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

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 BrosiusRobert K. Naviaux, Kumar Sharma

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)4888-4899
Number of pages12
JournalJournal of Clinical Investigation
Volume123
Issue number11
DOIs
Publication statusPublished - Nov 1 2013
Externally publishedYes

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AMP-Activated Protein Kinases
Superoxides
Kidney
Organelle Biogenesis
Aminoimidazole Carboxamide
Albuminuria
Pyruvic Acid
Oxidoreductases
Phosphorylation
Glucose
Rotenone
Electron Spin Resonance Spectroscopy
Diabetes Complications
Type 1 Diabetes Mellitus
Fluorescence Microscopy
Confocal Microscopy
Enzymes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Dugan, L. L., You, Y. H., Ali, S. S., Diamond-Stanic, M., Miyamoto, S., DeCleves, A. E., ... Sharma, K. (2013). AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function. Journal of Clinical Investigation, 123(11), 4888-4899. https://doi.org/10.1172/JCI66218

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

In: Journal of Clinical Investigation, Vol. 123, No. 11, 01.11.2013, p. 4888-4899.

Research output: Contribution to journalArticle

Dugan, LL, You, YH, Ali, SS, Diamond-Stanic, M, Miyamoto, S, DeCleves, AE, Andreyev, A, Quach, T, Ly, S, Shekhtman, G, Nguyen, W, Chepetan, A, Le, TP, Wang, L, Xu, M, Paik, KP, Fogo, A, Viollet, B, Murphy, A, Brosius, F, Naviaux, RK & Sharma, K 2013, 'AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function', Journal of Clinical Investigation, vol. 123, no. 11, pp. 4888-4899. https://doi.org/10.1172/JCI66218
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. / AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 11. pp. 4888-4899.
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AU - DeCleves, Anne Emilie

AU - Andreyev, Aleksander

AU - Quach, Tammy

AU - Ly, San

AU - Shekhtman, Grigory

AU - Nguyen, William

AU - Chepetan, Andre

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AU - Wang, Lin

AU - Xu, Ming

AU - Paik, Kacie P.

AU - Fogo, Agnes

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