Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db mice as a model of type 2 diabetes.
OBJECTIVE
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
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.
Department of Medical Cell Biology, Biomedical Center, Husargatan 3, Box 571, 751 23 Uppsala, Sweden. Malou.Friederich@mcb.uu.se
M Friederich
MF
Persson
S
S
Franzén
S-B
SB
Catrina
G
G
Dallner
P
P
Hansell
K
K
Brismar
F
F
Palm
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D006153:Guanosine Diphosphate / Q000378:metabolism; D007473:Ion Channels / Q000097:blood / Q000502:physiology*; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000503:physiopathology / Q000648:ultrastructure; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000097:blood / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D011507:Proteinuria / Q000188:drug therapy* / Q000503:physiopathology; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000071246:Uncoupling Protein 2; D014815:Vitamins / Q000627:therapeutic use*
D001786:Blood Glucose; D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D014815:Vitamins; D014451:Ubiquinone; D006153:Guanosine Diphosphate; C024989:coenzyme Q10