AMPK dysregulation promotes diabetes-related reduction of superoxide and
mitochondrial function.
Authors 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
Submitted By Kumar Sharma on 10/30/2013
Status Published
Journal The Journal of clinical investigation
Year 2013
Date Published 10/25/2013
Volume : Pages 123 : 4888 - 4899
PubMed Reference 24135141
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-ß-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.

Investigators with authorship
Frank BrosiusUniversity of Arizona
Agnes FogoVanderbilt University
Kumar SharmaUniversity of California San Diego