Role of genetic modifiers in an orthologous rat model of ARPKD.
Role of genetic modifiers in an orthologous rat model of ARPKD.
复制标题
遗传修饰剂在 ARPKD 直系同源大鼠模型中的作用。
DOI：
10.1152/physiolgenomics.00187.2011
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发表时间：
2012
影响因子：
4.6
通讯作者：
Moreno,Carol
中科院分区：
文献类型：
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作者：
O'Meara,CaitlinC;Hoffman,Matthew;SweeneyJr,WilliamE;Tsaih,Shirng-Wern;Xiao,Bing;Jacob,HowardJ;Avner,EllisD;Moreno,Carol
常染色体隐性遗传性多囊肾病（ARPKD）的人类数据和动物模型表明，遗传因素调节疾病的发作和严重程度。我们在此首次报道，通过将多囊肾（PCK）大鼠突变的Pkhd 1疾病等位基因渗入FHH（Fawn-Hooded Hypertensive）遗传背景，ARPKD易感性减弱。与PCK相比，FHH.Pkhd1菌株的肾囊肿形成显著减少，与平均肾脏重量减少3倍一致。进一步的分析表明，FHH.Pkhd1可以保护血压升高以及血浆肌酐和血尿素氮水平升高。另一方面，肝脏重量和胆汁囊肿形成显示PCK和FHH之间没有差异。Pkdh 1，表明FHH遗传背景内的基因阻止ARPKD的肾脏而非肝脏表现的发展。对30日龄PCK大鼠肾脏的微阵列表达分析显示，先前在PKD肾脏表达谱中鉴定的基因表达增加，例如炎症反应、细胞外基质合成和细胞增殖基因等，而FHH. Pkhd 1未显示这些常见疾病标志物的激活。这种新开发的菌株可以作为ARPKD肾脏疾病修饰基因图谱的工具，并为疾病变异性和病理生理学提供进一步的见解。
Human data and animal models of autosomal recessive polycystic kidney disease (ARPKD) suggest that genetic factors modulate the onset and severity of the disease. We report here for the first time that ARPKD susceptibility is attenuated by introgressing the mutatedPkhd1disease allele from the polycystic kidney (PCK) rat onto the FHH (Fawn-Hooded Hypertensive) genetic background. Compared with PCK, the FHH.Pkhd1strain had significantly decreased renal cyst formation that coincided with a threefold reduction in mean kidney weights. Further analysis revealed that the FHH.Pkhd1is protected from increased blood pressure as well as elevated plasma creatinine and blood urea nitrogen levels. On the other hand, liver weight and biliary cystogenesis revealed no differences between PCK and FHH.Pkdh1, indicating that genes within the FHH genetic background prevent the development of renal, but not hepatic, manifestations of ARPKD. Microarray expression analysis of kidneys from 30-day-old PCK rats revealed increased expression of genes previously identified in PKD renal expression profiles, such as inflammatory response, extracellular matrix synthesis, and cell proliferation genes among others, whereas the FHH.Pkhd1did not show activation of these common markers of disease. This newly developed strain can serve as a tool to map modifier genes for renal disease in ARPKD and provides further insight into disease variability and pathophysiology.