Mass Spectrometry Imaging Reveals Elevated Glomerular ATP/AMP in Diabetes/obesity and Identifies Sphingomyelin as a Possible Mediator
Journal
EBioMedicine
Journal Volume
7
Pages
121-134
Date Issued
2016
Author(s)
Miyamoto, S.
Hamm, G.
Darshi, M.
Diamond-Stanic, M.
Decl?ves, A.-E.
Slater, L.
Pennathur, S.
Stauber, J.
Dorrestein, P.C.
Sharma, K.
URI
Abstract
AMP-activated protein kinase (AMPK) is suppressed in diabetes and may be due to a high ATP/AMP ratio, however the quantitation of nucleotides in vivo has been extremely difficult. Via matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to localize renal nucleotides we found that the diabetic kidney had a significant increase in glomerular ATP/AMP ratio. Untargeted MALDI-MSI analysis revealed that a specific sphingomyelin species (SM(d18:1/16:0)) accumulated in the glomeruli of diabetic and high-fat diet-fed mice compared with wild-type controls. In vitro studies in mesangial cells revealed that exogenous addition of SM(d18:1/16:0) significantly elevated ATP via increased glucose consumption and lactate production with a consequent reduction of AMPK and PGC1α. Furthermore, inhibition of sphingomyelin synthases reversed these effects. Our findings suggest that AMPK is reduced in the diabetic kidney due to an increase in the ATP/AMP ratio and that SM(d18:1/16:0) could be responsible for the enhanced ATP production via activation of the glycolytic pathway. ? 2016 The Authors.
Subjects
AMPK; ATP; Chronic kidney disease; Glycolysis; Matrix-assisted laser desorption/ionization mass spectrometry imaging; Sphingomyelin
SDGs
Other Subjects
adenosine phosphate; adenosine triphosphate; hydroxymethylglutaryl coenzyme A reductase kinase; lactic acid; liposome; peroxisome proliferator activated receptor gamma coactivator 1alpha; sphingomyelin; sphingomyelin phosphodiesterase; adenosine phosphate; adenosine triphosphate; glucose; hydroxymethylglutaryl coenzyme A reductase kinase; lactic acid; peroxisome proliferator activated receptor gamma coactivator 1alpha; sphingomyelin; animal cell; animal tissue; Article; controlled study; diabetes mellitus; diabetic nephropathy; glomerulus; glucose intake; glycolysis; human; human tissue; immunoblotting; insulin dependent diabetes mellitus; kidney parenchyma; male; mass spectrometry; mouse; nonhuman; obesity; priority journal; animal; cell line; chemistry; cytology; diabetes mellitus; drug effects; glomerulus; matrix-assisted laser desorption-ionization mass spectrometry; mesangium cell; metabolism; obesity; procedures; signal transduction; Adenosine Monophosphate; Adenosine Triphosphate; AMP-Activated Protein Kinases; Animals; Cell Line; Diabetes Mellitus; Glucose; Humans; Kidney Glomerulus; Lactic Acid; Mesangial Cells; Mice; Obesity; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Signal Transduction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sphingomyelins
Type
journal article