The landscape of renal protein cysteine acylation in mice with kidney injury induced by a high fat diet

ABSTRACT: Background. Dyslipidemia is associated with chronic kidney disease (CKD). It has been shown that inhibition of β-oxidation and lipid accumulation are common threats in the onset of kidney injury and conducive to fibrosis. We characterized the S-acylated proteome of kidneys from mice with diet-induced nephropathy, to uncover novel lipid-related biochemical changes that might contribute to the lipid-induced kidney dysfunction. Methods. We conducted total and S-acylated proteomics, and lipidomics of the renal crude membrane fractions of mice fed a high-fat diet (HFD). Then, we investigated in vitro the effect of S-acylation inhibition on megalin expression and ligand binding. Results. HFD caused albuminuria with unchanged kidney function. The dietary 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 an overall reduction in acyl-CoA availability. S-acylation repression mostly affected proteins involved in endocytosis and intracellular transport. In particular, the kidney of the mice fed a HFD, which are characterized by albuminuria, 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 is important for total expression of megalin. Conclusions. The diet-induced derangement of fatty acids metabolism modifies the renal landscape of the S-acylated proteome during early stage of the kidney injury, which might reduce the maximal capacity of protein reabsorption by the proximal tubule.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Kidney

SUBMITTER: Witold Wolski  

LAB HEAD: Dr. Michele Visentin

PROVIDER: PXD052634 | Pride | 2025-03-21

REPOSITORIES: Pride