TY - JOUR
T1 - Mass Spectrometry Imaging Reveals Elevated Glomerular ATP/AMP in Diabetes/obesity and Identifies Sphingomyelin as a Possible Mediator
AU - Miyamoto, Satoshi
AU - Hsu, Cheng Chih
AU - Hamm, Gregory
AU - Darshi, Manjula
AU - Diamond-Stanic, Maggie
AU - Declèves, Anne Emilie
AU - Slater, Larkin
AU - Pennathur, Subramaniam
AU - Stauber, Jonathan
AU - Dorrestein, Pieter C.
AU - Sharma, Kumar
N1 - Funding Information:
We thank Dr. Christopher M. Rath for his guidance on MALDI-MSI analysis. K.S. was supported by grants from the Juvenile Diabetes Research Foundation , VA Merit Award 5101BX000277 and National Institute of Diabetes and Digestive and Kidney Diseases ( 1DP3DK094352 ). S.M. was supported in part by grants from JSPS International Training Program (ITP) and the Uehara Memorial Foundation . S.P. was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases ( DK082841 , DK094292 ).
Publisher Copyright:
© 2016 The Authors.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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.
AB - 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.
KW - AMPK
KW - ATP
KW - Chronic kidney disease
KW - Glycolysis
KW - Matrix-assisted laser desorption/ionization mass spectrometry imaging
KW - Sphingomyelin
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U2 - 10.1016/j.ebiom.2016.03.033
DO - 10.1016/j.ebiom.2016.03.033
M3 - Article
C2 - 27322466
AN - SCOPUS:84963543334
SN - 2352-3964
VL - 7
SP - 121
EP - 134
JO - EBioMedicine
JF - EBioMedicine
ER -
