Christian Doppler Laboratory for Molecular Stress Research in Peritoneal Dialysis, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, 1090 Vienna, Austria.
Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria.
Sci Transl Med. 2021 Aug 25;13(608). doi: 10.1126/scitranslmed.aaz9705.
Life-saving renal replacement therapy by peritoneal dialysis (PD) is limited in use and duration by progressive impairment of peritoneal membrane integrity and homeostasis. Preservation of peritoneal membrane integrity during chronic PD remains an urgent but long unmet medical need. PD therapy failure results from peritoneal fibrosis and angiogenesis caused by hypertonic PD fluid (PDF)-induced mesothelial cytotoxicity. However, the pathophysiological mechanisms involved are incompletely understood, limiting identification of therapeutic targets. We report that addition of lithium chloride (LiCl) to PDF is a translatable intervention to counteract PDF-induced mesothelial cell death, peritoneal membrane fibrosis, and angiogenesis. LiCl improved mesothelial cell survival in a dose-dependent manner. Combined transcriptomic and proteomic characterization of icodextrin-based PDF-induced mesothelial cell injury identified αB-crystallin as the mesothelial cell protein most consistently counter-regulated by LiCl. In vitro and in vivo overexpression of αB-crystallin triggered a fibrotic phenotype and PDF-like up-regulation of vascular endothelial growth factor (VEGF), CD31-positive cells, and TGF-β-independent activation of TGF-β-regulated targets. In contrast, αB-crystallin knockdown decreased VEGF expression and early mesothelial-to-mesenchymal transition. LiCl reduced VEGF release and counteracted fibrosis- and angiogenesis-associated processes. αB-crystallin in patient-derived mesothelial cells was specifically up-regulated in response to PDF and increased in peritoneal mesothelial cells from biopsies from pediatric patients undergoing PD, correlating with markers of angiogenesis and fibrosis. LiCl-supplemented PDF promoted morphological preservation of mesothelial cells and the submesothelial zone in a mouse model of chronic PD. Thus, repurposing LiCl as a cytoprotective PDF additive may offer a translatable therapeutic strategy to combat peritoneal membrane deterioration during PD therapy.
腹膜透析（PD）的救命性肾脏替代疗法受到腹膜完整性和内稳态进行性受损的限制，使用和持续时间受限。在慢性 PD 期间保持腹膜完整性仍然是一个紧迫但长期未满足的医疗需求。PD 治疗失败是由高渗 PD 液（PDF）诱导的间皮细胞细胞毒性引起的腹膜纤维化和血管生成引起的。然而，涉及的病理生理机制尚不完全清楚，限制了治疗靶点的确定。我们报告说，向 PDF 中添加氯化锂（LiCl）是一种可转化的干预措施，可以抵抗 PDF 诱导的间皮细胞死亡、腹膜膜纤维化和血管生成。LiCl 以剂量依赖性方式改善间皮细胞的存活率。基于 icodextrin 的 PDF 诱导的间皮细胞损伤的转录组和蛋白质组联合特征鉴定出αB-晶状体蛋白是间皮细胞蛋白中最一致被 LiCl 反向调节的蛋白。αB-晶状体蛋白在体外和体内的过表达会引发纤维化表型和 PDF 样血管内皮生长因子（VEGF）上调、CD31 阳性细胞和 TGF-β 非依赖性 TGF-β 调节靶标的激活。相比之下，αB-晶状体蛋白敲低会降低 VEGF 表达并减少早期间皮细胞向间充质转化。LiCl 减少了 VEGF 的释放并对抗纤维化和血管生成相关过程。在对 PDF 作出反应时，患者来源的间皮细胞中的αB-晶状体蛋白特异性上调，并在接受 PD 的儿科患者的腹膜间皮细胞活检中增加，与血管生成和纤维化的标志物相关。LiCl 补充的 PDF 可促进慢性 PD 小鼠模型中间皮细胞和亚间皮区的形态保存。因此，将 LiCl 重新用作细胞保护 PDF 添加剂可能提供一种可转化的治疗策略，以对抗 PD 治疗期间腹膜膜的恶化。
