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

Academic Article

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 thatmitochondrially 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. © 2010 The Author(s).
  • Digital Object Identifier (doi)

    Author List

  • Chacko BK; Reily C; Srivastava A; Johnson MS; Ye Y; Ulasova E; Agarwal A; Zinn KR; Murphy MP; Kalyanaraman B
  • Start Page

  • 9
  • End Page

  • 19
  • Volume

  • 432
  • Issue

  • 1