Histone Lactylation Facilitates Peritoneal Mesothelial Cell Senescence and Promotes Peritoneal Dialysis-Associated Fibrosis

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Background: Peritoneal fibrosis (PF) is a serious clinical complication in patients undergoing long-term peritoneal dialysis (PD). Recently, histone lactylation has been found to increase with glycolysis and intracellular lactate levels, leading to chronic organ damage. Here, we investigated the role and mechanism of histone lactylation in PD-associated fibrosis induced by high-glucose dialysate. Methods: Mouse models of PF were constructed by 4.25% glucose peritoneal dialysate combined with methylglyoxal. We used a lactylation enhancer (rotenone) and a lactylation inhibitor (oxamate) to validate the effects of histone lactylation in vivo and in vitro. The parietal peritoneum samples and cultured peritoneal mesothelial cells (PMCs) were analyzed for the senescence, fibrosis, glycolysis, and histone lactylation levels. We generated DcR2 (a senescent marker) knockout mice to verify the effects of histone lactylation by clearing senescent cells. Single-cell RNA sequencing (scRNA-seq) was used to characterize the heterogeneity of PMCs clusters under different lactylation intervention conditions. Results: We found that lactate and glycolysis levels were significantly higher in the PF group compared to the control group, and immunoprecipitation results also showed enhanced levels of histone lactylation modifications in the PF group. In vitro, we also verified that PMCs exhibited enhanced levels of lactate and lactylation in response to stimulation by high glucose, while we found an increasing expression of cell senescent marker (P16, P21, and DcR2) and senescence-associated secretory phenotype. Then we found that PMCs senescence was significantly enhanced in the lactylation-enhanced group, while the lactylation-inhibited group alleviated PMCs senescence. In the PF model of DcR2 knockout mice, compared with the wild group, the peritoneal thickness and the expression of fibrotic markers were significantly reduced. The transcriptomic analysis using scRNA-seq revealed the activation of senescence-related pathway in PMCs clusters of PF group, whereas the senescence-related pathway was down-regulated in the lactylation-inhibited group. The results indicated that histone lactylation may promote PF through PMCs senescence. Conclusions: Histone lactylation may play a vital role in the progression of PD-associated fibrosis by promoting PMCs senescence. Funding: Veterans Affairs Support, Government Support - Non-U.S.

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