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 Glardino, Michael Brownlee

Research output: Contribution to journalArticle

3164 Citations (Scopus)

Abstract

Diabetic hyperglycaemia causes a variety of pathological changes in small vessels, arteries and peripheral nerves. 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 isoforms; increased formation of glucose-derived advanced glycation end-products; and increased glucose flux through the aldose reductase pathway. The relevance of each of these pathways is supported by animal studies in which pathway-specific inhibitors prevent various hyperglycaemia-induced abnormalities. Hyperglycaemia increases the production of reactive oxygen species inside cultured bovine aortic endothelial cells. 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.

Original languageEnglish (US)
Pages (from-to)787-790
Number of pages4
JournalNature
Volume404
Issue number6779
DOIs
StatePublished - Apr 13 2000

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Superoxides
Hyperglycemia
Glucose
Reactive Oxygen Species
Advanced Glycosylation End Products
Protein Kinase C
Electron Transport Complex II
Endothelial Cells
Aldehyde Reductase
Sorbitol
Oxidative Phosphorylation
Peripheral Nerves
Superoxide Dismutase
Protein Isoforms
Arteries

ASJC Scopus subject areas

  • General

Cite this

Nishikawa, T., Edelstein, D., Du, X-L., Yamagishi, S. I., Matsumura, T., Kaneda, Y., ... Brownlee, M. (2000). Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature, 404(6779), 787-790. https://doi.org/10.1038/35008121

Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. / Nishikawa, Takeshi; Edelstein, Diane; Du, Xue-Liang; Yamagishi, Sho Ichi; Matsumura, Takeshi; Kaneda, Yasufumi; Yorek, Mark A.; Beebe, David; Oates, Peter J.; Hammes, Hans Peter; Glardino, Ida; Brownlee, Michael.

In: Nature, Vol. 404, No. 6779, 13.04.2000, p. 787-790.

Research output: Contribution to journalArticle

Nishikawa, T, Edelstein, D, Du, X-L, Yamagishi, SI, Matsumura, T, Kaneda, Y, Yorek, MA, Beebe, D, Oates, PJ, Hammes, HP, Glardino, I & Brownlee, M 2000, 'Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage', Nature, vol. 404, no. 6779, pp. 787-790. https://doi.org/10.1038/35008121
Nishikawa T, Edelstein D, Du X-L, Yamagishi SI, Matsumura T, Kaneda Y et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000 Apr 13;404(6779):787-790. https://doi.org/10.1038/35008121
Nishikawa, Takeshi ; Edelstein, Diane ; Du, Xue-Liang ; Yamagishi, Sho Ichi ; Matsumura, Takeshi ; Kaneda, Yasufumi ; Yorek, Mark A. ; Beebe, David ; Oates, Peter J. ; Hammes, Hans Peter ; Glardino, Ida ; Brownlee, Michael. / Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. In: Nature. 2000 ; Vol. 404, No. 6779. pp. 787-790.
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