Impact of Low Glucose Degradation Product Bicarbonate/Lactate-Buffered Dialysis Solution on the Epithelial-Mesenchymal Transition of Peritoneum

Abstract

Background: Epithelial-mesenchymal transition (EMT) is important in the development of peritoneal fibrosis. Glucose degradation products (GDPs) may induce EMT in human peritoneal mesothelial cells (HPMCs). Methods: The effects of individual GDPs and GDPs derived from peritoneal dialysis fluid (PDF) in both HPMCs and peritoneal membranes were evaluated. EMT was assessed with α-smooth muscle actin (α-SMA) and E-cadherin. Results: In vitro, α-SMA protein and mRNA levels increased in the presence of the GDPs (formaldehyde, glyoxal, methylglyoxal, and 3-deoxyglucosone), and E-cadherin decreased. Changes in the EMT markers were most prominent after exposure to 3-deoxyglucosone. Changes in both α-SMA and E-cadherin protein levels were less with low (L)-GDP bicarbonate/lactate-buffered PDF compared to high (H)-GDP PDF. In the rat model after 8 weeks’ PDF infusion, the α-SMA/E-cadherin mRNA ratio increased in the H-GDP group compared with the L-GDP group (p < 0.05). The peritoneum in the H-GDP group tended to be thicker (p = 0.052) and had more blood vessels than that in the L-GDP group (p < 0.05). Tissue staining for TGF-β1 decreased in the L-GDP group. Dual-stained cytokeratin and α-SMA-positive myofibroblasts in the submesothelial layer were more prominent in the H-GDP group. Conclusion: GDPs found in PDF induce EMT of HPMCs, which is associated with peritoneal fibrosis and vascularization. Conversely, L-GDP PDF reduces EMT and peritoneal fibrosis.

Influence of Bicarbonate/Low-GDP Peritoneal Dialysis Fluid (Bicavera) on in Vitro and Ex Vivo Epithelial-to-Mesenchymal Transition of Mesothelial Cells

“…In agreement with our results, a recent report showed that various GDPs present in standard PD fluids can induce EMT of MCs in vitro and that low-GDP fluids have less impact on peritoneal fibrosis and EMT in vivo in a rat model (27). All of those results accord with results obtained in several patient series, including the present report (16,17).…”

MiR-30b is involved in methylglyoxal-induced epithelial-mesenchymal transition of peritoneal mesothelial cells in rats

“…Glucose degradation products (GDPs), such as methylglyoxal (MGO) and glyoxal, are generated from the degradation of glucose during heat sterilization and storage [3]. MGO is an extremely toxic GDP that may cause peritoneal injury during the epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMC) [4,5]. EMT is a dynamic process in which epithelial cells undergo a phenotypic conversion that gives rise to a fibroblastoid appearance.…”

Human Peritoneal Mesothelial Cell Death Induced by High-Glucose Hypertonic Solution Involves Ca2+ and Na+ Ions and Oxidative Stress with the Participation of PKC/NOX2 and PI3K/Akt Pathways

“…Often, GDP are generated as a consequence of heat sterilizing peritoneal dialysis (PD) fluids. GDP triggers the formation of advanced glycation end-products in the peritoneal cavity, as well as producing extensive cytotoxicity and cell transformation by means of a poorly understood mechanism (Witowski and Jörres, 2000; Schwenger, 2005; Oh et al, 2010; Pischetsrieder and Gensberger, 2012). …”