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. and Forbes, Josephine M. (2009) Rage-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes. Journal of the American Society of Nephrology, 20 4: 742-752. doi:10.1681/ASN.2008050514

Author 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.
Title Rage-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes
Journal name Journal of the American Society of Nephrology   Check publisher's open access policy
ISSN 1046-6673
Publication date 2009-01-01
Year available 2009
Sub-type Article (original research)
DOI 10.1681/ASN.2008050514
Open Access Status Not yet assessed
Volume 20
Issue 4
Start page 742
End page 752
Total pages 11
Place of publication Washington, DC United States
Publisher American Society of Nephrology
Language eng
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. Copyright
Keyword Cell Biology
Medicine, Research & Experimental
Cell Biology
Research & Experimental Medicine
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID SFB405
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Mater Research Institute-UQ (MRI-UQ)
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