Abstract
BackgroundAutosomal dominant polycystic kidney disease (ADPKD), a common of monogenetic disorder caused by the polycystic kidney disease-1 (PKD1) or PKD2 genes deficiency. In this study, we have re-analyzed a microarray dataset to generate a holistic view of this disease.MethodologyGSE7869, an expression profiling dataset was downloaded from the Gene Expression Omnibus (GEO) database. After quality control assessment, using GEO2R tool of GEO, genes with adjusted p-value ≤ 0.05 were determined as differentially expressed (DE). The expression profiles from ADPKD samples in different sizes were compared. Using CluePedia plugin of Cytoscape software, the protein–protein interaction (PPI) networks were constructed and analyzed by Cytoscape NetworkAnalyzer tool and MCODE application. Pathway enrichment analysis of clustered genes by MCODE with the high centrality parameters in PPI networks was performed using Cytoscape ClueGO plugin. Moreover, by Enrichr database, microRNAs (miRNAs) and transcription factors (TFs) targeted DE genes were identified.ResultsIn this study to explore the molecular pathogenesis of kidney in ADPKD, mRNA expression profiles of cysts from patients in different sizes were re-analyzed. The comparisons were performed between normal with minimally cystic tissue (MCT) samples, MCTs with small cysts, and small cysts with large cysts. 512, 7024, and 655 DE genes were determined, respectively. The top central genes, e.g. END1, EGFR, and FOXO1 were identified with topology and clustering analysis. DE genes that were significantly enriched in PPI networks are critical genes and their roles in ADPKD remain to be assessed in future experimental studies beside miRNAs and TFs predicted. Furthermore, the functional analysis resulted in which most of them are expected to be associated with ADPKD pathogenesis, such as signal pathways that involved in cell growth, inflammation, and cell polarity.ConclusionWe have here explored systematic approaches for molecular mechanisms assay of ADPKD as a monogenic disease, which may also be used for other monogenetic diseases beside complex diseases to provide suitable therapeutic targets.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD), a common of monogenetic disorder caused by the polycystic kidney disease-1 (PKD1) or polycystic kidney disease-2 (PKD2) genes deficiency
differentially expressed (DE) genes that were significantly enriched in protein–protein interaction (PPI) networks are critical genes and their roles in ADPKD remain to be assessed in future experimental studies beside miRNAs and transcription factor (TF) predicted
The functional analysis resulted in which most of them are expected to be associated with ADPKD pathogenesis, such as signal pathways that involved in cell growth, inflammation, and cell polarity
Summary
Autosomal dominant polycystic kidney disease (ADPKD), a common of monogenetic disorder caused by the polycystic kidney disease-1 (PKD1) or PKD2 genes deficiency. ADPKD is genetically heterogeneous and results from mutations in at least two genes, Polycystic Kidney Disease-1 (PKD1) or PKD-2 [2] These genes encode transmembrane proteins, Polycystin-1 (PC-1) and Polycystin-2 (PC-2) which form a functional complex [3]. In spite of numerous studies related to polycystins functions, their roles are poorly understood Regarding this major limitation being sensible to recognize the underlying mechanisms, systems biology approaches with a holistic view of the molecular mechanisms of disorders, have the potential to overcome these limitations. For deeply understanding of central genes that related with phenotypes of disease in each step, network and clustering analysis were carried out. These revealed some of the key genes, such as EDN1, EGFR, ARF6, FOXO1, and ITGB5 involved during disease. For the purpose of assay the regulatory mechanisms of DE genes, microRNAs (miRNAs) and transcription factors (TFs) enriched with DE genes were predicted
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