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Mass Spectrometry Imaging Reveals Elevated Glomerular ATP/AMP in Diabetes/obesity and Identifies Sphingomyelin as a Possible Mediator

Satoshi Miyamoto (a, b, c, d), Cheng-Chih Hsu (e, f), Gregory Hamm (g), Manjula Darshi (a, b), Maggie Diamond-Stanic (a, b, c), Anne-Emilie DeclÇùves (b), Larkin Slater (a, b, c), Subramaniam Pennathur (h), Jonathan Stauber (g), Pieter C. Dorrestein (a, e, i), Kumar Sharma (a, b, c)

a Institute of Metabolomic Medicine, University of California San Diego, La Jolla, CA 92093, USA
b Center for Renal Translational Medicine, Division of Nephrology-Hypertension, University of California San Diego, La Jolla, CA 92093, USA
c Division of Nephrology-Hypertension, Veterans Affairs San Diego Healthcare System, La Jolla, CA 92093, USA
e Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA
f Department of Chemistry, National Taiwan University, Taipei 106, Taiwan
g ImaBiotech, MS Imaging Department, Lille 59120, France
h Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
i Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA

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 PGC1×ñ. 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.

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