Gattone V H, MacNaughton K A, Kraybill A L
Department of Anatomy & Cell Biology, Kansas University Kidney and Urological Research Center, Kansas City 66160-7400, USA.
Anat Rec. 1996 Jul;245(3):488-99. doi: 10.1002/(SICI)1097-0185(199607)245:3<488::AID-AR5>3.0.CO;2-O.
Autosomal recessive (AR) polycystic kidney disease (PKD) is characterized in humans and mice as a rapidly progressive, collecting duct cystic disease usually leading to uremia in the neonatal or infantile period. In humans, ARPKD renal pathology can be variable in severity and is associated with the development of prominent bile duct and liver pathology. The C57BL/6J-cpk/cpk mouse model of ARPKD is the most extensively studied murine model of inherited infantile PKD; however, these mice lack extrarenal pathology.
In the present study, the cpk gene was backbreed onto CD1 mice to examine the development of cpk-induced ARPKD in this outbred mouse background. Resulting cystic offspring were examined morphologically and their serum urea nitrogen levels were assessed.
The rapid development of PKD in CD1 mice homozygous for the cpk gene appears to be slightly more rapid but otherwise comparable to that seen in inbred C57BL/6J mice. In CD1-cpk/cpk mice, the principal renal pathological finding is collecting duct cysts, which are lined by a relatively uniform epithelium. This epithelium appears to be relatively undifferentiated based on almost total absence of intercalated cells. Proximal tubule cysts are prominent in the first postnatal week while collecting duct cysts predominate in the later stages of the disease. Extrarenal manifestations of the cpk gene are evident in the CD1 strain and include cysts of pancreatic, common bile, and major hepatic ducts. Intrahepatic bile ducts also have focal dilations. Primary (thymus) and secondary (spleen) lymphoid tissues become hypoplastic as azotemia progresses. The strain-related variability in renal and liver changes in cpk-induced ARPKD may reflect the influence of other genes (possibly modifier genes) expressed in this mouse strain. In older CD1-cpk/+ mice, renal (proximal tubular) cysts and prominent liver cysts (lined by a biliary epithelium) develop, indicating that the heterozygous state (cpk/+ genotype) causes renal and hepatic pathology.
The cpk gene, when placed on an appropriate mouse strain background, causes multiorgan disease that more closely mimics human ARPKD than when the cpk gene is expressed on the C57BL/6J strain. A gene dose effect is present as cystic pathology is present in kidney and liver of both suckling homozygous (cpk/cpk) and old heterozygous (cpk/+) mice.
常染色体隐性（AR）多囊肾病（PKD）在人类和小鼠中表现为一种快速进展的集合管囊性疾病，通常在新生儿期或婴儿期导致尿毒症。在人类中，ARPKD的肾脏病理严重程度可变，且与显著的胆管和肝脏病理发展相关。ARPKD的C57BL/6J-cpk/cpk小鼠模型是研究最广泛的遗传性婴儿PKD小鼠模型；然而，这些小鼠缺乏肾外病理表现。
在本研究中，将cpk基因回交至CD1小鼠，以研究在这种远交小鼠背景下cpk诱导的ARPKD的发展。对产生的囊性后代进行形态学检查，并评估其血清尿素氮水平。
纯合cpk基因的CD1小鼠中PKD的快速发展似乎稍快一些，但在其他方面与近交C57BL/6J小鼠中所见相似。在CD1-cpk/cpk小鼠中，主要的肾脏病理发现是集合管囊肿，其内衬相对均匀的上皮细胞。基于几乎完全没有闰细胞，这种上皮细胞似乎相对未分化。近端肾小管囊肿在出生后第一周很突出，而集合管囊肿在疾病后期占主导。cpk基因的肾外表现在CD1品系中很明显，包括胰腺、胆总管和主要肝管的囊肿。肝内胆管也有局灶性扩张。随着氮质血症进展，初级（胸腺）和次级（脾脏）淋巴组织发育不全。cpk诱导的ARPKD中肾脏和肝脏变化的品系相关变异性可能反映了该小鼠品系中表达的其他基因（可能是修饰基因）的影响。在年龄较大的CD1-cpk/+小鼠中，会出现肾脏（近端肾小管）囊肿和明显的肝囊肿（内衬胆管上皮），表明杂合状态（cpk/+基因型）会导致肾脏和肝脏病理。
当cpk基因置于合适的小鼠品系背景时，会导致多器官疾病，与cpk基因在C57BL/6J品系中表达时相比，更接近人类ARPKD。存在基因剂量效应，因为在哺乳纯合子（cpk/cpk）和老年杂合子（cpk/+）小鼠的肾脏和肝脏中都存在囊性病理。
