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AMP[K]-lifying view of the diabetic kidney


The presence of increased glucose levels in diabetes patients is considered to drive diabetes-associated complications, including retinopathy, neuropathy, and nephropathy. Cultured cells exposed to high levels of glucose produce reactive oxygen species (ROS), which is thought to contribute to diabetic phenotypes. Laura L Dugan, Young-Hyun You and colleagues at the University of California, San Diego determined that ROS production was actually reduced in kidneys of diabetic mice, and this decrease was associated with lowered activity of the major energy-sensing enzyme, AMPK. Furthermore, AMPK activity was also reduced in kidneys of diabetic patients. Treatment of diabetic mice with a compound that increased AMPK activity reduced kidney-associated symptoms, including fibrosis and albuminuria. In a companion commentary, Dwight Towler of the Sanford-Burnham Medical Institute discusses how this view of ROS in diabetes will require a new look at therapeutic approaches for relieving diabetes complications. In the above image, animals were given dihydroethidium (DHE), a compound that fluoresces when oxidized, indicating the presence of ROS. The image on the right shows live animal imaging of kidney through the intact skin. ox-DHE fluorescence (red) in kidney slices prepared from DHE-injected WT (center) and diabetic (left) mice demonstrate that there is less in vivo oxidation in diabetic kidneys.

Published October 25, 2013, by Corinne Williams

Scientific Show Stopper

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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 October 25, 2013
Citation Information: J Clin Invest. 2013;123(11):4888-4899. https://doi.org/10.1172/JCI66218.
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Research Article Article has an altmetric score of 78

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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Mitochondrial ROS deficiency and diabetic complications: AMP[K]-lifying the adaptation to hyperglycemia
Dwight A. Towler
Dwight A. Towler
Published October 25, 2013
Citation Information: J Clin Invest. 2013;123(11):4573-4576. https://doi.org/10.1172/JCI72326.
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Commentary Article has an altmetric score of 27

Mitochondrial ROS deficiency and diabetic complications: AMP[K]-lifying the adaptation to hyperglycemia

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Abstract

Global, sustained production of ROS has deleterious effects on tissue structure and function and gives rise to biochemical and physiological changes associated with organ senescence. Specific, localized ROS metabolites generated by mitochondria and NADPH oxidases also transduce homeostatic information in response to metabolic, mechanical, and inflammatory cues. In this issue of the JCI, Dugan and colleagues demonstrate that mitochondrial-derived ROS, which is maintained by a feed-forward AMP kinase activation cascade, is reduced in diabetes and plays an adaptive role in preserving renal glomerular function during hyperglycemia. This enlightened view of mitochondrial ROS biology forces us to reconsider therapeutic approaches to metabolic disease complications such as diabetic nephropathy.

Authors

Dwight A. Towler

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