Polycystic kidney disease (PKD) is a genetic disorder that affects cilia homeostasis and causes progressive growth of tubular-derived cysts within the kidney. Efforts to find safer drugs for PKD have increased in the past few years after the successful launch of tolvaptan, the first approved drug to combat autosomal dominant PKD progression. Here we investigate the effects of Quinomycin A on progression of PKD. Quinomycin A is a bis-intercalator peptide that has previously shown to be effective against cancer progression. Quinomycin A treatment decreased cyst progression of human ADPKD primary renal epithelial cells grown in a 3D collagen gel to form cysts. In an orthologous mouse model of PKD, Quinomycin A administration reduced kidney to body weight ratios, and reduced cystogenesis. This was accompanied by decreased cell proliferation and fibrosis. Quinomycin treatments efficiently reduced the expression of Notch pathway proteins, RBPjk and HeyL in kidneys of PKD mice. Interestingly, Quinomycin treatments also normalized cilia lengths of collecting duct cyst-lining renal epithelia of PKD mice. This is the first preclinical study to our knowledge that demonstrates Quinomycin A has protective effects against PKD progression, in part by reducing Notch signaling and renal epithelial cilia lengths. Our findings suggest Quinomycin A has potential therapeutic value for PKD patients.

中文翻译：

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奎诺霉素A降低多囊肾病的囊肿进展

多囊肾疾病（PKD）是一种遗传性疾病，会影响纤毛的体内平衡并导致肾小管来源的囊肿逐渐生长。成功推出托伐普坦后，在过去几年中，为PKD寻找更安全的药物的努力有所增加。在这里，我们研究了Quinomycin A对PKD进展的影响。Quinomycin A是一种双嵌入剂肽，以前已显示出可有效对抗癌症进展。Quinomycin A处理可降低在3D胶原蛋白凝胶中生长的人ADPKD原发性肾上皮细胞的囊肿进展，从而形成囊肿。在PKD的直系同源小鼠模型中，Quinomycin A的给药降低了肾脏与体重的比例，并减少了囊肿的形成。这伴随着细胞增殖和纤维化减少。奎宁霉素治疗有效降低了PKD小鼠肾脏中Notch通路蛋白，RBPjk和HeyL的表达。有趣的是，Quinomycin治疗还可以使PKD小鼠的收集导管囊肿衬里的肾上皮的纤毛长度正常化。这是我们所知的第一项临床前研究，证明奎诺霉素A具有抗PKD进展的保护作用，部分是通过减少Notch信号传导和肾脏上皮纤毛长度来实现的。我们的发现表明Quinomycin A对PKD患者具有潜在的治疗价值。这是我们所知的第一项临床前研究，证明奎诺霉素A具有抗PKD进展的保护作用，部分是通过减少Notch信号传导和肾脏上皮纤毛长度来实现的。我们的发现表明Quinomycin A对PKD患者具有潜在的治疗价值。这是我们所知的第一项临床前研究，证明奎诺霉素A具有抗PKD进展的保护作用，部分是通过减少Notch信号传导和肾脏上皮纤毛长度来实现的。我们的发现表明Quinomycin A对PKD患者具有潜在的治疗价值。