Abstract
Phenotype transition of peritoneum is an early mechanism of peritoneal fibrosis. Metformin, 5′-adenosine monophosphate-activated protein kinase (AMPK) activator, has recently received a new attention due to its preventive effect on organ fibrosis and cancer metastasis by inhibiting epithelial-to-mesenchymal transition (EMT). We investigated the effect of metformin on EMT of human peritoneal mesothelial cells (HPMC) and animal model of peritoneal dialysis (PD). TGF-β1-induced EMT in HPMC was ameliorated by metformin. Metformin alleviated NAPDH oxidase- and mitochondria-mediated ROS production with an increase in superoxide dismutase (SOD) activity and SOD2 expression. Metformin inhibited the activation of Smad2/3 and MAPK, GSK-3β phosphorylation, nuclear translocalization of β-catenin and Snail in HPMCs. Effect of metformin on TGF-β1-induced EMT was ameliorated by either AMPK inhibitor or AMPK gene silencing. Another AMPK agonist, 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide partially blocked TGF-β1-induced EMT. In animal model of PD, intraperitoneal metformin decreased the peritoneal thickness and EMT with an increase in ratio of reduced to oxidized glutathione and the expression of SOD whereas it decreased the expression of nitrotyrosine and 8-hydroxy-2′-deoxyguanosine. Therefore, a modulation of AMPK in peritoneum can be a novel tool to prevent peritoneal fibrosis by providing a favorable oxidant/anti-oxidant milieu in peritoneal cavity and ameliorating phenotype transition of peritoneal mesothelial cells.
Highlights
Tubular cells and breast cancer cells[15, 16], and alleviated hepatic and cardiac fibrosis by blocking TGF-β signaling pathway via AMPK-dependent manner[17, 18]
Inhibition of p38 MAPK (SB203589, 10 μM) or ERK1/2 MAPK (PD98059, 10 μM) alleviated epithelial-to-mesenchymal transition (EMT) of human peritoneal mesothelial cells (HPMC) exposed to TGF-β1 (Supplementary Fig. 1C)
The mRNA expression of matrix metalloproteinase (MMP)-7, a representative down-stream target gene of β-catenin/T-cell factor (TCF) signaling in HPMCs, was up-regulated by TGF-β1 (2.8-fold increase, 24 hours, N = 6), which was blocked by metformin (Fig. 4B)
Summary
Tubular cells and breast cancer cells[15, 16], and alleviated hepatic and cardiac fibrosis by blocking TGF-β signaling pathway via AMPK-dependent manner[17, 18]. Effect of metformin on peritoneal fibrosis was examined in animal model of peritoneal dialysis. Metformin decreased both NADPH oxidase (NOX)-mediated and mitochondrial ROS generation, and alleviated EMT and peritoneal thickening via AMPK-independent and -dependent mechanism. This data suggest the potential therapeutic use of metformin or other AMPK agonists for the prevention and/or treatment peritoneal fibrosis
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