Time-of-day defines the risk of thermally abused frying oil to renal injury by modulating the diurnal dynamics of oxylipins

Modulation of circadian rhythms results in impaired homeostasis and susceptibility to disease development. Thus, new perspectives on nutrition emphasize the circadian timing of food intake. Here, we find that fried oil disrupted the conversionof epoxides to diols in kidney, and led to aggravated renal injury. Interestingly, the circadian rhythm of epoxides and its diols in the kidney and plasma showed a significant light-dark manner. We demonstrated that time-imposed feeding of fried oil during the active period showed limited damage to renal function, conversely, renal function was impaired during the inactive period. Remarkably, time-imposed epoxy stearic acid (EpSA) from fried oil during the inactive period disrupted the rhythmicity of epoxide hydrolases and related metabolites, and fueled the progression of renal fibrosis and injury. The effect of EpSA on SMA and E-cadherin, renalfibrosis biomarkers, are lost in knockouts of Ephx1 and Ephx2, which encodes for epoxide hydrolase. Besides, the inhibition of epoxide hydrolases by dietary supplementation of linoleic acid rescues mice from the damages from time-imposed feeding of EpSA. Our findings unveil that the time-of-day dependence of epoxide hydrolases and circadian disruption at the inactive phase by EpSA from fried oil has adverse impacts on kidney function.