Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db mice as a model of type 2 diabetes

• Published in: Diabetologia Vol. 55; no. 5; pp. 1535 - 1543
• Main Authors: Persson, M. Friederich, Franzén, S., Catrina, S.-B., Dallner, G., Hansell, P., Brismar, K., Palm, F.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.05.2012; Springer Nature B.V
• Subjects: Animals; Blood Glucose - drug effects; db/db mice; Diabetes; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - physiopathology; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - physiopathology; Diabetic nephropathy; Disease Models, Animal; Enzymes; Glomerular Filtration Rate - drug effects; Glomerular Filtration Rate - physiology; Guanosine Diphosphate - metabolism; Human Physiology; Hypoxia; Internal Medicine; Ion Channels - blood; Ion Channels - physiology; Kidney; Kidney Glomerulus - drug effects; Kidney Glomerulus - physiopathology; Kidney Glomerulus - ultrastructure; Kidneys; MEDICIN; MEDICINE; Medicine & Public Health; Metabolic Diseases; Metabolism; Mice; Mitochondria; Mitochondria - drug effects; Mitochondria - ultrastructure; Mitochondrial Proteins - blood; Mitochondrial Proteins - physiology; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - physiology; Oxygen Consumption - drug effects; Oxygen Consumption - physiology; Proteins; Proteinuria - drug therapy; Proteinuria - physiopathology; Protons; Type 2 diabetes; Ubiquinone - analogs & derivatives; Ubiquinone - therapeutic use; Uncoupling Protein 2; Vitamins - therapeutic use; Sweden; Type 2 diabetes; Uncoupling protein-2; Mitochondria; mice; Kidney
• ISSN: 0012-186X; 1432-0428; 1432-0428
• DOI: 10.1007/s00125-012-2469-5

Aims/hypothesis Increased oxygen consumption results in kidney tissue hypoxia, which is proposed to contribute to the development of diabetic nephropathy. Oxidative stress causes increased oxygen consumption in type 1 diabetic kidneys, partly mediated by uncoupling protein-2 (UCP-2)-induced mitochondrial uncoupling. The present study investigates the role of UCP-2 and oxidative stress in mitochondrial oxygen consumption and kidney function in db/db mice as a model of type 2 diabetes. Methods Mitochondrial oxygen consumption, glomerular filtration rate and proteinuria were investigated in db/db mice and corresponding controls with and without coenzyme Q10 (CoQ10) treatment. Results Untreated db/db mice displayed mitochondrial uncoupling, manifested as glutamate-stimulated oxygen consumption (2.7 ± 0.1 vs 0.2 ± 0.1 pmol O 2 s −1 [mg protein] −1 ), glomerular hyperfiltration (502 ± 26 vs 385 ± 3 μl/min), increased proteinuria (21 ± 2 vs 14 ± 1, μg/24 h), mitochondrial fragmentation (fragmentation score 2.4 ± 0.3 vs 0.7 ± 0.1) and size (1.6 ± 0.1 vs 1 ± 0.0 μm) compared with untreated controls. All alterations were prevented or reduced by CoQ10 treatment. Mitochondrial uncoupling was partly inhibited by the UCP inhibitor GDP (−1.1 ± 0.1 pmol O 2 s −1 [mg protein] −1 ). UCP-2 protein levels were similar in untreated control and db/db mice (67 ± 9 vs 67 ± 4 optical density; OD) but were reduced in CoQ10 treated groups (43 ± 2 and 38 ± 7 OD). Conclusions/interpretation db/db mice displayed oxidative stress-mediated activation of UCP-2, which resulted in mitochondrial uncoupling and increased oxygen consumption. CoQ10 prevented altered mitochondrial function and morphology, glomerular hyperfiltration and proteinuria in db/db mice, highlighting the role of mitochondria in the pathogenesis of diabetic nephropathy and the benefits of preventing increased oxidative stress.