Therapeutic Potential for CFTR Correctors in Autosomal Recessive Polycystic Kidney Disease.
Therapeutic Potential for CFTR Correctors in Autosomal Recessive Polycystic Kidney Disease.
复制标题
DOI：
10.1016/j.jcmgh.2021.07.012
复制
发表时间：
2021
影响因子：
7.2
通讯作者：
Cebotaru L
中科院分区：
文献类型：
--
作者：
Yanda MK;Tomar V;Cebotaru L
常染色体隐性遗传性多囊肾病（ARPKD）是由PKHD 1突变引起的，编码纤维囊蛋白/多导管蛋白（FPC）。严重的疾病发生在围产期。新生儿期存活的患者面临着无数的合并症，包括全身性和门静脉高压症、肝纤维化和肝脾肿大。目的是揭示ARPKD的治疗策略。我们使用野生型和FPC突变的胆管细胞系在三维囊肿和汇合单层，以评估蛋白质表达，蛋白质印迹和蛋白质运输，共聚焦显微镜。我们发现囊性纤维化跨膜传导调节因子（CFTR）的蛋白水平下调。在FPC突变的胆管细胞中，热休克蛋白（HSP）的水平发生了改变，HSP 27下调，HSP 90和HSP 70上调。FPC突变胆管细胞形成囊肿，但正常细胞没有。通过增加HSP 27蛋白水平、HSP 90和HSP 70抑制剂治疗、通过信使RNA抑制沉默HSP 90或通过用CFTR校正剂VX-809治疗囊肿的新方法可以减少囊肿生长。在野生型胆管细胞中，CFTR存在于顶膜和基底外侧膜中。FPC功能障碍导致CFTR与顶膜和基底膜的共定位改变。而用VX-809处理，增加HSP 27或抑制HSP 70或HSP 90使CFTR定位恢复到正常值。FPC功能障碍诱导囊肿的形成，这是由热休克蛋白和CFTR蛋白水平和错误定位的改变推动的。我们认为，CFTR矫正剂，已经在临床上用于治疗囊性纤维化，也可以用作ARPKD的治疗。
Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in PKHD1, encoding fibrocystin/polyductin (FPC). Severe disease occurs in perinates. Those who survive the neonatal period face a myriad of comorbidities, including systemic and portal hypertension, liver fibrosis, and hepatosplenomegaly. The goal here was to uncover therapeutic strategies for ARPKD. We used wild-type and an FPC-mutant cholangiocyte cell line in 3-dimenional cysts and in confluent monolayers to evaluate protein expression using western blotting and protein trafficking using confocal microscopy. We found that the protein level of the cystic fibrosis transmembrane conductance regulator (CFTR) was downregulated. The levels of heat shock proteins (HSPs) were altered in the FPC-mutant cholangiocytes, with HSP27 being downregulated and HSP90 and HSP70 upregulated. FPC-mutant cholangiocytes formed cysts, but normal cells did not. Cyst growth could be reduced by increasing HSP27 protein levels, by HSP90 and HSP70 inhibitor treatments, by silencing HSP90 through messenger RNA inhibition, or by the novel approach of treating the cysts with the CFTR corrector VX-809. In wild-type cholangiocytes, CFTR is present in both apical and basolateral membranes. FPC malfunction resulted in altered colocalization of CFTR with both apical and basolateral membranes. Whereas, treatment with VX-809, increasing HSP27 or inhibiting HSP70 or HSP90 restored CFTR localization toward normal values. FPC malfunction induces the formation of cysts, which are fueled by alterations in HSPs and in CFTR protein levels and miss-localization. We suggest that CFTR correctors, already in clinical use to treat cystic fibrosis, could also be used as a treatment for ARPKD.
登录
查看更多内容
影响因子：
19.6
作者：
Menezes, LFC;Cai, YQ;Onuchic, LF
通讯作者：
Onuchic, LF
影响因子：
13.6
作者：
Hanaoka, K;Guggino, WB
通讯作者：
Guggino, WB
影响因子：
7.2
作者：
Balch, William E.;Roth, Daniela M.;Hutt, Darren M.
通讯作者：
Hutt, Darren M.
影响因子：
76.2
作者：
Elborn, J. Stuart;Ramsey, Bonnie W.;Wainwright, Claire E.
通讯作者：
Wainwright, Claire E.
影响因子：
4.3
作者：
Gyrd-Hansen, M;Nylandsted, J;Jäättelä, M
通讯作者：
Jäättelä, M