Rage-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes

Melinda T. Coughlan, David R. Thorburn, Sally A. Penfold, Adrienne Laskowski, Brooke E. Harcourt, Karly C. Sourris, Adeline L Y Tan, Kei Fukami, Vicki Thallas-Bonke, Peter P. Nawroth, Michael Brownlee, Angelika Bierhaus, Mark E. Cooper, Josephine M. Forbes

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Abstract

Damaged mitochondria generate an excess of superoxide, which may mediate tissue injury in diabetes. We hypothesized that in diabetic nephropathy, advanced glycation end-products (AGEs) lead to increases in cytosolic reactive oxygen species (ROS), which facilitate the production of mitochondrial superoxide. In normoglycemic conditions, exposure of primary renal cells to AGEs, transient overexpression of the receptor for AGEs (RAGE) with an adenoviral vector, and infusion of AGEs to healthy rodents each induced renal cytosolic oxidative stress, which led to mitochondrial permeability transition and deficiency of mitochondrial complex I. Because of a lack of glucose-derived NADH, which is the substrate for complex I, these changes did not lead to excess production of mitochondrial superoxide; however, when we performed these experiments in hyperglycemic conditions in vitro or in diabetic rats, we observed significant generation of mitochondrial superoxide at the level of complex I, fueled by a sustained supply of NADH. Pharmacologic inhibition of AGE-RAGE-induced mitochondrial permeability transition in vitro abrogated production of mitochondrial superoxide; we observed a similar effect in vivo after inhibiting cytosolic ROS production with apocynin or lowering AGEs with alagebrium. Furthermore, RAGE deficiency prevented diabetes-induced increases in renal mitochondrial superoxide and renal cortical apoptosis in mice. Taken together, these studies suggest that AGE-RAGE-induced cytosolic ROS production facilitates mitochondrial superoxide production in hyperglycemic environments, providing further evidence of a role for the advanced glycation pathway in the development and progression of diabetic nephropathy.

Original languageEnglish (US)
Pages (from-to)742-752
Number of pages11
JournalJournal of the American Society of Nephrology
Volume20
Issue number4
DOIs
StatePublished - Apr 2009

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Rage
Superoxides
Reactive Oxygen Species
Advanced Glycosylation End Products
Kidney
Diabetic Nephropathies
NAD
Permeability
Rodentia
Mitochondria
Oxidative Stress
Apoptosis
Glucose
Advanced Glycosylation End Product-Specific Receptor
Wounds and Injuries

ASJC Scopus subject areas

  • Nephrology

Cite this

Coughlan, M. T., Thorburn, D. R., Penfold, S. A., Laskowski, A., Harcourt, B. E., Sourris, K. C., ... Forbes, J. M. (2009). Rage-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes. Journal of the American Society of Nephrology, 20(4), 742-752. https://doi.org/10.1681/ASN.2008050514

Rage-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes. / Coughlan, Melinda T.; Thorburn, David R.; Penfold, Sally A.; Laskowski, Adrienne; Harcourt, Brooke E.; Sourris, Karly C.; Tan, Adeline L Y; Fukami, Kei; Thallas-Bonke, Vicki; Nawroth, Peter P.; Brownlee, Michael; Bierhaus, Angelika; Cooper, Mark E.; Forbes, Josephine M.

In: Journal of the American Society of Nephrology, Vol. 20, No. 4, 04.2009, p. 742-752.

Research output: Contribution to journalArticle

Coughlan, MT, Thorburn, DR, Penfold, SA, Laskowski, A, Harcourt, BE, Sourris, KC, Tan, ALY, Fukami, K, Thallas-Bonke, V, Nawroth, PP, Brownlee, M, Bierhaus, A, Cooper, ME & Forbes, JM 2009, 'Rage-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes', Journal of the American Society of Nephrology, vol. 20, no. 4, pp. 742-752. https://doi.org/10.1681/ASN.2008050514
Coughlan MT, Thorburn DR, Penfold SA, Laskowski A, Harcourt BE, Sourris KC et al. Rage-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes. Journal of the American Society of Nephrology. 2009 Apr;20(4):742-752. https://doi.org/10.1681/ASN.2008050514
Coughlan, Melinda T. ; Thorburn, David R. ; Penfold, Sally A. ; Laskowski, Adrienne ; Harcourt, Brooke E. ; Sourris, Karly C. ; Tan, Adeline L Y ; Fukami, Kei ; Thallas-Bonke, Vicki ; Nawroth, Peter P. ; Brownlee, Michael ; Bierhaus, Angelika ; Cooper, Mark E. ; Forbes, Josephine M. / Rage-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes. In: Journal of the American Society of Nephrology. 2009 ; Vol. 20, No. 4. pp. 742-752.
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