno S, Ueshima K, Morikawa T, Konishi Y, Imanishi M, Nishiyama A, Nakao K, Mukoyama M
  • Journal Title: PloS One Volume: 9 Issue: 2 Pages: e88942-e88942
  • DOI: 10.1371/journal.pone.0088942
  • Peer Reviewed / Open Access
• [Journal Article] Macrophage-mediated glucolipotoxicity via myeloid-related protein 8/toll-like receptor 4 signaling in diabetic nephropathy (2014)
  • Author(s): Kuwabara, T., Mori, K., Mukoyama, M., Kasahara, M., Yokoi, H., Nakao, K.
  • Journal Title: Clinical and Experimental Nephrology Volume: impress Issue: 4 Pages: 584-592
  • DOI: 10.1007/s10157-013-0922-5
  • NAID: 120005474441
  • Peer Reviewed
• [Journal Article] Do statins play a role in renoprotection? (2014)
  • Author(s): Kasahara M, Nakagawa T, Yokoi H, Kuwabara T, Yasuno S, Mori K, Mukoyama M
  • Journal Title: Ueshima K. Clin Exp Nephrol Volume: 18 Issue: 2 Pages: 282-285
  • DOI: 10.1007/s10157-013-0928-z
  • Peer Reviewed
• [Journal Article] Macrophage-mediated glucolipotoxicity via MRP8/TLR4 signaling in diabetic nephropathy. (2014)
  • Author(s): Kuwabara T, Mori K, Mukoyama M, Kasahara M, Yokoi H, Nakao K.
  • Journal Title: Clin Exp Nephrol Volume: in press
  • Peer Reviewed
• [Journal Article] An AKI biomarker lipocalin 2 in the blood derives from the kidney in renal injury but from neutrophils in normal and infected conditions. (2014)
  • Author(s): Kanda J, Mori K, Kawabata H, Kuwabara T, Mori KP, Imamaki H, Kasahara M, Yokoi H, Mizumoto C, Thoennissen NH, Koeffler HP, Barasch J, Takaori-Kondo A, Mukoyama M, Nakao K.
  • Journal Title: Clin Exp Nephrol Volume: in press
  • NAID: 120005678175
  • Peer Reviewed
• [Journal Article] Do statins play a role for renoprotection ? (2014)
  • Author(s): Kasahara M, Nakagawa T, Yokoi H, Kuwabara T, Yasuno S, Mori K, Mukoyama M, Ueshima K.
  • Journal Title: Clin Exp Nephrol Volume: in press
  • Peer Reviewed
• [Journal Article] Adrenomedullin-RAMP2 system suppresses ER stress-induced tubule cell death and is involved in kidney protection (2013)
  • Author(s): Uetake R, Tanaka M, et al.
  • Journal Title: PLoS One. Volume: 9 Issue: 2 Pages: e87667-e87667
  • DOI: 10.1371/journal.pone.0087667
  • Peer Reviewed / Open Access
• [Presentation] Glomerular MRP8 expression predicts progression of proteinuria in obese or type 2 diabetic patients. (2014)
  • Author(s): Takashige Kuwabara, Kiyoshi Mori, Hideki Yokoi, Shinji Yasuno, Masato Kasahara, Kenji Ueshima, Kazuwa Nakao, Masahito Imanishi, Akira Nishiyama, Motoko Yanagita, Masashi Mukoyama
  • Organizer: Annual Meeting of the American Society of Nephrology
  • Place of Presentation: Philadelaphia, USA
  • Year and Date: 2014-11-15
• [Presentation] 糖尿病性腎症進展に果たす自然炎症の役割とその活性化機序～脂質、RA系そして細胞間クロストーク～ (2014)
  • Author(s): 桒原孝成、森潔、笠原正登、中尾一和、柳田素子、向山政志
  • Organizer: 日本腎臓学会学術総会
  • Place of Presentation: パシフィコ横浜、横浜
  • Year and Date: 2014-07-04 – 2014-07-06
  • Invited
• [Presentation] Macrophage-mediated glucolipotoxicity via MRP8/TLR4 signaling in diabetic nephropathy
  • Author(s): Takashige Kuwabara, Kiyoshi Mori, Masashi Mukoyama, Masato Kasahara, Hideki Yokoi, Hirotaka Imamaki, Akira Ishii, Kenichi Koga, Keita P Mori, Yukiko Kato, Akira Sugawara, Kazuwa Nakao
  • Organizer: Kidney and Lipids, World Congress of Nephrology, Satellite Synposium
  • Place of Presentation: Fukuoka, Japan
• [Presentation] Role of chronic inflammation in diabetic nephropathy through glucolipotoxicity and intraglomerular crosstalk
  • Author(s): Takashige Kuwabara, Kiyoshi Mori, Motoko Yanagita, Masashi Mukoyama
  • Organizer: The 3rd CKD Frontier Meeting
  • Place of Presentation: Nagoya, Japan
  • Invited
• [Book] S100タンパク質ファミリーMyeloid-related protein 8（MRP8） (2014)
  • Author(s): 桒原孝成、向山政志
  • Total Pages: 5
  • Publisher: 北隆館
• [Remarks] 京都大学腎臓内科ホームページ
  • URL: http://www.kidney.kuhp.kyoto-u.ac.jp/
• [Remarks] 熊本大学腎臓内科ホームページ
  • URL: http://www.kumadai-nephrology.com/
• [Remarks] 京都大学腎臓内科ホームページ
  • URL: http://www.kidney.kuhp.kyoto-u.ac.jp/
• [Patent(Industrial Property Rights)] 腎疾患の診断方法 (2014)
  • Inventor(s): 桒原 孝成
  • Industrial Property Rights Holder: 国立大学法人京都大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-261973
  • Filing Date: 2014-12-25