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

Abstract

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 ithout 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 ?m) 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 itochondrial 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. © 2012 Springer-Verlag.