Abstract
Long-term peritoneal dialysis is associated with progressive fibrosis of the peritoneum. Epithelial-mesenchymal transition (EMT) of mesothelial cells is an important mechanism involved in peritoneal fibrosis, and TGF-β1 is considered central in this process. However, targeting currently known TGF-β1-associated pathways has not proven effective to date. Therefore, there are still gaps in understanding the mechanisms underlying TGF-β1-associated EMT and peritoneal fibrosis. We conducted network-based integrated analysis of transcriptomic and proteomic data to systemically characterize the molecular signature of TGF-β1-stimulated human peritoneal mesothelial cells (HPMCs). To increase the power of the data, multiple expression datasets of TGF-β1-stimulated human cells were employed, and extended based on a human functional gene network. Dense network sub-modules enriched with differentially expressed genes by TGF-β1 stimulation were prioritized and genes of interest were selected for functional analysis in HPMCs. Through integrated analysis, ECM constituents and oxidative stress-related genes were shown to be the top-ranked genes as expected. Among top-ranked sub-modules, TNFAIP6, ZC3H12A, and NNT were validated in HPMCs to be involved in regulation of E-cadherin, ZO-1, fibronectin, and αSMA expression. The present data shows the validity of network-based integrated analysis in discovery of novel players in TGF-β1-induced EMT in peritoneal mesothelial cells, which may serve as new prognostic markers and therapeutic targets for peritoneal dialysis patients.
Highlights
Peritoneal dialysis (PD) is an important renal replacement therapy in end-stage renal disease[1,2]
The peritoneal membrane is composed of a monolayer of mesothelial cells, and a key role in the induction of peritoneal fibrosis during exposure to PD fluids is played by epithelial to mesenchymal transition (EMT) of the mesothelial cells (MCs), named more properly mesothelial to mesenchymal transition (MMT)[6]
The most significant Gene ontology (GO) molecular function (MF) term overrepresented by up-regulated genes was extracellular matrix (ECM) structural constituent, which plays a central role in EMT (Fig. 1A)
Summary
Peritoneal dialysis (PD) is an important renal replacement therapy in end-stage renal disease[1,2]. Previous studies have reported that TGF-β1 levels in PD fluids correlate with deterioration of peritoneal membrane in dialysis patients and that TGF-β1 blocking peptides preserve the peritoneal membrane from PD fluid-induced damage in mice[10,12] Based on these findings, blockade of TGF-β1 has been regarded as an attractive therapeutic target for treatment of peritoneal fibrosis. In this study we conducted microarray- and proteomics-based differential expression analysis of genes and proteins to characterize the molecular signature of TGF-β1-stimulated human peritoneal mesothelial cells (HPMCs). Under the assumption that essential biological modules responsible for TGF-β1-mediated EMT and fibrosis would be represented as core network modules of integrated datasets, gene co-expression profiles were utilized to construct a functional gene network (EMT-network) and dense network clusters were extracted by topological analysis. To provide a causal link of the candidate genes with EMT in peritoneal cells, we evaluated the effect of genetic modulation of the target genes on TGF-β1-regulated epithelial and mesenchymal markers in HPMCs
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