Division of Toxicology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands.
NEXUS Personalized Health Technologies, ETH Zürich, Switzerland.
J Mol Cell Biol. 2020 Aug 1;12(8):644-653. doi: 10.1093/jmcb/mjz029.
Polycystic kidney disease (PKD) is a prevalent genetic disorder, characterized by the formation of kidney cysts that progressively lead to kidney failure. The currently available drug tolvaptan is not well tolerated by all patients and there remains a strong need for alternative treatments. The signaling rewiring in PKD that drives cyst formation is highly complex and not fully understood. As a consequence, the effects of drugs are sometimes difficult to predict. We previously established a high throughput microscopy phenotypic screening method for quantitative assessment of renal cyst growth. Here, we applied this 3D cyst growth phenotypic assay and screened 2320 small drug-like molecules, including approved drugs. We identified 81 active molecules that inhibit cyst growth. Multi-parametric phenotypic profiling of the effects on 3D cultured cysts discriminated molecules that showed preferred pharmacological effects above genuine toxicological properties. Celastrol, a triterpenoid from Tripterygium Wilfordii, was identified as a potent inhibitor of cyst growth in vitro. In an in vivo iKspCre-Pkd1lox,lox mouse model for PKD, celastrol inhibited the growth of renal cysts and maintained kidney function.
多囊肾病 (PKD) 是一种常见的遗传性疾病，其特征是肾脏囊肿的形成，这些囊肿会逐渐导致肾衰竭。目前可用的药物托伐普坦并不是所有患者都能耐受，因此仍然强烈需要替代治疗方法。PKD 中驱动囊肿形成的信号重排非常复杂，尚未完全了解。因此，药物的作用有时难以预测。我们之前建立了一种高通量显微镜表型筛选方法，用于定量评估肾脏囊肿的生长。在这里，我们应用这种 3D 囊肿生长表型测定法筛选了 2320 种小分子药物样化合物，包括已批准的药物。我们确定了 81 种可抑制囊肿生长的活性分子。对 3D 培养的囊肿的多参数表型分析可区分出具有优先药理作用而不是真正毒性作用的分子。雷公藤红素是从雷公藤中提取的一种三萜类化合物，被鉴定为体外抑制囊肿生长的有效抑制剂。在 PKD 的 iKspCre-Pkd1lox,lox 小鼠模型中，雷公藤红素抑制了肾脏囊肿的生长并维持了肾脏功能。
