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Abstract: FR-OR102

Inhibition of Hyperglycolysis in Mesothelial Cells Prevents Peritoneal Fibrosis

Session Information

Category: Dialysis

  • 703 Dialysis: Peritoneal Dialysis

Authors

  • Si, Meijun, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, GUANGDONG, China
  • Zhao, Wenbo, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, GUANGDONG, China
  • Li, Yin, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, GUANGDONG, China
  • Lin, Hongchun, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, GUANGDONG, China
  • Lou, Tan-qi, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, GUANGDONG, China
  • Hu, Zhaoyong, Baylor College of Medicine, Houston, Texas, United States
  • Peng, Hui, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, GUANGDONG, China
Background

Progressive peritoneal fibrosis is a dreaded problem for patients receiving peritoneal dialysis (PD) because it has no reliable treatment. There also are disagreements about the identification of mechanisms that initiate and sustain peritoneal fibrosis. To overcome these problems, we developed a strategy that prevents peritoneal fibrosis by suppressing PD-stimulated mesothelial to mesenchymal transition (MMT).

Methods

We evaluated single-cell transcriptomes of mesothelial cells obtained from normal peritoneal biopsy and effluent from PD-treated patients. We then examined the metabolic reprogramming in the peritoneal fibrogenesis in mouse model and mesothelial cells using metabolomics and cellular respiration tests. We finally developed a triad of AAV1 encoded microRNA therapy, and evaluated its therapeutic potential to treat peritoneal fibrosis.

Results

We analyzed 96,446 single cell transcriptomes including cells dissociated from normal peritoneum, peritoneal cells from effluent of short-term PD and from long-term PD patients. We found the expression of glycolytic enzymes was increased during the development of MMT. Using gene expression profiling and metabolomics analyses, we confirmed that PD fluid induces metabolic reprogramming, characterized as hyperglycolysis in peritoneum. We found that transforming growth factor β1 (TGF-β1) can substitute for PD fluid to stimulate hyperglycolysis. The mechanism involves suppressing mitochondrial respiration in mesothelial cells. Blockade of hyperglycolysis with 2-deoxy-glucose inhibited PD fluid-induced profibrotic cellular phenotype and fibrogenesis in mice. We developed a triad of adeno-associated viruses that overexpresses microRNA-26a and microRNA-200a plus inhibitor of microRNA-21a, which targets both hyperglycolysis and fibrotic signaling. Intraperitoneal injection of the viral triad in mice significantly inhibited the development of peritoneal fibrosis induced by PD fluid.

Conclusion

We conclude that hyperglycolysis is responsible for MMT and peritoneal fibrogenesis. This aberrant metabolic state can be principally corrected by modulating microRNA levels in the peritoneum. These results could provide a novel therapeutic strategy to combat peritoneal fibrosis.

Funding

  • Government Support - Non-U.S.