Institute of Physiology, University of Zürich, Zürich, Switzerland.
Department of Biomedicine, Cancer Immunology Laboratory, University Hospital Basel, Basel, Switzerland.
Sci Rep. 2018 Apr 3;8(1):5584. doi: 10.1038/s41598-018-22938-x.
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of kidney cysts leading to kidney failure in adulthood. Inhibition of mammalian target of rapamycin (mTOR) slows polycystic kidney disease (PKD) progression in animal models, but randomized controlled trials failed to prove efficacy of mTOR inhibitor treatment. Here, we demonstrate that treatment with mTOR inhibitors result in the removal of negative feedback loops and up-regulates pro-proliferative phosphatidylinositol 3-kinase (PI3K)-Akt and PI3K-extracellular signal-regulated kinase (ERK) signaling in rat and mouse PKD models. Dual mTOR/PI3K inhibition with NVP-BEZ235 abrogated these pro-proliferative signals and normalized kidney morphology and function by blocking proliferation and fibrosis. Our findings suggest that multi-target PI3K/mTOR inhibition may represent a potential treatment for ADPKD.
常染色体显性多囊肾病（ADPKD）的特征是肾脏囊肿的发展，导致成年后肾功能衰竭。哺乳动物雷帕霉素靶蛋白（mTOR）的抑制可减缓动物模型中的多囊肾病（PKD）进展，但随机对照试验未能证明 mTOR 抑制剂治疗的疗效。在这里，我们证明 mTOR 抑制剂的治疗导致负反馈环的消除，并上调大鼠和小鼠 PKD 模型中的促增殖磷脂酰肌醇 3-激酶（PI3K）-Akt 和 PI3K-细胞外信号调节激酶（ERK）信号。用 NVP-BEZ235 进行双重 mTOR/PI3K 抑制通过阻断增殖和纤维化来消除这些促增殖信号，并使肾脏形态和功能正常化。我们的研究结果表明，多靶点 PI3K/mTOR 抑制可能成为 ADPKD 的一种潜在治疗方法。
