Cyclooxygenase-2 mediates dialysate-induced alterations of the peritoneal membrane

Area of Science:

• Nephrology
• Cell Biology
• Inflammation Research

Background:

• Peritoneal dialysis (PD) involves exposing the peritoneal membrane to nonphysiologic solutions, causing inflammation and dysfunction.
• Mesothelial cells (MCs) can undergo epithelial-to-mesenchymal transition (EMT) to myofibroblasts, increasing peritoneal transport.
• Cyclooxygenase-2 (COX-2) is an enzyme induced by inflammation, potentially playing a role in PD-related peritoneal membrane damage.

Purpose of the Study:

• To investigate the role of COX-2 in peritoneal membrane deterioration during PD.
• To assess the therapeutic potential of COX-2 inhibition in mitigating PD-induced peritoneal damage.

Main Methods:

• Analysis of COX-2 levels in different MC phenotypes from peritoneal effluent.
• Correlation of MC phenotype and COX-2 levels with creatinine transport.
• In vitro studies on MCs to evaluate COX-2's role in EMT.
• In vivo studies using a mouse model of PD, treated with Celecoxib (a COX-2 inhibitor) or standard/low-glucose degradation product PD fluids.

Main Results:

• Nonepithelioid MCs in peritoneal effluent showed higher COX-2 expression than epithelioid MCs.
• COX-2 levels correlated with MC phenotype and creatinine transport.
• While COX-2 was upregulated during EMT in vitro, its inhibition did not prevent EMT.
• In mice, Celecoxib treatment reduced fibrosis, improved ultrafiltration, and decreased inflammatory cells.
• Low-glucose degradation product PD fluid reduced EMT and COX-2 induction, preserving peritoneal membrane integrity.

Conclusions:

• Upregulation of COX-2 during EMT may mediate peritoneal inflammation in PD.
• COX-2 inhibition presents a potential therapeutic strategy to ameliorate peritoneal membrane deterioration in PD patients.
• Optimizing PD fluid composition, specifically reducing glucose degradation products, can mitigate EMT and COX-2 induction.