Hepatic Cystogenesis Is Associated with Abnormal Expression and Location of Ion Transporters and Water Channels in an Animal Model of Autosomal Recessive Polycystic Kidney Disease
Hepatic Cystogenesis Is Associated with Abnormal Expression and Location of Ion Transporters and Water Channels in an Animal Model of Autosomal Recessive Polycystic Kidney Disease
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DOI：
10.2353/ajpath.2008.080125
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发表时间：
2008-12-01
影响因子：
6
通讯作者：
LaRusso, Nicholas F.
中科院分区：
文献类型：
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作者：
Banales, Jesus M.;Masyuk, Tatyana V.;LaRusso, Nicholas F.
多囊肾（PCK）大鼠是常染色体隐性遗传性多囊肾病的自发模型，表现出胆管细胞源性肝囊肿。我们以前曾报道，在正常的胆管细胞囊泡的一个子集含有三种蛋白质（即，水通道AQP 1，氯离子通道CFTR，和阴离子交换剂AE 2），占离子驱动的水运输。因此，我们假设这些功能相关蛋白的表达和位置改变有助于肝囊肿形成。我们发现在基础条件下，胰泌素和低渗反应，PCK大鼠的囊肿比正常胆管形成的囊肿扩大到更大的程度。定量逆转录聚合酶链反应，免疫印迹分析，共聚焦和免疫电镜后表明，这三种蛋白质的表达增加，在PCK胆管细胞与正常胆管细胞。在正常大鼠中，AQP 1、CFTR和AE 2优先定位于顶膜，而在基底侧过表达。PCK大鼠的膜。将胆管细胞基底外侧膜暴露于CFTR抑制剂[5-硝基-2-（3-苯丙氨基）苯甲酸和CFTRinh 172]或Cl-/HCO 3-交换抑制剂（4，4 '-二异硫氰酸芪-2，2'-二磺酸二钠盐水合物和4-乙酰氨基-4 '-异硫氰酸芪-2，2'-二磺酸二钠，盐水合物）可阻断分泌素刺激的PCK中的液体蓄积，但在正常囊肿中则不然。我们的数据表明，常染色体隐性遗传性多囊肾病的肝囊肿形成可能涉及由于囊性胆管细胞中AQP 1、CFTR和AE 2的过度表达和异常定位而导致的液体蓄积增加。阻断这些蛋白激活的治疗干预可能会抑制多囊肝病的囊肿扩张。(Am J Pathol 2008，173：1637-1646; DOI：10.2353/ajpath.2008.080125）
Polycystic kidney (PCK) rats are a spontaneous model of autosomal recessive polycystic kidney disease that exhibit cholangiocyte-derived liver cysts. We have previously reported that in normal cholangiocytes a subset of vesicles contain three proteins (ie, the water channel AQP1, the chloride channel CFTR, and the anion exchanger AE2) that account for ion-driven water transport. Thus, we hypothesized that altered expression and location of these functionally related proteins contribute to hepatic cystogenesis. We show here that under basal conditions and in response to secretin and hypotonicity, cysts from PCK rats expanded to a greater degree than cysts formed by normal bile ducts. Quantitative reverse transcriptase-polymerase chain reaction, immunoblot analysis, and confocal and immunoelectron microscopy aft indicated increased expression of these three proteins in PCK cholangiocytes versus normal cholangiocytes. AQP1, CFTR, and AE2 were localized preferentially to the apical membrane in normal rats while overexpressed at the basolateral. membrane in PCK rats. Exposure of the cholangiocyte basolateral membrane to CFTR inhibitors [5-nitro-2-(3-phenylpropylamino)benzoic acid and CFTRinh172], or Cl-/HCO3- exchange inhibitors (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid disodium salt hydrate and 4-acetamido-4'-isothiocyanato-2,2'-stilbenedisulfonic acid disodium, salt hydrate) blocked secretin-stimulated fluid accumulation in PCK but not in normal cysts. Our data suggest that hepatic cystogenesis in autosomal recessive polycystic kidney disease may involve increased fluid accumulation because of overexpression and abnormal location of AQP1, CFTR, and AE2 in cystic cholangiocytes. Therapeutic interventions that block the activation of these proteins might inhibit cyst expansion in polycystic liver disease. (Am J Pathol 2008,173:1637-1646; DOI: 10.2353/ajpath.2008.080125)