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

Biochem J. 2010 Nov 15;432(1):9-19. doi: 10.1042/BJ20100308.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Cell Nucleus / metabolism
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / complications
  • Diabetic Nephropathies / complications
  • Diabetic Nephropathies / genetics
  • Diabetic Nephropathies / prevention & control*
  • Fibrosis / prevention & control
  • Glomerular Mesangium / drug effects
  • Glomerular Mesangium / physiopathology
  • Immunohistochemistry
  • Insulin / deficiency*
  • Insulin / genetics
  • Kidney / drug effects
  • Kidney / pathology
  • Kidney / ultrastructure
  • Kidney Tubules / drug effects
  • Kidney Tubules / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Microscopy, Electron
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Phosphorylation / drug effects
  • Smad2 Protein / metabolism
  • Smad3 Protein / metabolism
  • Ubiquinone / pharmacology*
  • beta Catenin / metabolism

Substances

  • Blood Glucose
  • Insulin
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • beta Catenin
  • Ubiquinone