Inflammatory responses in the peritoneum contribute to
peritoneal dialysis (PD)-associated
peritoneal fibrosis. Results of our previous study showed that increased microsomal
prostaglandin E synthase-1-mediated production of
prostaglandin E2 (
PGE2) contributed to
peritoneal fibrosis. However, the role of its downstream receptor in the progression of
peritoneal fibrosis has not been established. Here, we examined the role of
PGE2 receptor 4 (EP4) in the development of
peritoneal fibrosis. EP4 was significantly upregulated in peritoneal tissues of PD patients with ultrafiltration failure, along with the presence of an enhanced inflammatory response. In vitro experiments showed that exposure to high
glucose concentrations enhanced EP4 expression in rat peritoneal mesothelial cells (RPMCs). High-
glucose-induced expression of inflammatory
cytokines (
monocyte chemoattractant protein-1, tumour
necrosis factor α, and
interleukin 1β) was significantly reduced in RPMCs treated with
ONO-AE3-208, an EP4 receptor antagonist.
ONO-AE3-208 also significantly decreased the expression of
extracellular matrix proteins induced by high
glucose concentrations. Furthermore,
ONO-AE3-208 blunted activation of the NLR family pyrin domain containing 3 (NLRP3)
inflammasome and phosphorylation of
nuclear factor kappa B (NF-κB) (p-p65). To further investigate the functional role of EP4,
ONO-AE3-208 was administrated for 4 weeks in a rat model of PD, the results of which showed that
ONO-AE3-208 inhibited
peritoneal fibrosis and improved peritoneal dysfunction. Additionally, inflammatory
cytokines in the peritoneum of PD rats treated with
ONO-AE3-208 were downregulated, in line with inhibition of the NLRP3
inflammasome and NF-κB phosphorylation. In conclusion, an EP4 antagonist reduced the development of
peritoneal fibrosis, possibly by suppressing NLRP3
inflammasome- and p-p65-mediated inflammatory responses. Our findings suggest that an EP4 antagonist may be therapeutically beneficial for PD-associated
peritoneal fibrosis.