Systems biology approach to identify transcriptional reprogramming and microRNA targets during the progression of Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cyst formation throughout the kidney parenchyma. It is caused by mutations in either of two genes, PKD1 and PKD2. Mice that lack functional Pkd1 (Pkd1null/null), develop rapidly progressive cystic disease during embryogenesis, and serve as a model to study human ADPKD. We examined the molecular pathways that modulate renal cyst growth in the Pkd1null/null model by performing global gene-expression profiling in embryonic kidneys at day 14 and 17. Gene Ontology and gene set enrichment analysis were used to identify over represented signaling pathways in Pkd1null/null kidneys. We found dysregulation of developmental, metabolic, and signaling pathways (e.g. Wnt, calcium, TGF-b and MAPK) in Pkd1null/null kidneys. Total RNA were obtained from kidneys of wild-type and Pkd1null/null animals at embryonic ages 14.5 and 17.5.常染色体显性遗传性多囊肾病（Autosomal dominant polycystic kidney disease, ADPKD）以全肾实质形成囊肿为特征。该疾病由PKD1与PKD2两个基因中的任意一个发生突变所导致。缺失功能性Pkd1基因的小鼠（Pkd1null/null）在胚胎发育过程中会出现快速进展的囊性肾病，可作为研究人类ADPKD的动物模型。本研究通过对胚胎第14天和第17天的肾脏开展全基因表达谱分析，探究了调控Pkd1null/null模型中肾囊肿生长的分子通路。我们采用基因本体（Gene Ontology）分析与基因集富集分析，鉴定出Pkd1null/null肾脏中显著富集的信号通路。研究发现Pkd1null/null肾脏内发育、代谢及信号通路（如Wnt、钙信号、转化生长因子-β（TGF-β）和丝裂原活化蛋白激酶（Mitogen-activated protein kinase, MAPK)）存在失调情况。本研究从胚胎发育14.5天和17.5天的野生型与Pkd1null/null小鼠肾脏中提取了总RNA。