Abstract
Peritoneal fibrosis is recognised as the main cause of the technical failure of peritoneal dialysis (PD), and currently, there are no specific and effective anti-fibrosis therapies. We have found that miR-200a is down-regulated in a rat model of PD-related peritoneal fibrosis (PF) and could inhibit transforming growth factor beta 1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) in peritoneal mesothelial cells by target ZEB1/2. However, its treatment role in vivo is still largely unclear. In this study, we examined the therapeutic potential for miR-200a on PD-related PF in a rat model of PD induced by daily infusion of 4.25% dextrose-containing dialysate. Male Sprague–Dawley rats were divided into four groups: control group, PD group, PD + miR-agomir-NC group, and PD + miR-200a-agomir group (n = 5 in each group). MiR-200a agomir was delivered into the peritoneum by intra-peritoneal injection on days 10 and 20 after PD. We found that treatment with miR-200a agomir significantly reduced the collagen volume fraction (CVF) of the peritoneum and prevented peritoneal dysfunction. The up-regulation of the EMT marker (decreased E-cadherin and increased α-smooth muscle actin) and extracellular matrix (fibronectin and collagen I) was significantly ameliorated by miR-200a in the PD + miR-200a-agomir group. Furthermore, we demonstrated that miR-200a inhibition of PF in vivo was associated with the suppression of ZEB1 and 2, which were proved to be the target of miR-200a in our previous study. In conclusion, results from the present study suggest that treatment with miR-200a may represent a novel and effective therapy for PD-related PF.
Highlights
Peritoneal dialysis (PD) is a major renal replacement therapy for patients with end-stage renal disease [1, 2]
We found that miR-200a was downregulated in the PD rat model with peritoneal fibrosis (PF)
TGF-β1induced epithelial-to-mesenchymal transition (EMT) was associated with down-regulation of miR-200a but up-regulation of ZEB1/2 in human peritoneal mesothelial cells
Summary
Peritoneal dialysis (PD) is a major renal replacement therapy for patients with end-stage renal disease [1, 2]. Long-term exposure to a bioincompatible dialysate containing a high glucose concentration and peritonitis, which can result in peritoneal fibrosis (PF), impairing peritoneal function and leading to system failure [3]. Some patients develop encapsulating peritoneal sclerosis, a rare condition. The pivotal role of epithelial-to-mesenchymal transition (EMT) in the pathogenesis of PD-related PF has been well demonstrated [5, 6]. Emerging evidence shows that highglucose conditions of dialysate and inflammation factors elevate the expression of transforming growth factor beta 1 (TGF-β1), which is the main factor controlling fibrosis in all organs. TGF-β1 binds its receptor on the cell membrane and triggers the activation of Snail, Slug, and ZEB1-2, which play a role in repressing E-cadherin expression and inducing EMT [7,8,9,10]. Targeting its downstream-related gene(s) may represent a better approach for the treatment of PF
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