Hyperlipidemia is a risk factor for initiation and progression of
diabetic nephropathy but the metabolic pathways altered in the diabetic kidney in a context of
hyperlipidemia remain incompletely described. Assuming that changes in urine composition reflect the alteration of renal metabolism and function, we analyzed the urine metabolite composition of diabetic (
streptozotocin-treatment) and control (non diabetic)
ApoE-/- mice fed a high
cholesterol diet using targeted quantitative metabolomics. Urine metabolome was also compared to the plasma metabolome of the same animals. As previously shown, urine
albuminuria/urine
creatinine ratio (uACR) and glomerular area and plasma
lipids (
cholesterol,
triglycerides) were more elevated in diabetic mice compared to control. After adjustment to urine
creatinine, the abundance of 52 urine metabolites was significantly different in diabetic mice compared to control. Among them was a unique metabolite, C14:2-
OH (3-hydroxytetradecadienoylcarnitine) that, in diabetic mice, was positively and significantly correlated with uACR, glomerular
hypertrophy,
blood glucose and plasma
lipids. That metabolite was not detected in plasma. C14:2-
OH is a long-chain
acylcarnitine reminiscent of altered
fatty acid beta oxidation. Other acylcarnitines, particularly the short chains C3-OH, C3-DC, C4:1, C5-DC, C5-M-DC, C5-OH that are reminiscent of altered oxidation of branched and
aromatic amino acids were also exclusively detected in urine but were only correlated with plasma
lipids. Finally, the renal gene expression of several
enzymes involved in
fatty acid and/or
amino acid oxidation was significantly reduced in diabetic mice compared to control. This included the bifunctional
enoyl-CoA hydratase/3-hydroxyacyl-
CoA (Ehhadh) that might play a central role in C14:2-
OH production. This study indicate that the development of diabetes in a context of
hyperlipidemia is associated with a reduced capacity of kidney to oxidize
fatty acids and
amino acids with the consequence of an elevation of urinary acetylcarnitines including C14:2-
OH that specifically reflects
diabetic nephropathy.