Abstract: FR-PO455
L-Cysteine Attenuates Peritoneal Fibrosis by Inhibiting Pyruvate Kinase M2 in Mesothelial Cells
Session Information
- Peritoneal Dialysis: Current Topics
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Dialysis
- 702 Dialysis: Home Dialysis and Peritoneal Dialysis
Authors
- Xiaokun, Ma, Department of Nephrology, The Third Affiliated Hospital of Sun Yat-sen University, GuangZhou, GuangDong, China
- Li, Yin, Department of Nephrology, The Third Affiliated Hospital of Sun Yat-sen University, GuangZhou, GuangDong, China
- Peng, Hui, Department of Nephrology, The Third Affiliated Hospital of Sun Yat-sen University, GuangZhou, GuangDong, China
Group or Team Name
- Department of Nephrology, The Third Affiliated Hospital of Sun Yat-sen University
Background
Peritoneal fibrosis is one of the main causes of peritoneal dialysis (PD) failure, our previous study has demonstrated that peritoneal dialysate-induced hyperglycolysis stimulates mesothelial-to-mesenchymal transition (MMT) in peritoneal mesothelium cells leading to peritoneal fibrosis but there is still a lack of effective and low-toxic drugs for preventing peritoneal hyperglycolysis and fibrosis in clinical practice.
Methods
The peritoneal dialysis effluents from patients with long-term or short-term peritoneal dialysis were collected for single cell transcriptome sequencing (scRNA-seq), and differential activation of glycolytic enzymes in the two groups was identified specifically in mesothelial cells. Human primary peritoneal mesothelial cell cultures and MET-5A cells were used to assess the relationship between specific glycolytic enzyme and MMT. Gene silencing, COIP, CHIP and other techniques were used to explore the mechanisms behind of this relationship. Finally, the therapeutic effect of glycolytic enzyme inhibitor was evaluated in mouse model of peritoneal fibrosis.
Results
scRNA-seq showed that long-term peritoneal dialysis reduced the number of peritoneal mesothelial cells, stimulated the expression of glycolysis enzymes, especially the pyruvate kinase isozymes M2 (PKM2), a key rate-limiting enzyme of glycolysis. In mesothelial cell cultures, TGF-β1 promoted MMT that was associated with the activation of PKM2, and addition of L-cysteine, an PKM2 inhibitor, significantly suppressed this response. Mechanically, PKM2 promoted the expression of transcription factor SNAIL2 through acetylation of H3K9, thus promoting the occurrence of MMT in mesotheila cells. In C57BL/6 mice, high glucose peritoneal dialysate induced peritoneal fibrosis with increased PKM2 expression in mesotheila cells. Administration of L-cysteine to these mice significantly reduced peritoneal fibrosis that was associated down-regulation of PKM2 activity and improved peritoneal ultrafiltration.
Conclusion
PKM2 activation is a critical step to induce mesotheila hyperglycolysis during peritoneal dialysis. Inhibition of PKM2 by L-cysteine suppresses mesotheila hyperglycolysis and hance peritoneal fibrosis, thus, providing a new therapeutical strategy for preventing peritoneal fibrosis in patients with peritoneal dialysis.