Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage

Takeshi Nishikawa, Diane Edelstein, Xue Liang Du, Sho-ichi Yamagishi, Takeshi Matsumura, Yasufumi Kaneda, Mark A. Yorek, David Beebe, Peter J. Oates, Hans-Peter Hammes, Ida Giardino and Michael Brownlee ()
Additional contact information
Takeshi Nishikawa: Albert Einstein College of Medicine, Diabetes Research Centre
Diane Edelstein: Albert Einstein College of Medicine, Diabetes Research Centre
Xue Liang Du: Albert Einstein College of Medicine, Diabetes Research Centre
Sho-ichi Yamagishi: Albert Einstein College of Medicine, Diabetes Research Centre
Takeshi Matsumura: Albert Einstein College of Medicine, Diabetes Research Centre
Yasufumi Kaneda: Division of Gene Therapy Science Osaka University Medical School
Mark A. Yorek: Department of Internal Medicine University of Iowa
David Beebe: Pfizer Inc.
Peter J. Oates: Pfizer Inc.
Hans-Peter Hammes: Justus-Liebig University III Medical Department
Ida Giardino: Albert Einstein College of Medicine, Diabetes Research Centre
Michael Brownlee: Albert Einstein College of Medicine, Diabetes Research Centre

Nature, 2000, vol. 404, issue 6779, 787-790

Abstract: Abstract Diabetic hyperglycaemia causes a variety of pathological changes in small vessels, arteries and peripheral nerves1. Vascular endothelial cells are an important target of hyperglycaemic damage, but the mechanisms underlying this damage are not fully understood. Three seemingly independent biochemical pathways are involved in the pathogenesis: glucose-induced activation of protein kinase C isoforms2; increased formation of glucose-derived advanced glycation end-products3; and increased glucose flux through the aldose reductase pathway4. The relevance of each of these pathways is supported by animal studies in which pathway-specific inhibitors prevent various hyperglycaemia-induced abnormalities3,5,6,7. Hyperglycaemia increases the production of reactive oxygen species inside cultured bovine aortic endothelial cells8. Here we show that this increase in reactive oxygen species is prevented by an inhibitor of electron transport chain complex II, by an uncoupler of oxidative phosphorylation, by uncoupling protein-1 and by manganese superoxide dismutase. Normalizing levels of mitochondrial reactive oxygen species with each of these agents prevents glucose-induced activation of protein kinase C, formation of advanced glycation end-products, sorbitol accumulation and NFκB activation.

Date: 2000
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DOI: 10.1038/35008121

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