Research ArticleFibrosis

Inhibition of hyperglycolysis in mesothelial cells prevents peritoneal fibrosis

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Science Translational Medicine  05 Jun 2019:
Vol. 11, Issue 495, eaav5341
DOI: 10.1126/scitranslmed.aav5341

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Preventing peritoneal fibrosis

Peritoneal dialysis is used to treat patients with end-stage renal disease, but many of these patients develop peritoneal fibrosis that limits treatment efficacy. Si et al. studied cells from patients undergoing peritoneal dialysis and used a mouse model to understand the mechanism underlying progression of peritoneal fibrosis. They found that transforming growth factor β1 stimulated hyperglycolysis in mesothelial cells, contributing to a mesothelial-to-mesenchymal transition phenotype and peritoneal fibrosis. Manipulating the expression of three microRNAs using adeno-associated viruses could inhibit fibrosis in the mouse model, suggesting that correcting the altered metabolic state in mesothelial cells could be therapeutic for peritoneal fibrosis.


Progressive peritoneal fibrosis affects patients receiving peritoneal dialysis (PD) and has no reliable treatment. The mechanisms that initiate and sustain peritoneal fibrosis remain incompletely elucidated. To overcome these problems, we developed a strategy that prevents peritoneal fibrosis by suppressing PD-stimulated mesothelial-to-mesenchymal transition (MMT). We evaluated single-cell transcriptomes of mesothelial cells obtained from normal peritoneal biopsy and effluent from PD-treated patients. In cells undergoing MMT, we found cellular heterogeneity and intermediate transition states associated with up-regulation of enzymes involved in glycolysis. The expression of glycolytic enzymes was correlated with the development of MMT. Using gene expression profiling and metabolomics analyses, we confirmed that PD fluid induces metabolic reprogramming, characterized as hyperglycolysis, in mouse peritoneum. We found that transforming growth factor β1 (TGF-β1) can substitute for PD fluid to stimulate hyperglycolysis, suppressing mitochondrial respiration in mesothelial cells. Blockade of hyperglycolysis with 2-deoxyglucose (2-DG) inhibited TGF-β1–induced profibrotic cellular phenotype and peritoneal fibrosis in mice. We developed a triad of adeno-associated viruses that overexpressed microRNA-26a and microRNA-200a while inhibiting microRNA-21a to target hyperglycolysis and fibrotic signaling. Intraperitoneal injection of the viral triad inhibited the development of peritoneal fibrosis induced by PD fluid in mice. We conclude that hyperglycolysis is responsible for MMT and peritoneal fibrogenesis, and this aberrant metabolic state can be corrected by modulating microRNAs in the peritoneum. These results could provide a therapeutic strategy to combat peritoneal fibrosis.

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