RAGE-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes
| Autor: | David R. Thorburn, Michael Brownlee, Mark E. Cooper, Adrienne Laskowski, Angelika Bierhaus, Sally A. Penfold, Kei Fukami, Peter P. Nawroth, Vicki Thallas-Bonke, Brooke E. Harcourt, Adeline L.Y. Tan, Melinda T. Coughlan, Karly C. Sourris, Josephine M. Forbes |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Glycation End Products
Advanced medicine.medical_specialty Kidney Cortex Receptor for Advanced Glycation End Products Oxidative phosphorylation Mitochondrion medicine.disease_cause Kidney Oxidative Phosphorylation Diabetes Mellitus Experimental Electron Transport Rats Sprague-Dawley chemistry.chemical_compound Superoxides Internal medicine medicine Animals Receptors Immunologic chemistry.chemical_classification Reactive oxygen species NADPH oxidase biology Superoxide General Medicine Mitochondria Rats Endocrinology Basic Research chemistry Mitochondrial permeability transition pore Nephrology Apocynin biology.protein Female Reactive Oxygen Species Oxidative stress |
| Zdroj: | Journal of the American Society of Nephrology : JASN. 20(4) |
| ISSN: | 1533-3450 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|