Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db-mice as a model of type 2 diabetes
2012 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 55, no 5, 1535-1543 p.Article in journal (Refereed) Published
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 mu l/min), increased proteinuria (21 +/- 2 vs 14 +/- 1, mu g/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 mu 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 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.
Place, publisher, year, edition, pages
2012. Vol. 55, no 5, 1535-1543 p.
db/db-mice, Kidney, Mitochondria, Type 2 diabetes, Uncoupling protein-2
IdentifiersURN: urn:nbn:se:uu:diva-167777DOI: 10.1007/s00125-012-2469-5ISI: 000302994600036OAI: oai:DiVA.org:uu-167777DiVA: diva2:488004