Comprehensive Lipidome Profiling of the Kidney in Early-Stage Diabetic Nephropathy

Abstract

Metabolic changes associated with diabetes are reported to lead to the onset of early-stage diabetic nephropathy (DN). Furthermore, lipotoxicity is implicated in renal dysfunction. Most studies of DN have focused on a single or limited number of lipids, and the lipidome of the kidney during early-stage DN remains to be elucidated. In the present study, we aimed to comprehensively identify lipid abnormalities during early-stage DN; to this end, we established an early-stage DN rat model by feeding a high-sucrose and high-fat diet combined with administration of low-dose streptozotocin. Using a high-coverage, targeted lipidomic approach, we established the lipid profile, comprising 437 lipid species and 25 lipid classes, of the kidney cortex in normal rats and the DN rat model. Our findings additionally confirmed that the DN rat model had been successfully established. We observed distinct lipidomic signatures in the DN kidney, with characteristic alterations in side chain composition and degree of unsaturation. Glyceride lipids, especially cholesteryl esters, showed a significant increase in the DN kidney cortex. The levels of most phospholipids exhibited a decline, except those of phospholipids with side chain of 36:1. Furthermore, the levels of lyso-phospholipids and sphingolipids, including ceramide and its derivatives, were dramatically elevated in the present DN rat model. Our findings, which provide a comprehensive lipidome of the kidney cortex in rats with DN, are expected to be useful for the identification of pathologically relevant lipid species in DN. Furthermore, the results represent novel insights into the mechanistic basis of DN.