Pathological significance of Nox isoforms of NADPH oxidase in diabetic nephropathy

• Project/Area Number: 25860694
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: Kawasaki Medical School
• Principal Investigator: NAMIKOSHI Tamehachi 川崎医科大学, 医学部, 講師 (90509332)
• Co-Investigator(Renkei-kenkyūsha): COOPER Mark Baker IDI Heart and Diabetes Institute, Prof. ; CHANNON Keith Oxford University, Prof. ; TANNER George Indiana University, Prof.
• Research Collaborator: KASHIHARA Naoki 川崎医科大学, 医学部, 教授 (10233701) ; SATOH Minoru 川崎医科大学, 医学部, 准教授 (70449891) ; KUWABARA Atsunori 川崎医科大学, 医学部, 講師 (50368627) ; YORIMITSU Daisuke 川崎医科大学, 医学部, 臨床助教 (50412177)
• 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: 糖尿病性腎症 / NADPHオキシダーゼ / Nox / オーストラリア：アメリカ

Outline of Final Research Achievements

Activated NADPH oxidase is associated with progression of diabetic nephropathy, but the pathological significance of Nox isoforms, cell membrane components of NADPH oxidase, remains to be elucidated. Here, we investigated ameliorative effects of genetic manipulation of Nox1 and Nox4, on diabetic mice kidneys, to clarify the role of Nox isoforms in diabetic nephropathy. Diabetic/control knockout (KO)/wild-type mice were used for the examination at ～20 weeks after induction of diabetes. Diabetes-induced albuminuria was attenuated in both Nox1KO and Nox4KO mice, while the glomerular sclerosis was mitigated in only Nox1KO kidneys. Increased mRNA expressions of Nox2, fibronectin, and alpha-SMA in diabetic kidneys were suppressed in only Nox1KO mice. Accumulation of nitrotyrosine in glomeruli of diabetic kidneys was completely suppressed in Nox1KO mice, although it was reduced insufficiently in Nox4KO mice. Collectively, activated Nox1 may contribute to progression of diabetic nephropathy.

Research Products

• [Journal Article] Genetic targeting or pharmacologic inhibition of NADPH oxidase Nox4 provides renoprotection in long-term diabetic nephropathy (2014)
  • Author(s): Jay C. Jha, Stephen P. Gray, David Barit, Jun Okabe, Assam El-Osta, Tamehachi Namikoshi, Vicki Thallas-Bonke, Kirstin Wingler, Cedric Szyndralewiez, Freddy Heitz, Rhian M. Touyz, Mark E. Cooper, Harald H.H.W. Schmidt, Karin A. Jandeleit-Dahm
  • Journal Title: JOURNAL OF AMERICAN SOCIETY OF NEPHROLOGY Volume: 25 Issue: 6 Pages: 1237-1254
  • DOI: 10.1681/asn.2013070810
  • Peer Reviewed
• [Journal Article] Role of Nox2 in diabetic kidney disease (2013)
  • Author(s): Young-Hyun You, Shinichi Okada, San Ly, Karin Jandeleit-Dahm, David Barit, Tamehachi Namikoshi, Kumar Sharma
  • Journal Title: AMERICAN JOURNAL OF PHYSIOLOGY RENAL PHYSIOLOGY Volume: 304巻 Issue: 7 Pages: F840-F848
  • DOI: 10.1152/ajprenal.00511.2012
  • Peer Reviewed