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l-Cysteine Alleviates Peritoneal Fibrosis by Repressing PKM2 in Peritoneal Mesothelial Cells
Xiaokun Ma1,2, Yin Li1, Yuebo Huang1
1Nephrology Division, Department of Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Summary
High glucose in dialysis fluid drives peritoneal fibrosis by upregulating pyruvate kinase M2 (PKM2), which promotes mesothelial-to-mesenchymal transition. Inhibiting PKM2 with l-cysteine offers a potential therapeutic strategy for patients undergoing peritoneal dialysis.
Area of Science:
- Nephrology
- Cell Biology
- Biochemistry
Background:
- Peritoneal fibrosis is a major complication of peritoneal dialysis (PD), leading to dysfunction and treatment withdrawal.
- High-glucose dialysis solutions are known to induce mesothelial-to-mesenchymal transition (MMT) and fibrosis, but the underlying molecular mechanisms are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms by which high-glucose dialysis solutions induce peritoneal fibrosis.
- To identify key molecular players and potential therapeutic targets for peritoneal fibrosis in PD patients.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) analysis of patient effluent cells.
- Co-immunoprecipitation, chromatin immunoprecipitation assays, and gene silencing techniques.
- In vitro experiments using a known PKM2 inhibitor, l-cysteine.
Main Results:
- Pyruvate kinase isozymes M2 (PKM2), a key enzyme in glucose metabolism, was significantly upregulated in mesothelial cells of long-term PD patients.
- PKM2 was found to promote SNAI2 expression via histone H3K9 acetylation (H3K9ac), driving MMT and peritoneal fibrosis.
- L-cysteine treatment inhibited these responses and prevented PD-induced peritoneal fibrosis.
Conclusions:
- PKM2 plays a critical role in high-glucose-induced peritoneal fibrosis by mediating MMT through epigenetic modifications.
- Targeting PKM2 with inhibitors like l-cysteine presents a promising therapeutic avenue for preventing or treating peritoneal fibrosis in PD patients.
