LAUSR

Peritoneal fibrosis (PF) is characterized by progressive extracellular matrix (ECM) accumulation. Increasing evidence has suggested that ECM synthesis was increased in human peritoneal mesothelial cells (HPMCs) under high-glucose conditions, but the effects of high-glucose peritoneal dialysis solution (PDS) on ECM synthesis have not been fully elucidated. The aim of this study was to explore the potential mechanisms of high-glucose PDS-induced production of ECM in HPMCs. HPMCs were stimulated by high-glucose PDS. The activity of mammalian target of rapamycin complex 1 (mTORC1) was inhibited by rapamycin or regulatory-associated protein of mTOR (raptor) siRNA. Morphological changes in the cells were observed under an inverted microscope. Oil red O, filipin staining and high-performance liquid chromatography were used to examine lipid accumulation. The expression of low-density lipoprotein receptor (LDLr) regulation, the mTORC1 pathway and ECM-associated markers were assessed by real-time polymerase chain reaction and western blot analysis. The results showed that after treatment with PDS, HPMCs showed notable elongation consistent with the morphology of myofibroblasts, and the expression of ECM proteins such as α-smooth muscle actin, fibroblast specific protein-1 and collagen I was increased. In addition, there was a parallel increase in the ECM and lipid accumulation. Moreover, the effect of intracellular lipid deposition was closely correlated with the dysregulation of LDLr, which was mediated through the upregulation of LDLr, sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), and SREBP-2 and through the enhanced coexpression of the SCAP with the Golgin. Further analysis showed that PDS enhanced the protein phosphorylation of mTOR, eukaryotic initiation factor 4E-binding protein 1, and p70 S6 kinase. Interestingly, blocking mTORC1 activity reversed the dysregulation of LDLr, even in the presence of PDS. These effects were also accompanied by a decrease in the expression of ECM components. Our findings demonstrated that increased mTORC1 activity exacerbated ECM formation in HPMCs by disrupting LDLr regulation, which contributed to lipid disorder-mediated PF.