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      AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function.

      The Journal of clinical investigation

      AMP-Activated Protein Kinases, deficiency, genetics, metabolism, Aminoimidazole Carboxamide, analogs & derivatives, pharmacology, Animals, Diabetes Mellitus, Experimental, pathology, Diabetic Nephropathies, Enzyme Activation, drug effects, Humans, Kidney, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Knockout, Mitochondria, Pyruvate Dehydrogenase Complex, Ribonucleotides, Rotenone, Superoxide Dismutase, Superoxides

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          Abstract

          Diabetic microvascular complications have been considered to be mediated by a glucose-driven increase in mitochondrial superoxide anion production. Here, we report that superoxide production was reduced in the kidneys of a steptozotocin-induced mouse model of type 1 diabetes, as assessed by in vivo real-time transcutaneous fluorescence, confocal microscopy, and electron paramagnetic resonance analysis. Reduction of mitochondrial biogenesis and phosphorylation of pyruvate dehydrogenase (PDH) were observed in kidneys from diabetic mice. These observations were consistent with an overall reduction of mitochondrial glucose oxidation. Activity of AMPK, the major energy-sensing enzyme, was reduced in kidneys from both diabetic mice and humans. Mitochondrial biogenesis, PDH activity, and mitochondrial complex activity were rescued by treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). AICAR treatment induced superoxide production and was linked with glomerular matrix and albuminuria reduction in the diabetic kidney. Furthermore, diabetic heterozygous superoxide dismutase 2 (Sod2(+/-)) mice had no evidence of increased renal disease, and Ampka2(-/-) mice had increased albuminuria that was not reduced with AICAR treatment. Reduction of mitochondrial superoxide production with rotenone was sufficient to reduce AMPK phosphorylation in mouse kidneys. Taken together, these results demonstrate that diabetic kidneys have reduced superoxide and mitochondrial biogenesis and activation of AMPK enhances superoxide production and mitochondrial function while reducing disease activity.

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          Author and article information

          Journal
          24135141
          3809777
          10.1172/JCI66218

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