Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
State Key Laboratory of Natural and Biomimetic Drugs, Beijing, China.
FASEB J. 2019 May;33(5):6185-6196. doi: 10.1096/fj.201801338RRR. Epub 2019 Feb 15.
Human autosomal dominant polycystic kidney disease (ADPKD) is characterized by bilateral renal cysts that lead to a decline in kidney function. Previous studies reported aquaporin (AQP)-3 expression in cysts derived from collecting ducts in ADPKD. To study the role of AQP3 in cyst development, we generated 2 polycystic kidney disease (PKD) mouse models: kidney-specific knockout mice and inducible knockout mice, each without and with AQP3 deletion. In both models, kidney sizes and cyst indexes were significantly reduced in AQP3-null PKD mice compared with AQP3-expressing PKD mice, with the difference seen mainly in collecting duct cysts. AQP3-deficient kidneys showed significantly reduced ATP content, increased phosphorylated (p)-AMPK, and decreased p-ERK and p-mammalian target of rapamycin (mTOR). In a matrix-grown Madin-Darby canine kidney cyst model, AQP3 expression promoted cyst enlargement and was associated with increased expression of hypoxia-inducible factor 1-α and glucose transporter 1 and increased glucose uptake. Our data suggest that the slowed renal cyst enlargement in AQP3 deficiency involves impaired energy metabolism in the kidney through AMPK and mTOR signaling and impaired cellular glucose uptake. These findings implicate AQP3 as a novel determinant of renal cyst enlargement and hence a potential drug target in ADPKD.-Wang, W., Geng, X., Lei, L., Jia, Y., Li, Y., Zhou, H., Verkman, A. S., Yang, B. Aquaporin-3 deficiency slows cyst enlargement in experimental mouse models of autosomal dominant polycystic kidney disease.
人类常染色体显性多囊肾病（ADPKD）的特征是双侧肾脏囊肿，导致肾功能下降。先前的研究报道了水通道蛋白（AQP）-3 在 ADPKD 集合管来源的囊肿中的表达。为了研究 AQP3 在囊肿发育中的作用，我们生成了 2 种多囊肾病（PKD）小鼠模型：肾特异性敲除小鼠和诱导型敲除小鼠，每种小鼠均没有和有 AQP3 缺失。在这两种模型中，与 AQP3 表达的 PKD 小鼠相比，AQP3 缺失的 PKD 小鼠的肾脏大小和囊肿指数显著降低，差异主要见于集合管囊肿。AQP3 缺陷肾脏的 ATP 含量显著降低，磷酸化（p）-AMPK 增加，而 p-ERK 和 p-哺乳动物雷帕霉素靶蛋白（mTOR）减少。在基质培养的 Madin-Darby 犬肾囊肿模型中，AQP3 表达促进了囊肿增大，并与缺氧诱导因子 1-α和葡萄糖转运蛋白 1 的表达增加以及葡萄糖摄取增加相关。我们的数据表明，AQP3 缺乏导致的肾脏囊肿增大速度减慢涉及通过 AMPK 和 mTOR 信号转导损害肾脏的能量代谢和细胞葡萄糖摄取。这些发现表明 AQP3 是肾脏囊肿增大的一个新决定因素，因此是 ADPKD 的一个潜在药物靶点。-Wang, W., Geng, X., Lei, L., Jia, Y., Li, Y., Zhou, H., Verkman, A. S., Yang, B. Aquaporin-3 deficiency slows cyst enlargement in experimental mouse models of autosomal dominant polycystic kidney disease.
