Pathophysiology of non-diabetic/obesity induced renal injuries

• Project/Area Number: 26461236
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Keio University
• Principal Investigator: Tokuyama Hirobumi 慶應義塾大学, 医学部(信濃町), 講師 (50276250)
• Co-Investigator(Kenkyū-buntansha): 脇野 修 慶應義塾大学, 医学部(信濃町), 准教授 (50265823) ; 林 晃一 東京歯科大学, 歯学部, 教授 (80164937)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2016: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: rho-kinase / mDia / p27 / proximal tubule / cell cycle / Rhoキナーゼ / RhoA / PHD2 / Rho / Cell Cycle / 虚血 / PHD / HIF / 肥満関連腎症 / 近位尿細管

Outline of Final Research Achievements

Excess fat intake causes obesity-induced renal injury, which are mediated by an activated Rho/Rho-kinase pathway in proximal tubules and inflammatory process. It is surmised that hypertrophic process in proximal tubules during obesity formation affects Rho-kinase activation presumably through mechanical stress. mDia is induced in an early phase and subsequently the induction of Rho-kinase is observed in obesity. In parallel with that, p27 is suppressed, thereby leading to the hyperplastic state of cell cycle, which is contrary to the hypoplastic state in diabetes. This process subsequently induces inflammation and accelerates the histological changes of proximal tubules. The intervention of Rho/Rho-kinase may constitute a novel strategy blocking the progression process of obesity-induced renal damages from an early stage.

Research Products

• [Journal Article] Obesity-induced kidney injury is attenuated by amelioration of aberrant PHD2 activation in proximal tubules (2016)
  • Author(s): Futatsugi K, Tokuyama H, Shibata S, Naitoh M, Kanda T, Minakuchi H, Yamaguchi S, Hayashi K, Minamishima YA, Yanagita M, Wakino S, Itoh H
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 365331-12
  • DOI: 10.1038/srep36533
  • Peer Reviewed / Open Access
• [Journal Article] Communication from Tubular Epithelial Cells to Podocytes through Sirt1 and Nicotinic Acid Metabolism. (2016)
  • Author(s): Hasegawa K, Wakino S, Sakamaki Y, Muraoka H, Umino H, Minakuchi H, Yoshifuji A, Naitoh M, Shinozuka K, Futatsugi K, Urai H, Kanda T, Tokuyama H, Hayashi K, Itoh H.
  • Journal Title: Curr Hypertens Rev. Curr Hypertens Rev. Volume: 12 (2) Pages: 95-104
• [Journal Article] Communication from Tubular Epithelial Cells to Podocytes through Sirt1 and Nicotinic Acid Metabolism. (2016)
  • Author(s): Hasegawa K, Wakino S, Sakamaki Y, Muraoka H, Umino H, Minakuchi H, Yoshifuji A, Naitoh M, Shinozuka K, Futatsugi K, Urai H, Kanda T, Tokuyama H, Hayashi K, Itoh H.
  • Journal Title: Curr Hypertens Rev. Volume: *
  • Peer Reviewed
• [Journal Article] The role of adipose tissue asymmetric dimethylarginine/dimethylarginine dimethylaminohydrolase pathway in adipose tissue phenotype and metabolic abnormalities in subtotally nephrectomized rats. (2015)
  • Author(s): Minakuchi H, Wakino S, Hosoya K, Sueyasu K, Hasegawa K, Shinozuka K, Yoshifuji A, Futatsugi K, Komatsu M, Kanda T, Tokuyama H, Hayashi K, Itoh H.
  • Journal Title: Nephrol Dial Transplant. Volume: 31(3) Issue: 3 Pages: 413-423
  • DOI: 10.1093/ndt/gfv367
  • Peer Reviewed
• [Journal Article] Renin-angiotensin blockade resets podocyte epigenome through Kruppel-like Factor 4 and attenuates proteinuria. (2015)
  • Author(s): Hayashi K, Sasamura H, Nakamura M, Sakamaki Y, Azegami T, Oguchi H, Tokuyama H, Wakino S, Hayashi K, Itoh H
  • Journal Title: Kidney Int Volume: 88(4) Issue: 4 Pages: 745-753
  • DOI: 10.1038/ki.2015.178
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Insulin resistance in chronic kidney disease is ameliorated by spironolactone in rats and humans. (2014)
  • Author(s): Hosoya K, Minakuchi H, Wakino S (Corresponding Author), Fujimura K, Hasegawa K, Komatsu M, Yoshifuji A, Futatsugi K, Shinozuka K, Washida N, Kanda T, Tokuyama H, Hayashi K, Itoh H.
  • Journal Title: Kidney Int Volume: 87 Issue: 4 Pages: 749-60
  • DOI: 10.1038/ki.2014.348
  • Peer Reviewed / Open Access
• [Journal Article] 肥満症とCKD-その病態と管理 (2014)
  • Author(s): 徳山博文、伊藤裕
  • Journal Title: 肥満研究 Volume: 20(3) Pages: 144-148
  • NAID: 40020321146
• [Presentation] 肥満関連腎症の近位尿細管Rho/Rhoキナーゼ/p27経路の果たす役割． (2016)
  • Author(s): 内藤真規子、徳山博文、二木功治、脇野修、伊藤裕
  • Organizer: 第59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: 2016-06-17
• [Presentation] 肥満関連腎症の病態生理の解明 (2015)
  • Author(s): 内藤真紀子、徳山博文、二木功治、脇野修、林晃一、伊藤裕
  • Organizer: 第19回日本心血管内分泌代謝学会学術総会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-10
• [Presentation] 非糖尿病・肥満関連腎症の病態生理- 相対的虚血による尿細管間質障害 (2015)
  • Author(s): 二木功治、徳山博文、内藤真紀子、脇野修、林晃一、伊藤裕
  • Organizer: 第19回日本心血管内分泌代謝学会学術総会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-10
• [Presentation] 肥満関連腎症における近位尿細管Rho/Rhoキナーゼの役割 (2015)
  • Author(s): 内藤真紀子
  • Organizer: 日本腎臓学会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-06-05 – 2015-06-07
• [Presentation] 非糖尿病・肥満関連腎症における病態生理－虚血に注目した尿細管間質障害の分析 (2015)
  • Author(s): 二木功治
  • Organizer: 日本腎臓学会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-06-05 – 2015-06-07
• [Presentation] 非糖尿病・肥満関連腎症の病態生理―相対的虚血による尿細管間質障害． (2015)
  • Author(s): 二木功治、徳山博文、内藤真規子、林晃一、脇野修、伊藤裕
  • Organizer: 第58回日本腎臓学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-06-05
• [Presentation] 肥満関連腎症における近位尿細管Rho/Rhoキナーゼの役割 (2015)
  • Author(s): 内藤真規子、徳山博文、二木功治、林晃一、脇野修、伊藤裕
  • Organizer: 第58回日本腎臓学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-06-05
• [Presentation] 腎不全に伴う脂肪組織機能障害と異所性脂肪沈着 (2015)
  • Author(s): 水口斉、脇野修、細谷幸司、藤村慶子、吉藤歩、長谷川一宏、神田武志、徳山博文、林晃一、伊藤裕
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: ホテルニューオータニ東京（東京都千代田区）
  • Year and Date: 2015-04-23
• [Presentation] 肥満関連腎症における近位尿細管Rho/Rhoキナーゼの役割 (2015)
  • Author(s): 内藤真規子、徳山博文、二木功治、林晃一、脇野修、伊藤裕
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: ホテルニューオータニ東京（東京都千代田区）
  • Year and Date: 2015-04-23
• [Book] 内科 (2016)
  • Author(s): 徳山博文、伊藤裕
  • Total Pages: 5
  • Publisher: 南江堂