Excess fat intake is associated with kidney toxicity and dysfunction. Because fatty acids can also be reversibly attached onto cysteine residues and modulate the function of several membrane-bound proteins, we studied the effect of high-fat diet (HFD) on the S-acylated proteome of mouse kidneys to uncover novel biochemical changes that might contribute to lipid-induced nephrotoxicity. We compared the S-acylated proteome of kidneys from mice fed a chow diet (CD) or a HFD. HFD caused albuminuria. The HFD intervention induced a large-scale repression of protein S-acylation as well as of the most abundant ceramides and sphingomyelin species, which are highly suggestive of a reduction in acyl-CoA availability. The HFD-induced S-acylation repression mostly affected proteins involved in endocytosis and intracellular transport. Notably, the kidneys of mice fed a HFD displayed a marked decrease in the total amount and in the S-acylated form of megalin, the main tubular protein retrieval system. Further in vitro experiments indicated that S-acylation inhibition results in a reduction of megalin protein level. We conclude that diet-induced derangement of fatty acid metabolism modifies the renal landscape of the S-acylated proteome during the early stages of the kidney injury, which might reduce the efficiency of protein reabsorption by the proximal tubule.
Keywords: Chronic kidney disease; High-fat diet; Proteinuria; Proteomics, S-acylation; S-palmitoylation.
© 2025. The Author(s).