Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of bilateral renal cysts which enlarge continuously, leading to compression of adjacent intact nephrons. The growing cysts lead to a progressive decline in renal function. Cyst growth is driven by enhanced cell proliferation and chloride secretion into the cyst lumen. Chloride secretion is believed to occur mainly by the cAMP-activated cystic fibrosis transmembrane conductance regulator (CFTR), with some contribution by the calcium-activated chloride channel TMEM16A. However, our previous work suggested TMEM16A as a major factor for renal cyst formation. The contribution of CFTR to cyst formation has never been demonstrated in an adult ADPKD mouse model. We used mice with an inducible tubule-specific Pkd1 knockout, which consistently develop polycystic kidneys upon deletion of Pkd1. Cellular properties, ion currents, and cyst development in these mice were compared with that of mice carrying a co-deletion of Pkd1 and Cftr. Knockout of Cftr did not reveal any significant impact on cyst formation in the ADPKD mouse model. Furthermore, knockout of Cftr did not attenuate the largely augmented cell proliferation observed in Pkd1 knockout kidneys. Patch clamp analysis on primary renal epithelial cells lacking expression of Pkd1 indicated an only marginal contribution of CFTR to whole cell Cl⁻ currents, which were clearly dominated by calcium-activated TMEM16A currents. In conclusion, CFTR does not essentially contribute to renal cyst formation in mice caused by deletion of Pkd1. Enhanced cell proliferation and chloride secretion is caused primarily by upregulation of the calcium-activated chloride channel TMEM16A.

中文翻译：

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ADPKD 小鼠模型中的囊肿生长不需要氯通道 CFTR

常染色体显性多囊肾病 (ADPKD) 的特征是双侧肾囊肿不断扩大，导致相邻完整肾单位受压。不断增长的囊肿导致肾功能进行性下降。囊肿生长是由增强的细胞增殖和氯化物分泌到囊腔中驱动的。氯化物分泌被认为主要由 cAMP 激活的囊性纤维化跨膜电导调节剂 (CFTR) 发生，钙激活的氯化物通道 TMEM16A 也有一些贡献。然而，我们之前的工作表明 TMEM16A 是肾囊肿形成的主要因素。CFTR 对囊肿形成的贡献从未在成年 ADPKD 小鼠模型中得到证实。我们使用了具有诱导性小管特异性 Pkd1 敲除的小鼠，在 Pkd1 缺失后持续发展为多囊肾。将这些小鼠的细胞特性、离子电流和囊肿发育与携带 Pkd1 和 Cftr 共同缺失的小鼠进行比较。在 ADPKD 小鼠模型中，Cftr 的敲除未显示对囊肿形成的任何显着影响。此外，敲除 Cftr 并没有减弱在 Pkd1 敲除肾脏中观察到的大量增强的细胞增殖。对缺乏 Pkd1 表达的原代肾上皮细胞的膜片钳分析表明 CFTR 对全细胞 Cl 的贡献仅微不足道 Cftr 的敲除并没有减弱在 Pkd1 敲除肾脏中观察到的大量增强的细胞增殖。对缺乏 Pkd1 表达的原代肾上皮细胞的膜片钳分析表明 CFTR 对全细胞 Cl 的贡献仅微不足道 Cftr 的敲除并没有减弱在 Pkd1 敲除肾脏中观察到的大量增强的细胞增殖。对缺乏 Pkd1 表达的原代肾上皮细胞的膜片钳分析表明 CFTR 对全细胞 Cl 的贡献仅微不足道⁻电流，明显由钙激活的 TMEM16A 电流主导。总之，CFTR 基本上不会导致 Pkd1 缺失引起的小鼠肾囊肿形成。增强的细胞增殖和氯离子分泌主要是由钙激活的氯离子通道 TMEM16A 的上调引起的。