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

The Journal of clinical investigation, 2013-11, Vol.123 (11), p.4888-4899 [Peer Reviewed Journal]

COPYRIGHT 2013 American Society for Clinical Investigation ;COPYRIGHT 2013 American Society for Clinical Investigation ;Copyright American Society for Clinical Investigation Nov 2013 ;Copyright © 2013, American Society for Clinical Investigation 2013 ;ISSN: 0021-9738 ;EISSN: 1558-8238 ;DOI: 10.1172/JCI66218 ;PMID: 24135141

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Title:
AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function
Author: Dugan, Laura L ; You, Young-Hyun ; Ali, Sameh S ; Diamond-Stanic, Maggie ; Miyamoto, Satoshi ; DeCleves, Anne-Emilie ; Andreyev, Aleksander ; Quach, Tammy ; Ly, San ; Shekhtman, Grigory ; Nguyen, William ; Chepetan, Andre ; Le, Thuy P ; Wang, Lin ; Xu, Ming ; Paik, Kacie P ; Fogo, Agnes ; Viollet, Benoit ; Murphy, Anne ; Brosius, Frank ; Naviaux, Robert K ; Sharma, Kumar
Subjects: Aminoimidazole Carboxamide - analogs & derivatives ; Aminoimidazole Carboxamide - pharmacology ; AMP-Activated Protein Kinases - deficiency ; AMP-Activated Protein Kinases - genetics ; AMP-Activated Protein Kinases - metabolism ; Animals ; Care and treatment ; Cell culture ; Cyclic adenylic acid ; Diabetes ; Diabetes Mellitus, Experimental - metabolism ; Diabetes Mellitus, Experimental - pathology ; Diabetic Nephropathies - metabolism ; Diabetic Nephropathies - pathology ; Diagnosis ; Enzyme Activation - drug effects ; Genetic aspects ; Humans ; Kidney - drug effects ; Kidney - metabolism ; Kidneys ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Mice, Knockout ; Mitochondria - drug effects ; Mitochondria - metabolism ; Physiological aspects ; Protein kinases ; Pyruvate Dehydrogenase Complex - metabolism ; Ribonucleotides - pharmacology ; Rodents ; Rotenone - pharmacology ; Software ; Storm damage ; Studies ; Superoxide ; Superoxide Dismutase - deficiency ; Superoxide Dismutase - genetics ; Superoxide Dismutase - metabolism ; Superoxides - metabolism ; Type 1 diabetes
Is Part Of: The Journal of clinical investigation, 2013-11, Vol.123 (11), p.4888-4899
Description: 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.
Publisher: United States: American Society for Clinical Investigation
Language: English
Identifier: ISSN: 0021-9738
EISSN: 1558-8238
DOI: 10.1172/JCI66218
PMID: 24135141
Source: Open Access: PubMed Central
Geneva Foundation Free Medical Journals at publisher websites
AUTh Library subscriptions: ProQuest Central
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AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function

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