Departments of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA.
FASEB J. 2021 May;35(5):e21533. doi: 10.1096/fj.202002490R.
Polycystic kidney disease (PKD) is a genetic disorder characterized by aberrant renal epithelial cell proliferation and formation and progressive growth of numerous fluid-filled cysts within the kidneys. Previously, we showed that there is elevated Notch signaling compared to normal renal epithelial cells and that Notch signaling contributes to the proliferation of cystic cells. Quinomycin A, a bis-intercalator peptide, has previously been shown to target the Notch signaling pathway and inhibit tumor growth in cancer. Here, we show that Quinomycin A decreased cell proliferation and cyst growth of human ADPKD cyst epithelial cells cultured within a 3D collagen gel. Treatment with Quinomycin A reduced kidney weight to body weight ratio and decreased renal cystic area and fibrosis in Pkd1 ; Pkd2 mice, an orthologous PKD mouse model. This was accompanied by reduced expression of Notch pathway proteins, RBPjk and HeyL and cell proliferation in kidneys of PKD mice. Quinomycin A treatments also normalized cilia length of cyst epithelial cells derived from the collecting ducts. This is the first study to demonstrate that Quinomycin A effectively inhibits PKD progression and suggests that Quinomycin A has potential therapeutic value for PKD patients.
多囊肾病（PKD）是一种遗传性疾病，其特征是肾脏上皮细胞异常增殖和形成，并在肾脏内逐渐形成多个充满液体的囊肿。以前，我们发现与正常肾上皮细胞相比，PKD 中 Notch 信号通路的表达水平升高，并且 Notch 信号通路有助于囊性细胞的增殖。喹诺霉素 A 是一种双嵌入肽，先前已被证明可以靶向 Notch 信号通路并抑制癌症中的肿瘤生长。在这里，我们表明喹诺霉素 A 可减少在 3D 胶原凝胶中培养的人 ADPKD 囊上皮细胞的增殖和囊肿生长。喹诺霉素 A 处理可降低 Pkd1 ; Pkd2 小鼠（同源 PKD 小鼠模型）的肾重与体重比，并减少肾脏囊性区域和纤维化。这伴随着 Notch 通路蛋白、RBPjk 和 HeyL 的表达减少以及 PKD 小鼠肾脏中的细胞增殖减少。喹诺霉素 A 处理还可使从集合管衍生的囊上皮细胞的纤毛长度正常化。这是第一项表明喹诺霉素 A 可有效抑制 PKD 进展的研究，并表明喹诺霉素 A 对 PKD 患者具有潜在的治疗价值。
