Inhibition of hyperglycolysis in mesothelial cells prevents peritoneal fibrosis
Inhibition of hyperglycolysis in mesothelial cells prevents peritoneal fibrosis
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抑制间皮细胞糖酵解过度可预防腹膜纤维化
DOI：
10.1126/scitranslmed.aav5341
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发表时间：
2019-06-05
影响因子：
17.1
通讯作者：
Peng, Hui
中科院分区：
文献类型：
--
作者：
Si, Meijun;Wang, Qianqian;Peng, Hui
由间皮细胞糖酵解过度引起的腹膜纤维化可以通过三种microRNA来预防。腹膜透析用于治疗终末期肾病患者，但其中许多患者发生腹膜纤维化，限制了治疗效果。Si等人研究了来自接受腹膜透析的患者的细胞，并使用小鼠模型来了解腹膜纤维化进展的潜在机制。他们发现转化生长因子β1刺激间皮细胞的糖酵解过度，导致间皮向间质转化表型和腹膜纤维化。使用腺相关病毒操纵三种microRNA的表达可以抑制小鼠模型中的纤维化，这表明纠正间皮细胞中改变的代谢状态可以治疗腹膜纤维化。进行性腹膜纤维化影响接受腹膜透析（PD）的患者，并且没有可靠的治疗方法。引发和维持腹膜纤维化的机制仍不完全阐明。为了克服这些问题，我们开发了一种通过抑制PD刺激的间皮-间充质转化（MMT）来预防腹膜纤维化的策略。我们评估了从正常腹膜活检和PD治疗患者流出液中获得的间皮细胞的单细胞转录组。在接受MMT的细胞中，我们发现细胞异质性和中间过渡状态与参与糖酵解的酶的上调相关。糖酵解相关酶的表达与MMT的形成密切相关。使用基因表达谱和代谢组学分析，我们证实，腹膜透析液诱导代谢重编程，其特征在于高糖酵解，在小鼠腹膜。我们发现转化生长因子β1（transforming growth factor β 1，TGF-β1）可以替代PD液刺激大鼠间皮细胞的糖酵解，抑制线粒体呼吸。用2-脱氧葡萄糖（2-DG）阻断高糖酵解抑制TGF-β1诱导的小鼠促纤维化细胞表型和腹膜纤维化。我们开发了一种过表达microRNA-26 a和microRNA-200 a的三重腺相关病毒，同时抑制microRNA-21 a以靶向糖酵解和纤维化信号传导。腹腔内注射病毒三联体抑制小鼠腹膜透析液诱导的腹膜纤维化的发展。我们的结论是，高糖酵解是负责MMT和腹膜纤维化，这种异常的代谢状态可以通过调节腹膜中的microRNA来纠正。这些结果可以提供一种治疗腹膜纤维化的策略。
Peritoneal fibrosis due to hyperglycolysis in mesothelial cells can be prevented by a triad of microRNAs. 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.