Rapamycin inhibits peritoneal fibrosis by modifying lipid homeostasis in the peritoneum.

Peritoneal fibrosis (PF) is characterized by progressive accumulation of extracellular matrix (ECM) components in the peritoneum under high glucose conditions. Rapamycin has previously been shown to inhibit ECM accumulation of peritoneal mesothelial cells (PMCs) and prevent PF. Here we explored the undefined mechanisms by which rapamycin inhibits ECM accumulation of PMCs. We used high-glucose peritoneal dialysis solution (PDS) in a mouse peritoneal dialysis model to induce in vivo PF and in human PMCs in vitro to stimulate ECM accumulation. The mice that received chronic PDS infusions showed typical features of PF, including markedly increased peritoneal thickness, excessive matrix deposition, increased peritoneal permeability, and higher expressions of α-smooth muscle actin and collagen I. Rapamycin significantly ameliorated these pathological changes. There was a parallel decrease in lipid accumulation in the peritoneum of rapamycin-treated mice. Rapamycin significantly inhibited high-glucose PDS-induced ECM accumulation and reduced the lipid droplet in human PMCs in the presence of PDS. The effects of rapamycin on intracellular lipid metabolism correlated with a series of steps in lipid homeostasis; namely, a decrease in low density lipoprotein receptor-mediated lipid influx, which was mediated through the downregulation of sterol regulatory element-binding protein-2 (SREBP-2) and SREBP cleavage-activating protein (SCAP), and an increase in adenosine triphosphate-binding cassette transporter A1-mediated lipid efflux, which was mediated through the upregulation of the liver X receptor α and peroxisome proliferator-activated receptor α. We conclude that rapamycin shows a clear protective effect on high-glucose PDS-induced PF by improving the disruption of intracellular lipid homeostasis.