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.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
National Diabetes Data Group Diabetes in America 2nd edn (National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, USA, 1994).
Koya,D. & King,G. L. Protein kinase C activation and the development of diabetic complications. Diabetes 47, 859–866 (1998).
Brownlee,M. Advanced protein glycosylation in diabetes and aging. Annu. Rev. Med. 46, 223–234 ( 1995).
Lee,A. Y., Chung,S. K. & Chung,S. S. Demonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldose reductase gene in the lens. Proc. Natl Acad. Sci. USA 92, 2780–2784 (1995).
Ishii,H. et al. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science 272, 728– 731 (1996).
Park,L. et al. Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. Nature Med. 4, 1025–1031 (1998).
Sima,A. A., Prashar,A., Zhang,W. X., Chakrabarti,S. & Greene, D. A. Preventive effect of long-term aldose reductase inhibition (ponalrestat) on nerve conduction and sural nerve structure in the spontaneously diabetic Bio-Breeding rat. J. Clin. Invest. 85, 1410–1420 (1990).
Giardino,I., Edelstein,D. & Brownlee, M. BCL-2 expression or antioxidants prevent hyperglycemia-induced formation of intracellular advanced glycation endproducts in bovine endothelial cells. J. Clin. Invest. 97, 1422– 1428 (1996).
Wallace,D. C. Diseases of the mitochondrial DNA. Annu. Rev. Biochem. 61, 1175–1212 (1992).
Trumpower,B. L. The protonmotive Q cycle. J. Biol. Chem. 265, 11409–11412 (1990).
Korshunov,S. S., Skulachev,V. P. & Starkov, A. A. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett. 416, 15–18 (1997).
Kwong,L. K. & Sohal,R. S. Substrate and site specificity of hydrogen peroxide generation in mouse mitochondria. Arch. Biochem. Biophys. 350, 118–126 ( 1998).
Ishihara,H. et al. Effect of Mitochondrial and/or cytosolic glycerol 3-phosphate dehydrogenase overexpression on glucose-stimulated insulin secretion from MIN6 and HIT cells. Diabetes 45, 1238– 1244 (1996).
Casteilla,L. et al. Stable expression of functional mitochondrial uncoupling protein in Chinese hamster ovary cells. Proc. Natl Acad. Sci. USA 87, 5124–5128 (1990).
Manna,S. K. et al. Overexpression of manganese superoxide dismutase suppresses tumor necrosis factor-induced apoptotsis and activation of nuclear transcription factor-κB and activated protein-1. J. Biol. Chem. 273, 13245–13254 (1998).
Shinohara,M. et al. Overexpression of glyoxalase-I in bovine endothelial cells inhibits intracellular advanced glycation product formation and prevents hyperglycemia-induced increases in macromolecular endocytosis. J. Clin. Invest. 101, 1142–1147 (1998).
Knight,R. J., Kofoed,K. F., Schelbert,H. R. & Buxton,D. B. Inhibition of glyceraldehyde-3-phosphate dehydrogenase in post-ischemic myocardium. Cardiovasc. Res. 32, 1016– 1023 (1996).
Chandra,A., Srivastava,S., Petrash,J. M., Bhatnagar,A. & Srivastava,S. K. Active site modification of aldose reductase by nitric oxide donors. Biochim. Biophys. Acta 1341, 217–222 ( 1997).
Pieper,G. M., Langenstroer,P. & Siebeneich, W. Diabetic-induced endothelial dysfunction in rat aorta: role of hydroxyl radicals. Cardiovasc. Res. 34, 145–156 (1997).
Pieper,G. M. & Haq,R. U. Activation of nuclear factor κB in cultured endothelial cells by increased glucose concentration: prevention by calphostin C. J. Cardiovasc. Pharmacol. 30, 528–532 (1997).
Saeki,Y., Wataya-Kaneda,M., Tanaka, K. & Kaneda,Y. Sustained transgene expression in vitro and in vivo using an Epstein-Barr virus replicon vector system combined with HVJ liposomes. Gene Therapy 5, 1031–1037 (1998).
Saeki,Y. et al. Development and characterization of cationic liposomes conjugated with HVJ (Sendai virus): reciprocal effect of cationic lipid for in vitro and in vivo gene transfer. Human Gene Therapy 8, 2133–2144 (1997).
Yorek,M. A., Dunlap,J. A. & Lowe,W. L. Osmotic regulation of the Na+/myo-inositol cotransporter and postinduction normalization. Kidney Int. 55, 215–224 (1999).
Kurose,I. et al. CD18/ICAM-1-dependent oxidative NFκB activation leading to nitric oxide production in rat kupffer cells cocultured with syngeneic hepatoma cells. J. Clin. Invest. 99, 867 –878 (1997).
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).
About this article
Cite this article
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
This article is cited by
Effects of antioxidants on diabetic kidney diseases: mechanistic interpretations and clinical assessment
Chinese Medicine (2023)
Cardiovascular Diabetology (2023)
Mitochondrial ATP synthase as a direct molecular target of chromium(III) to ameliorate hyperglycaemia stress
Nature Communications (2023)
Ultrastructural features mirror metabolic derangement in human endothelial cells exposed to high glucose
Scientific Reports (2023)
Nature Reviews Nephrology (2023)