Protein lactylation promotes AKI–CKD transition in mice

ABSTRACT: Interstitial renal inflammation contributes to the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). Recently, protein lactylation modification has emerged as a novel mechanism mediating chronic organ damage. We investigated lactylated protein profiles and the role of protein lactylation during AKI progression. Severe and moderate AKI mouse models were constructed by bilateral renal ischemia for 35 and 25 min respectively. The lactylation enhancer and inhibitors were used to verify the effect of protein lactylation. Lactylated proteomics was used to detect lactylated protein changes in kidneys, and the lactylated proteins related to kidney injury were screened for verification. We observed significantly higher lactate and protein lactylation levels in the severe than in the moderate AKI model 1–28 days post-injury. Inhibition of protein lactylation protected against renal interstitial fibrosis. In vitro and in vivo experiments demonstrated that protein lactylation activated Nod-like receptor protein 3 (NLRP3) inflammasomes, promoting the AKI–CKD transition. Comprehensive lactylome profiling of severe AKI models revealed a role for lactylated proteins in metabolic pathways, primarily the tricarboxylic acid (TCA) cycle where the rate-limiting enzyme, citrate synthase (CS), exhibited significantly elevated lactylation levels 3–7 days post-AKI induction; K370 was the most significant lysine residue. In vitro, following hypoxia/reoxygenation, the modified/lactylated K370T group significantly decreased CS activity and mitochondrial function. Furthermore, CS-K370 lactylation activated the NLRP3 inflammasome. Lactylation of CS promotes the AKI–CKD transition through NLRP3 inflammasome activation. Inhibition of CS lactylation shows therapeutic potential for preventing this transition.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Kidney

SUBMITTER: kehong chen  

LAB HEAD: Kehong Chen

PROVIDER: PXD058023 | Pride | 2025-07-07

REPOSITORIES: Pride