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Lithium preserves peritoneal membrane integrity by suppressing mesothelial cell αB-crystallin
Science Translational Medicine ( IF 15.8 ) Pub Date : 2021-08-25 , DOI: 10.1126/scitranslmed.aaz9705
Rebecca Herzog 1, 2 , Juan Manuel Sacnun 1, 2, 3 , Guadalupe González-Mateo 4 , Maria Bartosova 5 , Katarzyna Bialas 1, 3 , Anja Wagner 1, 2 , Markus Unterwurzacher 1, 2 , Isabel J Sobieszek 1, 2 , Lisa Daniel-Fischer 1, 2 , Krisztina Rusai 2 , Lucía Pascual-Antón 4 , Klaus Kaczirek 6 , Andreas Vychytil 7 , Claus Peter Schmitt 5 , Manuel López-Cabrera 4 , Seth L Alper 8, 9 , Christoph Aufricht 2 , Klaus Kratochwill 1, 2
Affiliation  

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.



中文翻译:

锂通过抑制间皮细胞αB-晶状体蛋白保持腹膜完整性

通过腹膜透析 (PD) 挽救生命的肾脏替代疗法在使用和持续时间方面受到限制,因为腹膜完整性和体内平衡逐渐受损。在慢性 PD 期间保持腹膜完整性仍然是一项紧迫但长期未得到满足的医疗需求。PD 治疗失败是由高渗 PD 液 (PDF) 诱导的间皮细胞毒性引起的腹膜纤维化和血管生成造成的。然而,所涉及的病理生理机制尚不完全清楚,限制了治疗靶点的识别。我们报告将氯化锂 (LiCl) 添加到 PDF 是一种可转化的干预措施,可抵消 PDF 诱导的间皮细胞死亡、腹膜纤维化和血管生成。LiCl 以剂量依赖性方式改善间皮细胞存活。结合基于艾考糊精的 PDF 诱导的间皮细胞损伤的转录组学和蛋白质组学表征,将 αB-晶状体蛋白鉴定为最一致地被 LiCl 反调节的间皮细胞蛋白。体外和体内 αB-晶状体蛋白的过表达引发了血管内皮生长因子 (VEGF)、CD31 阳性细胞的纤维化表型和 PDF 样上调,以及 TGF-β 调节靶点的 TGF-β 非依赖性激活。相比之下,αB-晶状体蛋白敲低降低了 VEGF 表达和早期间皮到间充质转化。LiCl 减少 VEGF 释放并抵消纤维化和血管生成相关过程。患者来源的间皮细胞中的 αB-晶状体蛋白在响应 PDF 时特异性上调,并在来自接受 PD 的儿科患者活检组织的腹膜间皮细胞中增加,与血管生成和纤维化标志物相关。LiCl 补充的 PDF 促进了慢性 PD 小鼠模型中间皮细胞和间皮下区的形态学保存。因此,将 LiCl 重新用作细胞保护性 PDF 添加剂可能会提供一种可转化的治疗策略,以对抗 PD 治疗期间的腹膜退化。

更新日期:2021-08-26
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