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Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage

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.

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Figure 1: Effect of agents that alter mitochondrial metabolism on formation of hyperglycaemia-induced reactive oxygen species (ROS) in bovine aortic endothelial cells.
Figure 2: Effect of agents that alter mitochondrial metabolism on the three main pathways of pathogenesis.
Figure 3: Effect of agents that alter mitochondrial metabolism on hyperglycaemia-induced activation of NFκB.

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Acknowledgements

We thank K. Preissner for his critical reading of the manuscript and M. Quon for his gift of plasmid pCIS-eGFP. This research was supported by grants from the National Institutes of Health (USA).

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Correspondence to Michael Brownlee.

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Nishikawa, T., Edelstein, D., Du, X. et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404, 787–790 (2000). https://doi.org/10.1038/35008121

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