Redox phospholipidomics analysis reveals specific oxidized phospholipids and regions in the diabetic mouse kidney

While it is generally accepted that oxidative stress impacts the diabetic kidney and contributes to pathogenesis, there is a substantial lack of knowledge about the molecular entity and anatomic location of a variety of reactive species. Here we provide a novel “oxidative stress map” of the diabetic kidney – the first of its kind, and identify specific, oxidized and other reactive lipids and their location. We used the db/db mouse model and Desorption Electrospray Ionization (DESI) mass spectrometry combined with heatmap image analysis. We analyzed a comprehensive array of phospholipid peroxide species in normal (db/m) and diabetic (db/db) kidneys using DESI imaging. Oxilipidomics heatmaps of the kidneys were generated focusing on phospholipids and their potential peroxidized products. We identified those lipids that undergo peroxidation in diabetic nephropathy. Several phospholipid peroxides and their spatial distribution were identified that were specific to the diabetic kidney, with significant enrichment in oxygenated phosphatidylethanolamines (PE) and lysophosphatidylethanolamine. Beyond qualitative and semi-quantitative information about the targets, the approach also reveals the anatomic location and the extent of lipid peroxide signal propagation across the kidney. Our approach provides novel, in-depth information of the location and molecular entity of reactive lipids in an organ with a very heterogeneous landscape. Many of these reactive lipids have been previously linked to programmed cell death mechanisms. Thus, the findings may be relevant to understand what impact phospholipid peroxidation has on cell and mitochondria membrane integrity and redox lipid signaling in diabetic nephropathy.