Kelli M Sas1, Jiahe Lin2, Chih-Hong Wang1, Hongyu Zhang1, Jharna Saha1, Thekkelnaycke M Rajendiran3,4, Tanu Soni4, Viji Nair1,5, Felix Eichinger1,5, Matthias Kretzler1,5, Frank C Brosius1,6, George Michailidis7, Subramaniam Pennathur8,9,10. 1. Division of Nephrology, Department of Internal Medicine, University of Michigan, 5309 Brehm Center, 1000 Wall St., Ann Arbor, Michigan, 48105, USA. 2. Department of Statistics, University of Michigan, Ann Arbor, Michigan, 48109, USA. 3. Department of Pathology, University of Michigan, Ann Arbor, Michigan, 48109, USA. 4. Michigan Regional Comprehensive Metabolomics Resource Core, Ann Arbor, Michigan, 48105, USA. 5. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, 48109, USA. 6. Division of Nephrology, Department of Medicine, University of Arizona, Tucson, Arizona, 85724, USA. 7. Department of Statistics and Computer and Information Sciences, University of Florida, Gainesville, Florida, 32611, USA. 8. Division of Nephrology, Department of Internal Medicine, University of Michigan, 5309 Brehm Center, 1000 Wall St., Ann Arbor, Michigan, 48105, USA. spennath@umich.edu. 9. Michigan Regional Comprehensive Metabolomics Resource Core, Ann Arbor, Michigan, 48105, USA. spennath@umich.edu. 10. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, 48109, USA. spennath@umich.edu.
Abstract
OBJECTIVE: Dyslipidemia is a significant risk factor for progression of diabetic kidney disease (DKD). Determining the changes in individual lipids and lipid networks across a spectrum of DKD severity may identify lipids that are pathogenic to DKD progression. METHODS: We performed untargeted lipidomic analysis of kidney cortex tissue from diabetic db/db and db/db eNOS-/- mice along with non-diabetic littermate controls. A subset of mice were treated with the renin-angiotensin system (RAS) inhibitors, lisinopril and losartan, which improves the DKD phenotype in the db/db eNOS-/- mouse model. RESULTS: Of the three independent variables in this study, diabetes had the largest impact on overall lipid levels in the kidney cortex, while eNOS expression and RAS inhibition had smaller impacts on kidney lipid levels. Kidney lipid network architecture, particularly of networks involving glycerolipids such as triacylglycerols, was substantially disrupted by worsening kidney disease in the db/db eNOS-/- mice compared to the db/db mice, a feature that was reversed with RAS inhibition. This was associated with decreased expression of the stearoyl-CoA desaturases, Scd1 and Scd2, with RAS inhibition. CONCLUSIONS: In addition to the known salutary effect of RAS inhibition on DKD progression, our results suggest a previously unrecognized role for RAS inhibition on the kidney triacylglycerol lipid metabolic network.
OBJECTIVE: Dyslipidemia is a significant risk factor for progression of diabetic kidney disease (DKD). Determining the changes in individual lipids and lipid networks across a spectrum of DKD severity may identify lipids that are pathogenic to DKD progression. METHODS: We performed untargeted lipidomic analysis of kidney cortex tissue from diabetic db/db and db/db eNOS-/- mice along with non-diabetic littermate controls. A subset of mice were treated with the renin-angiotensin system (RAS) inhibitors, lisinopril and losartan, which improves the DKD phenotype in the db/db eNOS-/- mouse model. RESULTS: Of the three independent variables in this study, diabetes had the largest impact on overall lipid levels in the kidney cortex, while eNOS expression and RAS inhibition had smaller impacts on kidney lipid levels. Kidney lipid network architecture, particularly of networks involving glycerolipids such as triacylglycerols, was substantially disrupted by worsening kidney disease in the db/db eNOS-/- mice compared to the db/db mice, a feature that was reversed with RAS inhibition. This was associated with decreased expression of the stearoyl-CoA desaturases, Scd1 and Scd2, with RAS inhibition. CONCLUSIONS: In addition to the known salutary effect of RAS inhibition on DKD progression, our results suggest a previously unrecognized role for RAS inhibition on the kidney triacylglycerol lipid metabolic network.
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