Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053, Regensburg, Germany.
Department of Nephrology and Hypertension, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
Nat Commun. 2020 Aug 28;11(1):4320. doi: 10.1038/s41467-020-18104-5.
In autosomal dominant polycystic kidney disease (ADPKD) multiple bilateral renal cysts gradually enlarge, leading to a decline in renal function. Transepithelial chloride secretion through cystic fibrosis transmembrane conductance regulator (CFTR) and TMEM16A (anoctamin 1) are known to drive cyst enlargement. Here we demonstrate that loss of Pkd1 increased expression of TMEM16A and CFTR and Cl secretion in murine kidneys, with TMEM16A essentially contributing to cyst growth. Upregulated TMEM16A enhanced intracellular Ca signaling and proliferation of Pkd1-deficient renal epithelial cells. In contrast, increase in Ca signaling, cell proliferation and CFTR expression was not observed in Pkd1/Tmem16a double knockout mice. Knockout of Tmem16a or inhibition of TMEM16A in vivo by the FDA-approved drugs niclosamide and benzbromarone, as well as the TMEM16A-specific inhibitor Ani9 largely reduced cyst enlargement and abnormal cyst cell proliferation. The present data establish a therapeutic concept for the treatment of ADPKD.
常染色体显性多囊肾病（ADPKD）中，多个双侧肾脏囊肿逐渐增大，导致肾功能下降。已知通过囊性纤维化跨膜电导调节因子（CFTR）和 TMEM16A（ANOCTAMIN 1）的跨上皮氯离子分泌会推动囊肿增大。本文中，我们证明 Pkd1 的缺失会增加 TMEM16A 和 CFTR 的表达，并促进小鼠肾脏中的氯离子分泌，其中 TMEM16A 主要促进囊肿生长。上调的 TMEM16A 增强了 Pkd1 缺陷的肾上皮细胞的细胞内 Ca 信号和增殖。相比之下，在 Pkd1/Tmem16a 双敲除小鼠中，并未观察到 Ca 信号、细胞增殖和 CFTR 表达的增加。体内敲除 Tmem16a 或使用美国食品和药物管理局批准的药物尼氯柳胺和苯溴马隆以及 TMEM16A 特异性抑制剂 Ani9 抑制 TMEM16A，均可显著减少囊肿增大和异常囊肿细胞增殖。本研究数据为 ADPKD 的治疗提供了一个概念。
