Renal and biliary abnormalities in a new murine model of autosomal recessive polycystic kidney disease

Abstract

Current models of autosomal recessive polycystic kidney disease (ARPKD) fail to demonstrate biliary abnormalities in association with renal cysts. We therefore studied a new murine model of ARPKD in which dual renal tubular and biliary epithelial abnormalities are present. Affected homozygous animals typically die 1 month postnatally in renal failure with progressively enlarged kidneys. Renal cysts shift in site from inner cortical proximal tubules at birth to collecting tubules 20 days later, as determined by segment-specific lectin binding. Increased numbers of mitosis were demonstrated in proximal and collecting tubular cysts. In addition, epithelial hyperplasia was demonstrated morphometrically in the intra- and extrahepatic biliary tract of affected animals. The number of intrahepatic biliary epithelial cells was increased by 50% on postnatal day 5 and by 100% on postnatal day 25 (P < 0.01). Despite an increased frequency of "chaotic" portal areas in mice with renal cysts, no intrahepatic cysts or shape abnormalities of the biliary lumen were detected using biliary casts and morphometry. Additionally there was nonobstructive hyperplastic dilatation of the extrahepatic biliary tract which was linked in all animals to the presence of renal cysts. The hyperplastic abnormalities in both renal and biliary epithelium make this new mouse strain a good model for the study of the dual organ cellular pathophysiology of ARPKD.

Congenital Cystic Disease of the Liver and Kidney in a Pygmy Goat

“…The literature contains reports of polycystic disorders in African gazelles, cats, dogs, mice, pigs, and, most recently, a 3.5-week-old Nubian goat. 4,6,8,[10][11][12][13][14] The present case has a clinical and pathologic presentation similar to 1 case described previously in a Nubian goat kid, but, in contrast, there were both gross and histologic lesions in the kidney and liver and the pancreas was unaffected.…”

“…14 The mode of inheritance has not been documented for many animal species although it is autosomal recessive in one Balb/c mouse mutant and was recently reported to be autosomal recessive in two litters of West Highland white terriers. 10,11,14 Cystic disease was suspected in four juvenile Nubian goats over a 5-year period in the herd with the documented case, but necropsy examinations were not performed to confirm this suspicion. 8 The goat described in this case report was from a primiparous doe and was born with a twin that died from unknown causes at birth.…”

Candidate Gene Associated with a Mutation Causing Recessive Polycystic Kidney Disease in Mice

“…The recessive cpk (congenital polycystic kidneys) mutation (8) has been examined in considerable detail (9,10). More recently, additional spontaneous recessive mutations in micebpk (BALB/c polycystic kidneys) (11), pcy (polycystic kidneys) (12), and jck (juvenile cystic kidneys) (13)-have been reported. The cystic disease that develops in the cpk, bpk, and jck models shows similarities to clinical features of human ARPKD, but the dual hepatorenal pathology that is a hallmark of ARPKD has been reported as a consistent feature only in the bpk mouse (11).…”

“…More recently, additional spontaneous recessive mutations in micebpk (BALB/c polycystic kidneys) (11), pcy (polycystic kidneys) (12), and jck (juvenile cystic kidneys) (13)-have been reported. The cystic disease that develops in the cpk, bpk, and jck models shows similarities to clinical features of human ARPKD, but the dual hepatorenal pathology that is a hallmark of ARPKD has been reported as a consistent feature only in the bpk mouse (11). The cpk locus has been mapped to a region of mouse chromosome 12 with homology to human chromosome 2p24-2p25 (14), and the pcy locus to a region of mouse chromosome 9 homologous to human chromosome 3 (12).…”

Screening and Identification of Mouse <I>Bicc1</I> RNAi

“…小鼠的 Bicc1 基因定位于 10 号染色体的 C1 区 域，其蛋白质 N 端含有 KH 结构域，用于介导蛋白 质与 RNA 的相互作用；C 端的 SAM 结构域则在蛋 白质与蛋白质相互结合中发挥作用 (Michele et al, 1995;Wessely et al, 2001;Bouvrette et al, 2008;Schultz et al, 1997)。目前已发现 3 种与 Bicc1 基因 相关的小鼠突变体模型--jcpk、bpk 和 67Gso，这 些小鼠突变体中 Bicc1 基因在不同位点发生突变， 产生异常的蛋白质产物，结果导致小鼠肾脏发生胞 囊化，并且影响身体其他器官的正常形态及功能， 病 理 表 型 特 征 与 人 类 的 多 囊 肾 病 极 为 相 似 (Cogswell et al, 2003;Chittenden et al, 2002)。因此， Bicc1 小鼠突变体模型已经成为研究人类多囊肾病 的重要工具。研究表明，Bicc1 突变体会导致纤毛 形成异常以及胞囊的形成，因而推测 Bicc1 可能是 负责维持表皮细胞动态平衡的信号通路的成分之 一 Nauta et al, 1993)。本文部分研 究希望能够找到 Bicc1 基因的有效 RNAi 序列，通 过 RNAi 诱发的基因沉默现象来建立 Bicc1 低表达 的稳定细胞株，从而通过研究这些细胞形态结构以 及功能的变化来揭示 Bicc1 基因对于细胞正常生长 增殖的必要性，以及缺失该蛋白后细胞出现的异常 变化。 RNA 干扰（RNA interference, RNAi）是指在进 化过程中高度保守的、 由双链 RNA （double-stranded RNA，dsRNA）诱发的基因沉默现象。当细胞中导 入与内源性 mRNA 编码区同源的双链 RNA 时，该 mRNA 发生降解而导致基因表达水平下降 (Tuschl et al, 2002;Srensen et al, 2003) …”