Global gene expression profiling in PPAR-¿ agonist-treated kidneys in an orthologous rat model of human autosomal recessive polycystic kidney disease

Kidneys are enlarged by aberrant proliferation of tubule epithelial cells leading to the formation of numerous cysts, nephron loss, and interstitial fibrosis in polycystic kidney disease (PKD). Pioglitazone (PIO), a PPAR-¿ agonist, decreased cell proliferation, interstitial fibrosis and inflammation, and ameliorated PKD progression in PCK rats. To examine the genetic mechanisms in this efficacy, we analyzed changes in global gene expression. By Gene Set Enrichment Analysis of 30655 genes, 13 of the top 20 down-regulated gene ontology biological process gene sets, and six of the top 20 curated gene set canonical pathways identified to be down-regulated by PIO-treatment were related to cell cycle and proliferation, including EGF, PDGF and JNK pathways. Their relevant pathways were identified using the Kyoto Encyclopedia of Gene and Genomes database. Stearoyl-Coenzyme A desaturase 1 is a key enzyme in fatty acid metabolism found in the top 5 genes down-regulated by PIO treatment. Immunohistochemical analysis revealed that the gene product of this enzyme was highly expressed in PCK kidneys, and decreased by PIO. These data show that PIO alters the expression of genes involved in cell cycle progression, cell proliferation, and fatty acid metabolism.多囊肾病（polycystic kidney disease, PKD）的病理特征为肾小管上皮细胞异常增殖引发肾脏体积增大，进而形成大量囊肿，伴随肾单位丢失与间质纤维化。吡格列酮（Pioglitazone, PIO）作为过氧化物酶体增殖物激活受体γ（PPAR-γ）激动剂，可抑制PCK大鼠的细胞增殖、减轻间质纤维化与炎症反应，并延缓多囊肾病的疾病进展。为阐明该疗效的遗传调控机制，本研究对全局基因表达变化进行了分析。通过对30655个基因开展基因集富集分析（Gene Set Enrichment Analysis），经吡格列酮处理后下调的前20个基因本体（Gene Ontology, GO）生物学过程基因集中有13个，以及前20个经人工整理的经典通路基因集中有6个，均与细胞周期及细胞增殖密切相关，涵盖表皮生长因子（EGF）、血小板衍生生长因子（PDGF）及c-Jun氨基末端激酶（JNK）通路。研究人员借助京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）数据库，对上述相关通路进行了鉴定。硬脂酰辅酶A去饱和酶1（Stearoyl-Coenzyme A desaturase 1）是脂肪酸代谢的关键酶，位列经吡格列酮处理后下调的前5个基因之一。免疫组化分析结果显示，该酶的基因产物在PCK大鼠肾脏中呈高表达状态，经吡格列酮处理后其表达水平显著下调。上述实验数据表明，吡格列酮可调控参与细胞周期进程、细胞增殖及脂肪酸代谢的相关基因的表达。