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AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function
Laura L. Dugan, … , Robert K. Naviaux, Kumar Sharma
Laura L. Dugan, … , Robert K. Naviaux, Kumar Sharma
Published November 1, 2013; First published October 25, 2013
Citation Information: J Clin Invest. 2013;123(11):4888-4899. https://doi.org/10.1172/JCI66218.
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Category: Research Article

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

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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.

Authors

Laura L. Dugan, Young-Hyun You, Sameh S. Ali, Maggie Diamond-Stanic, Satoshi Miyamoto, Anne-Emilie DeCleves, Aleksander Andreyev, Tammy Quach, San Ly, Grigory Shekhtman, William Nguyen, Andre Chepetan, Thuy P. Le, Lin Wang, Ming Xu, Kacie P. Paik, Agnes Fogo, Benoit Viollet, Anne Murphy, Frank Brosius, Robert K. Naviaux, Kumar Sharma

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Figure 1

Imaging of kidney superoxide production in normal and diabetic mice.

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Imaging of kidney superoxide production in normal and diabetic mice.
(A)...
(A) Live animal imaging of kidney through the intact skin in a prone, isofluorane-anesthetized mouse. Kidneys were first localized using the FITC channel, and then the filter settings were changed to the ox-DHE channel (Ex 470 nm, EM > 590 nm) to image superoxide production in control and STZ-induced diabetic mice (DM). Fluorescence is shown using a linear pseudocolor scale (images representative of n = 6 mice per group). Original magnification, ×1 (top panel); ×1.25 (bottom panels). (B) ox-DHE fluorescence (red, top; linear pseudocolor, bottom) in kidney slices prepared from DHE-injected control and DM mice with less in vivo oxidation in DM kidney. Diabetic kidneys had a reduced level of glomerular DHE oxidation-derived fluorescence (white arrow). Original magnification, ×63. (C) Kidneys from Sod2+/– mice, which are deficient in mitochondrial SOD, were evaluated and demonstrated the expected higher superoxide than controls. n ≥ 15 each for control and diabetic groups, n = 3 for Sod2+/– group, *P < 0.05 vs control. (D) In vivo analysis of [14C]-labeled DHE with STZ-diabetic mice and control mice.
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