Abstract
Epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMC) is a major contributor to the pathogenesis of peritoneal fibrosis. EMT is at least in part caused by repeated exposure to glucose degradation products (GDPs), such as methylglyoxal (MGO). MiRNA contributes greatly to the EMT of PMCs. In this study, we tried to profile whether differences exist between the peritoneal membrane (PM) miRNA expression seen in control rats and that seen in rats injected intraperitoneally with MGO. We assessed whether miR-30b has a possible role in MGO-induced EMT of PMCs in rats. Comparative miRNA expression array and real-time PCR analyses were conducted for the control group at the start of the experiment and for the MGO group after 1 and 2 weeks. During the second week, the MGO rats were treated with: a chemically modified antisense RNA oligonucleotide (ASO) complementary to the mature miR-30b (ASO group); an miR-30b mismatch control sequence (MIS group); or a citrate buffer (EMT group). Bioinformatic analyses indicated that the 3′ untranslated region (3′-UTR) of bone morphogenetic protein 7 (BMP7) mRNA did contain a putative binding site for miR-30b. We also tried to investigate whether miR-30b targeted BMP7 in vitro by transfection. Of the upregulated miRNAs, miR-30b expression demonstrated the greatest increase. The administration of miR-30b ASO for two weeks significantly reduced α-SMA excretion and upregulated E-cadherin and BMP-7 expression. Our in vitro study showed that miR-30b directly targeted and inhibited BMP7 by binding to its 3’-UTR. Our results revealed that miR-30b is involved in MGO-induced EMT of PMCs in rats.
Highlights
Peritoneal dialysis (PD) is a blood-purifying treatment for patients with endstage renal disease (ESRD)
To explore the functional roles of miRNAs that might correlate with epithelial-mesenchymal transition (EMT) in peritoneal mesothelial cells (PMC), we profiled the differences in peritoneal miRNA expression between rats injected with MGO and control rats
To determine the possible role of miR-30b in the EMT of PMCs, we focused on miR-30b antisense RNA oligonucleotide (ASO) for further study by intraperitoneal injection in MGO-treated rats
Summary
Peritoneal dialysis (PD) is a blood-purifying treatment for patients with endstage renal disease (ESRD). MGO is an extremely toxic GDP that may cause peritoneal injury during the epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMC) [4, 5]. The transformed cells, which express α-smooth muscle actin (α-SMA), possess a mesenchymal phenotype and the increased ability to proliferate, migrate and synthesize extracellular matrix while they lose epithelial markers [6]. Previous research showed that MGO may induce peritoneal fibrous thickening with the proliferation of mesenchymal-like mesothelial cells, which may be transdifferentiated from PMCs by EMT [13]. We hypothesize that miRNA expression patterns might serve as a signature of the EMT of PMCs in rats after intraperitoneal injections of MGO. We investigated whether miR-30b is involved in MGO-induced EMT of PMCs in rats and expected to find novel insights into the mechanisms underlying peritoneal fibrosis in terms of miRNA
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