Prevention of diabetic nephropathy in Ins2(+/)⁻(AkitaJ) mice by the mitochondria-targeted therapy MitoQ.

TitlePrevention of diabetic nephropathy in Ins2(+/)⁻(AkitaJ) mice by the mitochondria-targeted therapy MitoQ.
Publication TypeJournal Article
Year of Publication2010
AuthorsChacko, BK, Reily, C, Srivastava, A, Johnson, MS, Ye, Y, Ulasova, E, Agarwal, A, Zinn, KR, Murphy, MP, Kalyanaraman, B, Darley-Usmar, V
JournalBiochem J
Date Published2010 Nov 15
KeywordsAnimals, beta Catenin, Blood Glucose, Cell Nucleus, Diabetes Mellitus, Type 1, Diabetic Nephropathies, Fibrosis, Glomerular Mesangium, Immunohistochemistry, Insulin, Kidney, Kidney Tubules, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Microscopy, Electron, Mitochondria, Phosphorylation, Smad2 Protein, Smad3 Protein, Ubiquinone

Mitochondrial production of ROS (reactive oxygen species) is thought to be associated with the cellular damage resulting from chronic exposure to high glucose in long-term diabetic patients. We hypothesized that a mitochondria-targeted antioxidant would prevent kidney damage in the Ins2(+/)⁻(AkitaJ) mouse model (Akita mice) of Type 1 diabetes. To test this we orally administered a mitochondria-targeted ubiquinone (MitoQ) over a 12-week period and assessed tubular and glomerular function. Fibrosis and pro-fibrotic signalling pathways were determined by immunohistochemical analysis, and mitochondria were isolated from the kidney for functional assessment. MitoQ treatment improved tubular and glomerular function in the Ins2(+/)⁻(AkitaJ) mice. MitoQ did not have a significant effect on plasma creatinine levels, but decreased urinary albumin levels to the same level as non-diabetic controls. Consistent with previous studies, renal mitochondrial function showed no significant change between any of the diabetic or wild-type groups. Importantly, interstitial fibrosis and glomerular damage were significantly reduced in the treated animals. The pro-fibrotic transcription factors phospho-Smad2/3 and β-catenin showed a nuclear accumulation in the Ins2(+/)⁻(AkitaJ) mice, which was prevented by MitoQ treatment. These results support the hypothesis that mitochondrially targeted therapies may be beneficial in the treatment of diabetic nephropathy. They also highlight a relatively unexplored aspect of mitochondrial ROS signalling in the control of fibrosis.

Alternate JournalBiochem. J.
Citation Key10.1042/BJ20100308
PubMed ID20825366
PubMed Central IDPMC2973231
Grant List1P30 DK 079337 / DK / NIDDK NIH HHS / United States
DK075865 / DK / NIDDK NIH HHS / United States
P30CA013148 / CA / NCI NIH HHS / United States