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DESI-MSI and METASPACE indicates lipid abnormalities and altered mitochondrial membrane components in diabetic renal proximal tubules

Abstract

Introduction

Diabetic kidney disease (DKD) is the most prevalent complication in diabetic patients, which contributes to high morbidity and mortality. Urine and plasma metabolomics studies have been demonstrated to provide valuable insights for DKD. However, limited information on spatial distributions of metabolites in kidney tissues have been reported.

Objectives

In this work, we employed an ambient desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) coupled to a novel bioinformatics platform (METASPACE) to characterize the metabolome in a mouse model of DKD.

Methods

DESI-MSI was performed for spatial untargeted metabolomics analysis in kidneys of mouse models (F1 C57BL/6J-Ins2Akita male mice at 17 weeks of age) of type 1 diabetes (T1D, n = 5) and heathy controls (n = 6).

Results

Multivariate analyses (i.e., PCA and PLS-DA (a 2000 permutation test: P < 0.001)) showed clearly separated clusters for the two groups of mice on the basis of 878 measured m/z’s in kidney cortical tissues. Specifically, mice with T1D had increased relative abundances of pseudouridine, accumulation of free polyunsaturated fatty acids (PUFAs), and decreased relative abundances of cardiolipins in cortical proximal tubules when compared with healthy controls.

Conclusion

Results from the current study support potential key roles of pseudouridine and cardiolipins for maintaining normal RNA structure and normal mitochondrial function, respectively, in cortical proximal tubules with DKD. DESI-MSI technology coupled with METASPACE could serve as powerful new tools to provide insight on fundamental pathways in DKD.

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Acknowledgements

K.S. and G.Z. were supported by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant (5R24DK082841-08 to KS). L.S.E. was supported by the National Cancer Institute of the National Institutes of Health under Award R00CA190783.

Author information

GZ performed experiments, analyzed and interpreted the data, contributed to discussion, and wrote the manuscript. JZ and RD performed experiments and analyzed the data. JZ, RD, SP, DH, CA, MAV, TA, and LSE contributed to discussion and edited the manuscript. KS conceived and designed study, contributed to discussion, reviewed and edited the manuscript. All authors read and approved the final manuscript.

Correspondence to Kumar Sharma.

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Zhang, G., Zhang, J., DeHoog, R.J. et al. DESI-MSI and METASPACE indicates lipid abnormalities and altered mitochondrial membrane components in diabetic renal proximal tubules. Metabolomics 16, 11 (2020) doi:10.1007/s11306-020-1637-8

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Keywords

  • Diabetic kidney disease
  • DESI-MSI
  • Renal proximal tubule
  • Lipid metabolism