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Abstract: FR-PO119

Protein Lactylation Promotes AKI-CKD Transition by Activating NLRP3 Inflammasome

Session Information

  • AKI: Mechanisms - II
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Author

  • Chen, Kehong, Army Medical Center of PLA, Chongqing, chongqing, China
Background

Renal interstitial inflammation contributes to the progression of AKI-CKD transition. Recent studies have shown that protein lactylation caused by lactic acid accumulation can regulate chronic organ injury. So we investigated the role and mechanism of protein lactalylation in AKI-CKD transition.

Methods

Severe renal ischemia-reperfusion(I/R) injury (severe AKI) was constructed by bilateral renal ischemia for 35min. The lactylation enhancer rotenone and the lactylation inhibitor sodium dichloroacetate (DCA) were used to verify the effect of protein lactylation. Lactylated proteomics was used to detect the changes of lactylated proteins in renal cortex at different time points, and the lactylated proteins related to renal function were screened for verification.

Results

The SCr of BUN levels did not return to normal value at 14 days after I/R injury. At day 28, renal interstitial fibrosis was observed with AKI-CKD transformation. The renal injury score was significantly increased at day 7 and renal interstitial fibrosis was enhanced at day 28 after treatment with protein lactylation enhancer. IL-1b and IL-18 were found to be the most significantly enhanced inflammatory cytokines in the blood of mice, and the NLRP3 inflammasome activation was significantly enhanced in renal tissues at 7 days. Meanwhile, lactylation inhibitor had a protective effect on AKI-CKD transition. Lactylated proteins in kidney were detected by Lactylated proteomics analysis at 0, 3 and 7 days after I/R, and the enrichment of differential lactylated proteins was analyzed. GO enrichment analysis was performed on lactylated differential proteins associated with renal function trends at 0-7 days. The results showed that the seven differential proteins with significant difference mainly existed in the tricarboxylic acid cycle. One of them is citrate synthase (CS), a key rate-limiting enzyme in the tricarboxylic acid cycle. Citrate synthase lactylation level increased significantly on day 3 after AKI, recovered slightly on day 7, but still failed to return to normal level on day 28.

Conclusion

Renal protein lactylation promotes activation of NLRP3 inflammasome, leading to AKI-CKD transition. Citrate synthase may be the key lactoacylated protein.