The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.
Am J Physiol Cell Physiol. 2023 Sep 1;325(3):C682-C693. doi: 10.1152/ajpcell.00197.2023. Epub 2023 Jul 31.
Defects in the primary cilium are associated with autosomal dominant polycystic kidney disease (ADPKD). We used a combination of animal models, Western blotting, and confocal microscopy and discovered that CFTR and polycystin 2 (PC2) are both colocalized to the cilium in normal kidneys, with the levels of both being decreased in cystic epithelia. Cilia were longer in CFTR-null mice and in cystic cells in our ADPKD animal models. We examined septin 2, known to play a role in cilia length, to act as a diffusion barrier and to serve as an enhancer of proliferation. We found that septin 2 protein levels were upregulated and colocalized strongly with CFTR in cystic cells. Application of VX-809, the CFTR corrector, restored CFTR and PC2 toward normal in the cilia, decreased the protein levels of septin 2, and drastically reduced septin 2 colocalization with CFTR. Our data suggest that CFTR is present in the cilia and plays a role there, perhaps through its conductance of Cl. We also postulate that septin 2 is important for localizing CFTR to the apical membrane in cystic epithelia. CFTR is present in the primary cilia together with polycystin 2 (PC2). Ablation of CFTR makes cilia longer suggesting that CFTR plays a role there, perhaps through its conductance of Cl.
原发性纤毛缺陷与常染色体显性多囊肾病（ADPKD）有关。我们结合使用动物模型、Western blot 和共聚焦显微镜，发现 CFTR 和多囊蛋白 2（PC2）在正常肾脏中均定位于纤毛，而在囊性上皮中这两种蛋白的水平均降低。CFTR 基因敲除小鼠和我们的 ADPKD 动物模型中的囊性细胞中的纤毛更长。我们研究了已知在纤毛长度中起作用的 septin 2，作为扩散屏障并作为增殖增强剂。我们发现 septin 2 蛋白水平上调，并在囊性细胞中与 CFTR 强烈共定位。CFTR 校正剂 VX-809 的应用使纤毛中的 CFTR 和 PC2 恢复正常，降低了 septin 2 的蛋白水平，并大大减少了 septin 2 与 CFTR 的共定位。我们的数据表明 CFTR 存在于纤毛中并在那里发挥作用，可能通过其传导 Cl。我们还假设 septin 2 对于将 CFTR 定位在囊性上皮的顶膜很重要。CFTR 与多囊蛋白 2（PC2）一起存在于初级纤毛中。CFTR 的缺失使纤毛变长，这表明 CFTR 在那里发挥作用，可能通过其传导 Cl。
