KCa3.1 potassium channels are critical for cAMP-dependent chloride secretion and cyst growth in autosomal-dominant polycystic kidney disease
KCa3.1 potassium channels are critical for cAMP-dependent chloride secretion and cyst growth in autosomal-dominant polycystic kidney disease
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DOI：
10.1038/ki.2008.246
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发表时间：
2008-09-01
影响因子：
19.6
通讯作者：
Skolnik, Edward Y.
中科院分区：
文献类型：
--
作者：
Albaqumi, Mamdouh;Srivastava, Shekhar;Skolnik, Edward Y.
常染色体显性遗传性多囊肾病（ADPKD）的特征是大量充满液体的肾囊肿。肾囊肿的净液体分泌是由顶端囊性纤维化跨膜传导调节剂氯离子通道介导的跨上皮转运引起的，这导致囊肿扩大。在这里，我们发现，毛喉素，一种有效的腺苷酸环化酶激动剂，刺激阴离子分泌的单层肾细胞来自患者的ADPKD。TRAM-34是一种特异性KCa 3.1钾通道阻滞剂，可抑制该电流，并抑制体外胶原凝胶内培养的细胞形成囊肿和扩大。净氯化物分泌增强KCa3.1激活剂DCEBIO和氯化物分泌和体外囊肿生长抑制过表达的肌微管蛋白相关蛋白-6，磷酸酶，特异性抑制KCa3.1通道活性。我们的研究表明，KCa3.1通道在跨细胞氯分泌和净液体运输到ADPKD患者的肾囊肿中发挥关键作用，通过维持通过顶端氯通道的氯流出的电化学驱动力。KCa3.1通道的药理学抑制剂可能为ADPKD患者延迟进展为肾衰竭提供一种新的有效治疗方法。
Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by numerous fluid-filled kidney cysts. Net fluid secretion into renal cysts is caused by transepithelial transport mediated by the apical cystic fibrosis transmembrane conductance regulator chloride channel, which leads to cyst enlargement. Here we found that forskolin, a potent adenylyl cyclase agonist, stimulated anion secretion by monolayers of kidney cells derived from patients with ADPKD. TRAM-34, a specific KCa3.1 potassium channel blocker, inhibited this current, and in vitro cyst formation and enlargement by the cells cultured within a collagen gel. Net chloride secretion was enhanced by the KCa3.1 activator DCEBIO and both chloride secretion and in vitro cyst growth were inhibited by overexpression of myotubularin-related protein-6, a phosphatase that specifically inhibits KCa3.1 channel activity. Our study suggests that KCa3.1 channels play a critical role in transcellular chloride secretion and net fluid transport into the kidney cysts of patients with ADPKD by maintaining the electrochemical driving force for chloride efflux through apical chloride channels. Pharmacological inhibitors of KCa3.1 channels may provide a novel and effective therapy to delay progression to kidney failure in patients with ADPKD.