A mouse model of autosomal recessive polycystic kidney disease with biliary duct and proximal tubule dilatation
A mouse model of autosomal recessive polycystic kidney disease with biliary duct and proximal tubule dilatation
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DOI：
10.1038/sj.ki.5002294
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发表时间：
2007-08-01
影响因子：
19.6
通讯作者：
Ward, C. J.
中科院分区：
文献类型：
--
作者：
Woollard, J. R.;Punyashtiti, R.;Ward, C. J.
常染色体隐性遗传性多囊肾病（ARPKD）是由多囊肾和肝病（PKHD 1）基因突变引起的，该基因编码纤维囊蛋白/多导管蛋白。本研究的目的是建立一种没有功能性纤维囊蛋白/多导管蛋白的ARPKD小鼠模型，以研究肾脏和非肾脏组织中囊性和纤维囊性疾病的病理生理学。该基因的外显子2被删除，并用侧翼为IoxP位点的新霉素抗性盒取代，该位点随后可以通过Cre-Iox重组酶去除。纯合子Pkhd 1（del 2/del 2）小鼠存活，可生育，并表现出肝脏，胰腺和肾脏异常。胆道表型显示进行性胆管扩张，导致所有动物的肝脏严重囊性和纤维化。这些突变小鼠的胆管中的初级纤毛具有结构异常，并且比野生型（WT）动物的初级纤毛显著短。Pkhd 1（del 2/del 2）小鼠经常出现胰腺囊肿，有些表现出胰腺肿大。在受影响的雌性小鼠的肾脏中，从约9月龄开始，近端小管（PT）的S3段出现肾小管扩张，而雄性小鼠的肾脏正常至18月龄。将突变近交到BALBc/J或C57 BL/6 J背景小鼠上导致雌性在3月龄时发生PT扩张。这些近交系小鼠将为研究ARPKD的发病机制提供有用的资源。
Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the polycystic kidney and hepatic disease (PKHD1) gene encoding the protein fibrocystin/polyductin. The aim of our study was to produce a mouse model of ARPKD in which there was no functional fibrocystin/polyductin to study the pathophysiology of cystic and fibrocystic disease in renal and non-renal tissues. Exon 2 of the gene was deleted and replaced with a neomycin resistance cassette flanked by IoxP sites, which could be subsequently removed by Cre-Iox recombinase. Homozygous Pkhd1(del2/del2) mice were viable, fertile and exhibited hepatic, pancreatic, and renal abnormalities. The biliary phenotype displayed progressive bile duct dilatation, resulting in grossly cystic and fibrotic livers in all animals. The primary cilia in the bile ducts of these mutant mice had structural abnormalities and were significantly shorter than those of wild-type (WT) animals. The Pkhd1(del2/del2) mice often developed pancreatic cysts and some exhibited gross pancreatic enlargement. In the kidneys of affected female mice, there was tubular dilatation of the S3 segment of the proximal tubule (PT) starting at about 9 months of age, whereas male mice had normal kidneys up to 18 months of age. Inbreeding the mutation onto BALBc/J or C57BL/6J background mice resulted in females developing PT dilatation by 3 months of age. These inbred mice will be useful resources for studying the mechanisms underlying the pathogenesis of ARPKD.