title: Prevention of diabetic nephropathy in Ins2(+/)⁻(AkitaJ) mice by the mitochondria-targeted therapy MitoQ.
abstract: 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.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, 35294, USA.
authors.forename: Balu K
authors.initials: BK
authors.lastname: Chacko
authors.forename: Colin
authors.initials: C
authors.lastname: Reily
authors.forename: Anup
authors.initials: A
authors.lastname: Srivastava
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Johnson
authors.forename: Yaozu
authors.initials: Y
authors.lastname: Ye
authors.forename: Elena
authors.initials: E
authors.lastname: Ulasova
authors.forename: Anupam
authors.initials: A
authors.lastname: Agarwal
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Zinn
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.forename: Balaraman
authors.initials: B
authors.lastname: Kalyanaraman
authors.forename: Victor
authors.initials: V
authors.lastname: Darley-Usmar
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications; D003928:Diabetic Nephropathies / Q000150:complications / Q000235:genetics / Q000517:prevention & control*; D005355:Fibrosis / Q000517:prevention & control; D005920:Glomerular Mesangium / Q000187:drug effects / Q000503:physiopathology; D007150:Immunohistochemistry; D007328:Insulin / Q000172:deficiency* / Q000235:genetics; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D007684:Kidney Tubules / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D014451:Ubiquinone / Q000494:pharmacology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051176:beta Catenin; D014451:Ubiquinone
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