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Research Group for Development of New Drugs for Redox Stress-related Diseases

Diabetic complications are leading causes of individual physical illness and socioeconomic disbenefit worldwide. Oxidative stress is acknowledged as an important pathogenic factor in the development of diabetic vascular complications. We have demonstrated a human evidence for the contribution of redox state to diabetic organ injury that constitutional hyperbilirubinemia protects against the development of retinopathy, microalbuminuria and ischemic heart disease in diabetic subjects1. In vivo study, we also showed the mechanism that bilirubin suppressed the production of superoxide by NAD(P)H oxidase in diabetic kidney2. NAD(P)H oxidase, a major source of reactive oxygen species (ROS), is stimulated by high glucose in a protein kinase C (PKC)-dependent manner3. Angiotensin II (AngII) is also known to induce NAD(P)H oxidase-dependent ROS production via a PKC activation. The enhancement of chymase expression in diabetes accelerates superoxide production via the elevation of local AngII levels4. Our primary aim is to develop new chemical compounds including tetrapyrroles and chymase inhibitors which specifically target the molecules involved in the PKC-NAD(P)H oxidase theory. Now we are also constructing conceptual models of pathology for the other diseases associated to oxidative stress, such as chronic kidney disease and cognitive impairment. Some of these studies in progress are collaborated with research groups in the Innovation Center for Medical Redox Navigation. Discovery of new biomarkers and the development of imaging technology for redox state using our in vivo samples are promising for the prediction of hostile events and the assessment of therapeutic effects on existing organ injuries. The outcomes from our studies based on the pathological hypotheses of redox-related diseases will meet the unsolved medical needs above.

  1. Inoguchi, T., Sasaki, S., Kobayashi, K., Takayanagi, R. & Yamada, T. Relationship between Gilbert syndrome and prevalence of vascular complications in patients with diabetes. Jama 298, 1398-1400 (2007).
  2. Fujii, M., et al. Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD(P)H oxidase. Kidney Int 78, 905-919 (2010).
  3. Inoguchi, T. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD (P) H oxidase in cultured vascular cells. Diabetes 49, 1939-1945 (2000).
  4. Maeda, Y., et al. Inhibition of chymase protects against diabetes-induced oxidative stress and renal dysfunction in hamsters. Am J Physiol Renal Physiol 299, F1328-1338 (2010).

Member

Kyushu University

Ryoichi Takayanagi Professor, Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University
Toyoshi Inoguchi Professor, Innovation Center for Medical Redox Navigation, Kyushu University
Masatoshi Nomura Assistant professor, Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University
Hisato Igarashi Assistant professor, Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University
Noriyuki Sonoda Assistant professor, Innovation Center for Medical Redox Navigation, Kyushu University
Yasutaka Maeda Assistant professor, Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University

Mitsubishi Tanabe Pharma Corporation

Hiroaki Inoue Head, Advanced Medical Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation
Minoru Muramatsu General Manager of Research and Executive Managing Director, Mitsubishi Tanabe Pharma Corporation
Tetsuya Ohta Chief Researcher, Target Discovery and Biomarker Research Department, Advanced Medical Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation
Kenji Arakawa Group Manager, Pharmacology Group 2A, Pharmacology Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation

Collaboration Company