Role of CFTR in autosomal recessive polycystic kidney disease
Role of CFTR in autosomal recessive polycystic kidney disease
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DOI：
10.1681/asn.v124719
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发表时间：
2001-04-01
影响因子：
13.6
通讯作者：
Avner, ED
中科院分区：
文献类型：
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作者：
Nakanishi, K;Sweeney, WE;Avner, ED
大量的体外数据表明，上皮氯分泌通过囊性纤维化跨膜传导调节因子（CFTR）蛋白介导，在MDCK细胞和人常染色体显性多囊肾病（ADPKD）中产生或维持充满液体的囊肿。相反，很少有研究涉及常染色体隐性遗传性多囊肾病（ARPKD）囊肿形成和扩大中液体分泌的病理生理学。特定基因的靶向破坏或缺失的鼠类模型为研究个体基因产物在正常发育和/或疾病病理生理学中的作用创造了机会。缺乏功能性CFTR蛋白的CF小鼠模型的建立提供了确定体内肾囊肿形成是否需要CFTR活性的机会。因此，本研究试图确定是否可以通过用CFTR敲除小鼠对ARPKD的BPK小鼠模型进行遗传互补来预防肾囊肿形成。这项研究的结果表明，在囊性基因（bpk）纯合的动物中，囊性上皮顶端表面缺乏功能性CFTR蛋白不能防止囊肿生长和随后的肾功能下降。双突变小鼠（bpk -/-; cftr -/-）出现了巨大的肾脏肿大，平均比囊性非CF小鼠（bpk -/-; cftr +/+/-）早7天死亡。这表明与ADPKD相比，ARPKD动物模型中经前庭液体分泌机制存在根本差异。
An extensive body of in vitro data implicates epithelial chloride secretion, mediated through cystic fibrosis transmembrane conductance regulator (CFTR) protein, in generating or maintaining fluid filled cysts in MDCK cells and in human autosomal dominant polycystic kidney disease (ADPKD). In contrast, few studies have addressed the pathophysiology of fluid secretion in cyst formation and enlargement in autosomal recessive polycystic kidney disease (ARPKD). Murine models of targeted disruptions or deletions of specific genes have created opportunities to examine the role of individual gene products in normal development and/or disease pathophysiology. The creation of a murine model of CF, which lacks functional CFTR protein, provides the opportunity to determine whether CFTR activity is required for renal cyst formation in vivo. Therefore, this study sought to determine whether renal cyst formation could be prevented by genetic complementation of the BPK murine model of ARPKD with the CFTR knockout mouse. The results of this study reveal that in animals that are homozygous for the cystic gene (bpk), the lack of functional CFTR protein on the apical surface of cystic epithelium does not provide protection against cyst growth and subsequent decline in renal function. Double mutant mice (bpk -/-; cftr -/-) developed massively enlarged kidneys and died, on average, 7 d earlier than cystic, non-CF mice (bpk -/-; cftr +/+/-). This suggests fundamental differences in the mechanisms of transtubular fluid secretion in animal models of ARPKD compared with ADPKD.