DHA–Triacylglycerol Accumulation in Tacrolimus-Induced Nephrotoxicity Identified by Lipidomic Profiling

TL;DR

This study identifies a unique buildup of DHA-rich fats in the kidneys of mice treated with tacrolimus, a drug linked to kidney damage in transplant patients.

Contribution

The study reveals that DHA-containing triacylglycerols are uniquely elevated in tacrolimus-induced nephrotoxicity, offering a potential metabolic signature.

Findings

TAC-treated mice showed reduced low-carbon unsaturated TGs and increased high-carbon TGs.

DHA-containing TGs were significantly elevated in TAC-treated kidneys.

DHA-enriched TGs may serve as a metabolic signature for TAC nephrotoxicity.

Abstract

Tacrolimus (TAC)-induced chronic nephrotoxicity (TAC nephrotoxicity) remains a major contributor to late allograft dysfunction in kidney transplant recipients. Although detailed mechanisms remain incompletely understood, our previous metabolomic studies revealed disruptions in carnitine-related and redox pathways, suggesting impaired mitochondrial β-oxidation of fatty acids. To further characterize metabolic alterations associated with this condition, we conducted an untargeted lipidomic analysis of renal tissues using a murine model of TAC nephrotoxicity. TAC (1 mg/kg/day) or saline was subcutaneously administered to male ICR mice for 28 days, and kidney tissues were harvested for comprehensive lipidomic profiling. Lipidomic analysis was performed with liquid chromatography–tandem mass spectrometry (p < 0.05, n = 5/group). Triacylglycerols (TGs) were the predominant lipid class identified. TAC-treated mice exhibited reduced levels of unsaturated TG species with low carbon numbers, whereas TGs with higher carbon numbers and various degrees of unsaturation were increased. All detected TGs containing docosahexaenoic acid (DHA) showed an increasing trend in TAC-treated kidneys. Although accumulation of polyunsaturated TGs has been previously observed in chronic kidney disease, the preferential increase in DHA-containing TGs appears to be a unique feature of TAC-induced nephrotoxicity. These results suggest that DHA-enriched TGs may serve as a metabolic signature of TAC nephrotoxicity and offer new insights into its pathophysiology.

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