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Peritoneal fibrosis (PF) is a significant factor in the failure of peritoneal dialysis (PD) techniques. Recent research has shown that histone lactylation levels increase with glycolysis and intracellular lactate levels, highlighting the impact of protein lactylation in regulating chronic organ injury. In this study, we investigated the role and mechanisms of histone lactylation in peritoneal fibrosis induced by high-glucose (HG) peritoneal dialysate in mice.
We employed PF mouse models induced by HG peritoneal dialysate and treated these mice with a lactylation inhibitor (oxamate). And single-cell RNA sequencing (scRNA-seq) is used to distinguish cell types and detected changes in peritoneal mesothelial cells (PMCs), identifying protein lactylation linked to PF. We confirmed the effects of protein lactylation on peritoneal fibrosis and PMCs using a lactylation enhancer (rotenone) and a lactylation inhibitor (oxamate) in vitro and in vivo. The samples of parietal peritoneum and cultured PMCs in various groups were then analyzed for evidence of cellular senescence, fibrosis, and lactylation levels.
In this study, we observed a significant increase in glycolysis and lactate levels in the PF group compared to the control group. Additionally, immunoprecipitation results revealed higher levels of histone lactylation modifications in the PF group. Furthermore, our in vitro experiments confirmed that PMCs exhibited elevated levels of glycolysis and lactylation in response to stimulation by high glucose. We then present the results of a comprehensive transcriptomic analysis of the peritoneum of mice using scRNA‐seq, including control group, PF group, and PF+lactylation-inhibited (oxamate) group. After quality control screening, a total of 17,757 cells were obtained from the samples of mouse parietal peritoneum. scRNA‐seq analysis identified 20 cell clusters and 15 cell types, mainly including mesothelial cells, fibroblasts, myofibroblasts, endothelial cells, macrophages, T cells, and B cells. The single-cell transcriptomes of PMCs cluster were evaluated, revealing seven distinct cell subclusters based on principal component analysis. Further results indicated the activation of senescence-related pathway in PMCs of PF group, while the senescence-related pathway was down-regulated in the PF+lactylation-inhibited group. These results suggest that histone lactylation may promote peritoneal fibrosis by regulating PMCs senescence. After manipulating lactylation, we observed a significant increase in PMCs senescence in the lactylation-enhanced group. Conversely, the lactylation-inhibited group showed a decrease in PMCs senescence.
Histone lactylation may play a crucial role in the development of PF, and inhibition of histone lactylation may alleviate PF by downregulating PMCs senescence. These findings could provide a novel therapeutic strategy for delaying PD-related fibrosis.