Renin-Angiotensin System Inhibition Alters Triacylglycerol Metabolism in Diabetic Kidney Disease

Abstract

Lipids are essential metabolites with diverse functions impacting physiology. We recently identified several lipidomic abnormalities in diabetic kidney disease (DKD), including remodeling of triacylglycerol (TAG) fatty acid composition to increase availability of long, polyunsaturated TAGs. Using the BKS eNOS-/- db/db diabetic mouse model, we studied the effect of renin-angiotensin system (RAS) inhibition with combination treatment of lisinopril (20 mg/kg/d) and losartan (30 mg/kg/d) for 12 weeks, an intervention which ameliorates DKD in this mouse model without impacting glycemia. We examined the kidney cortical lipidome to identify lipid alterations that may be pathogenic in DKD. As expected, RAS inhibition did not significantly alter glycemic control or total plasma triglycerides or cholesterol, but decreased the 24-hour urine albumin/creatinine ratio (2564 vs. 615 μg/mg creatinine) and decreased the glomerular periodic acid-Schiff stained area by 13% (p<0.05). We performed mass-spectrometry based untargeted lipidomic profiling to quantify 635 lipids across 17 lipid classes in kidney cortex. Lisinopril/losartan treatment remodeled TAG fatty acid composition and increased conversion between TAGs and several glycerophospholipid classes, particularly medium-chain phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols and cardiolipins (p<0.05). These correlations in lipid levels were associated with changes in corresponding enzymes of lipid metabolism, suggesting increased metabolism of TAGs into glycerophospholipids, which are key components of cell membranes and precursors for signaling molecules. In addition to the known salutary effect of RAS inhibition on DKD, our results suggest a previously unrecognized role of RAS inhibition on kidney complex lipid levels through increased TAG metabolism. These findings raise the possibility that TAG metabolism might be a target for intervention aimed at decreasing DKD progression. Disclosure K. Sas: None. J. Lin: None. V. Nair: None. M. Kretzler: Research Support; Self; AstraZeneca, Novo Nordisk Inc., Boehringer Ingelheim GmbH, National Institute of Diabetes and Digestive and Kidney Diseases, Eli Lilly and Company, Gilead Sciences, Inc.. F. Brosius: None. S. Pennathur: None.