title: AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function.
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.forename: Laura L
authors.initials: LL
authors.lastname: Dugan
authors.forename: Young-Hyun
authors.initials: YH
authors.lastname: You
authors.forename: Sameh S
authors.initials: SS
authors.lastname: Ali
authors.forename: Maggie
authors.initials: M
authors.lastname: Diamond-Stanic
authors.forename: Satoshi
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Anne-Emilie
authors.initials: AE
authors.lastname: DeCleves
authors.forename: Aleksander
authors.initials: A
authors.lastname: Andreyev
authors.forename: Tammy
authors.initials: T
authors.lastname: Quach
authors.forename: San
authors.initials: S
authors.lastname: Ly
authors.forename: Grigory
authors.initials: G
authors.lastname: Shekhtman
authors.forename: William
authors.initials: W
authors.lastname: Nguyen
authors.forename: Andre
authors.initials: A
authors.lastname: Chepetan
authors.forename: Thuy P
authors.initials: TP
authors.lastname: Le
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.forename: Kacie P
authors.initials: KP
authors.lastname: Paik
authors.forename: Agnes
authors.initials: A
authors.lastname: Fogo
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Anne
authors.initials: A
authors.lastname: Murphy
authors.forename: Frank
authors.initials: F
authors.lastname: Brosius
authors.forename: Robert K
authors.initials: RK
authors.lastname: Naviaux
authors.forename: Kumar
authors.initials: K
authors.lastname: Sharma
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D012402:Rotenone / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
chemical_list: D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide; D011768:Pyruvate Dehydrogenase Complex; D012265:Ribonucleotides; D012402:Rotenone; D013482:Superoxide Dismutase; D013481:Superoxides; D000099156:Superoxide Dismutase 2; C534978:Prkaa2 protein, mouse; C031143:AICA ribonucleotide