PDF(Pubmed)
Abstract：
Systemic and portal hypertension, liver fibrosis, and hepatomegaly are manifestations associated with autosomal recessive polycystic kidney disease (ARPKD), which is caused by malfunctions of fibrocystin/polyductin (FPC). The goal is to understand how liver pathology occurs and to devise therapeutic strategies to treat it. We injected 5-day-old Pkhd1del3-4/del3-4 mice for 1 mo with the cystic fibrosis transmembrane conductance regulator (CFTR) modulator VX-809 designed to rescue processing and trafficking of CFTR folding mutants. We used immunostaining and immunofluorescence techniques to evaluate liver pathology. We assessed protein expression via Western blotting. We detected abnormal biliary ducts consistent with ductal plate abnormalities, as well as a greatly increased proliferation of cholangiocytes in the Pkhd1del3-4/del3-4 mice. CFTR was present in the apical membrane of cholangiocytes and increased in the Pkhd1del3-4/del3-4 mice, consistent with a role for apically located CFTR in enlarged bile ducts. Interestingly, we also found CFTR in the primary cilium, in association with polycystin (PC2). Localization of CFTR and PC2 and overall length of the cilia were increased in the Pkhd1del3-4/del3-4 mice. In addition, several of the heat shock proteins; 27, 70, and 90 were upregulated, suggesting that global changes in protein processing and trafficking had occurred. We found that a deficit of FPC leads to bile duct abnormalities, enhanced cholangiocyte proliferation, and misregulation of heat shock proteins, which all returned toward wild type (WT) values following VX-809 treatment. These data suggest that CFTR correctors can be useful as therapeutics for ARPKD. Given that these drugs are already approved for use in humans, they can be fast-tracked for clinical use.NEW & NOTEWORTHY ARPKD is a multiorgan genetic disorder resulting in newborn morbidity and mortality. There is a critical need for new therapies to treat this disease. We show that persistent cholangiocytes proliferation occurs in a mouse model of ARPKD along with mislocalized CFTR and misregulated heat shock proteins. We found that VX-809, a CFTR modulator, inhibits proliferation and limits bile duct malformation. The data provide a therapeutic pathway for strategies to treat ADPKD.
摘要：
系统性和门静脉高压症，肝纤维化,和肝肿大是与常染色体隐性遗传性多囊肾病（ARPKD）相关的表现，这是由纤维囊素/polyductin的故障引起的。目标是了解肝脏病理学是如何发生的，并设计治疗策略来治疗它。我们用CFTR调节剂注射5天大的Pkhd1del3-4/del3-4小鼠一个月，VX-809,设计用于拯救CFTR折叠突变体的加工和运输(1)。我们使用免疫染色和免疫荧光技术来评估肝脏病理。我们通过蛋白质印迹法评估蛋白质表达。我们发现胆管异常与导管板异常一致，以及Pkhd1del3-4/del3-4小鼠中胆管细胞的增殖大大增加。CFTR存在于胆管细胞的顶端膜中，并在Pkhd1del3-4/del3-4小鼠中增加，与位于顶部的CFTR在胆管扩大中的作用一致。有趣的是,我们还在初级纤毛中发现了CFTR，与PC2相关。在Pkhd1del3-4/del3-4小鼠中，CFTR和PC2的定位以及纤毛的总长度增加。此外,几种热休克蛋白（27、70和90）被上调，表明蛋白质加工和贩运的全球变化已经发生。我们发现FPC缺乏会导致胆管异常，增强的胆管细胞增殖，和热休克蛋白的错误调节，全部返回到wt。VX-809治疗后的值。这些数据表明CFTR校正剂可用作ARPKD的治疗剂。鉴于这些药物已经被批准用于人类，它们可以快速跟踪用于临床。
