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首页> 外文期刊>American Journal of Physiology >High-content screening assay-based discovery of paullones as novel podocyte-protective agents
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High-content screening assay-based discovery of paullones as novel podocyte-protective agents

机译：基于高含量的筛选测定的Paullones发现作为新型泛孔细胞保护剂

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Podocyte dysfunction and loss is an early event and a hallmark of proteinuric kidney diseases. A podocyte's normal function is maintained via its unique cellular architecture that relies on an intracellular network of filaments, including filamentous actin (F-actin) and microtubules, that provides mechanical support. Damage to this filamentous network leads to changes in cellular morphology and results in podocyte injury, dysfunction, and death. Conversely, stabilization of this network protects podocytes and ameliorates prolein-uria. This suggests that stabilization of podocyte architecture via its filamentous network could be a key therapeutic strategy for protein-uric kidney diseases. However, development of podocyte-directed therapeutics, especially those that target the cell's filamentous network, is still lacking, partly because of unavailability of appropriate cellular assays for use in a drug discovery environment. Here, we describe a new high-content screening-based methodology and its implementation on podocytes to identify paullone derivatives as a novel group of podocyte-protective compounds. We find that three compounds, i.e., kenpaullone, 1-azakenpaullone, and alsterpaullone, dose dependently protect podocyles from puromycin aminonucleoside (PAN)-mediated injury in vitro by reducing PAN-induced changes in both the filamentous actin and microtubules, with alsterpaullone providing maximal protection. Mechanistic studies further show that alsterpaullone suppressed PAN-induced activation of signaling downstream of GSK3P and p38 mitogen-activated protein kinase. In vivo it reduced ADR-induced glomerular injury in a zebrafish model. Together, these results identify paullone derivatives as novel podocyte-protective agents for future therapeutic development.
机译：Podocyte功能障碍和损失是蛋白质肾病的早期事件和标志。通过其独特的蜂窝架构维持Podocyte的正常功能，其依赖于细胞内细胞内网络，包括提供机械支撑的丝状肌动蛋白（F-actin）和微管。这种丝状网络的损坏导致细胞形态的变化，并导致足细胞损伤，功能障碍和死亡。相反，该网络的稳定性保护多粒细胞和改善普罗林 - uria。这表明通过其丝状网络稳定足细胞建筑可能是蛋白质 - 尿肾疾病的关键治疗策略。然而，Podocyte指导的治疗剂的发展，特别是那些靶向细胞丝网的那些，部分原因是由于适当的细胞测定用于药物发现环境的不可用。在这里，我们描述了一种新的高含量筛选的方法和其在足粒细胞上的实施，以鉴定普伦酮衍生物作为一种新型的泛细胞保护化合物。我们发现三种化合物，即Kenpaullone，1-Azakenpaullone和Alsterpaullone，通过减少丝状肌动蛋白和微管中的泛诱导的变化，依赖于体外保护来自嘌呤霉素氨基核苷（PAN）介导的损伤的PodoCyles，其中Alsterpaullone提供最大保护。机械研究进一步表明阿尔特淘抑制了GSK3P和P38丝裂剂活化蛋白激酶下游的泛诱导的信号传导激活。体内，它减少了斑马鱼模型中的ADR诱导的肾小球损伤。这些结果在一起鉴定普伦酮衍生物作为新型泛细胞保护剂，用于未来治疗发育。

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