Department of Biological Science, Sookmyung Women's University, Seoul 04310, Republic of Korea.
Department of Biology, Ewha Womans University, Seoul 03760, Republic of Korea.
EBioMedicine. 2020 Oct;60:102986. doi: 10.1016/j.ebiom.2020.102986. Epub 2020 Sep 16.
Polycystic kidney disease (PKD) involves renal cysts arising from proliferating tubular cells. Autophagy has been recently suggested as a potential therapeutic target in PKD, and mammalian target of rapamycin (mTOR) is a key negative regulator of autophagy. However, the effect of autophagy regulation on cystogenesis has not been elucidated in PKD mice.
Clinical validation was performed using GEO datasets and autosomal dominant polycystic kidney disease (ADPKD) patient samples. Newly established PKD and LC3 transgenic mice were used for in vivo verifications, and additional tests were performed in vitro and in vivo using multiple autophagy drugs.
Neither autophagy stimulation nor LC3 overexpression alleviated PKD. Furthermore, we observed the inhibitory effect of an autophagy inhibitor on cysts, indicating its possible therapeutic use in a specific group of patients with ADPKD.
Our findings provide a novel insight into the pathogenesis related to autophagy in PKD, suggesting that drugs related to autophagy regulation should be considered with caution for treating PKD.
This work was supported by grants from the Bio & Medical Technology Development Program; the Collaborative Genome Program for Fostering New Post-Genome Industry of the NRF; the Basic Science Program.
多囊肾病（PKD）涉及由增殖性管状细胞引起的肾囊肿。自噬最近被认为是 PKD 的一个潜在治疗靶点，哺乳动物雷帕霉素靶蛋白（mTOR）是自噬的关键负调节因子。然而，自噬调节对 PKD 小鼠囊肿发生的影响尚未阐明。
使用 GEO 数据集和常染色体显性多囊肾病（ADPKD）患者样本进行临床验证。使用新建立的 PKD 和 LC3 转基因小鼠进行体内验证，并使用多种自噬药物在体外和体内进行额外的测试。
自噬刺激或 LC3 过表达均不能减轻 PKD。此外，我们观察到自噬抑制剂对囊肿的抑制作用，表明其在特定的 ADPKD 患者群体中可能具有治疗用途。
我们的研究结果为 PKD 中与自噬相关的发病机制提供了新的见解，表明应谨慎考虑与自噬调节相关的药物来治疗 PKD。
这项工作得到了生物和医疗技术发展计划；NRF 促进新基因组产业合作基因组计划；基础科学计划的支持。
