Abstract
Peritoneal dialysis (PD) is an effective renal replacement therapy, but a significant proportion of patients suffer PD-related complications, which limit the treatment duration. Mesothelial-to-mesenchymal transition (MMT) contributes to the PD-related peritoneal dysfunction. We analyzed the genetic reprograming of MMT to identify new biomarkers that may be tested in PD-patients. Microarray analysis revealed a partial overlapping between MMT induced in vitro and ex vivo in effluent-derived mesothelial cells, and that MMT is mainly a repression process being higher the number of genes that are down-regulated than those that are induced. Cellular morphology and number of altered genes showed that MMT ex vivo could be subdivided into two stages: early/epithelioid and advanced/non-epithelioid. RT-PCR array analysis demonstrated that a number of genes differentially expressed in effluent-derived non-epithelioid cells also showed significant differential expression when comparing standard versus low-GDP PD fluids. Thrombospondin-1 (TSP1), collagen-13 (COL13), vascular endothelial growth factor A (VEGFA), and gremlin-1 (GREM1) were measured in PD effluents, and except GREM1, showed significant differences between early and advanced stages of MMT, and their expression was associated with a high peritoneal transport status. The results establish a proof of concept about the feasibility of measuring MMT-associated secreted protein levels as potential biomarkers in PD.
Highlights
Peritoneal dialysis (PD) is an effective and cost-efficient alternative to hemodialysis in the treatment of end stage renal disease[1], covering approximately 10 to 15% of the dialysis population[2]
To screen novel biomarkers associated with peritoneal membrane failure, we analyzed the changes of gene expression profile along the mesenchymal transition (MMT) process by microarray analysis
The global microarray analysis showed a progressive reprogramming along the ex vivo MMT process, being higher the number of changed genes in cells with NE phenotype
Summary
Peritoneal dialysis (PD) is an effective and cost-efficient alternative to hemodialysis in the treatment of end stage renal disease[1], covering approximately 10 to 15% of the dialysis population[2]. One possibility to reduce the adverse effects of both classical and novel PD fluids on the peritoneum is by decreasing the dwell time of the dialysate[17,18] Another alternative approach to preserve the peritoneal membrane could be the use of pharmacological agents protecting the mesothelium or targeting inflammation and fibrosis[7,19]. It was described that ex vivo cultures of effluent MCs showed two main morphologies: epithelioid and non-epithelioid (fibroblast-like)[22] These morphological changes as well as the down-regulation of epithelial molecules (cytokeratin and E-cadherin) and the induction of mesenchymal markers (snail, N-cadherin, fibronectin, collagen I, α-smooth-muscle actin (α-SMA), and fibroblast specific protein-1 (FSP-1)) were described to be indicative of a mesenchymal conversion[7,21,22]. By using whole genome microarray analysis of MCs undergoing MMT in vitro and ex vivo, we aimed to identify novel molecular biomarkers that may facilitate diagnosis of the integrity and functionality of the patient’s peritoneum and allow early adaption of treatment to the patient’s needs
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