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Enhanced mPGES-1 Contributes to PD-Related Peritoneal Fibrosis via Activation of the NLRP3 Inflammasome
Qimei Luo1, Qinghua Hu1, Qingkun Zheng1
1Department of Nephrology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China.
Abstract:
Background: Microsomal prostaglandin E synthase-1 (mPGES-1)-derived prostaglandin E2 (PGE2) is a chief mediator of inflammation. However, the role and mechanism of mPGES-1 in peritoneal dialysis (PD)-associated peritoneal fibrosis have not been investigated. Material and Methods: In PD patients, mPGES-1 expression in peritoneum tissues and the levels of PGE2, IL-1β, and IL-18 in the dialysate were examined. In rat peritoneal mesothelial cells (RPMCs), the regulation and function of mPGES-1 and NLRP3 inflammasome were investigated. The expression of extracellular matrix proteins and the components of NLRP3 inflammasome were detected by Western blotting or real-time quantitative PCR. Results: In PD patients with ultrafiltration failure (UFF), mPGES-1 was enhanced in the peritoneum, which was associated with the degree of peritoneal fibrosis. Accordingly, the intraperitoneal PGE2 levels were also positively related to the PD duration, serum C-reactive protein levels, and serum creatinine levels in incident PD patients. In RPMCs, high-glucose treatment significantly induced mPGES-1 expression and PGE2 secretion without affecting the expressions of mPGES-2 and cPGES. Inhibition of mPGES-1 via short hairpin RNA significantly ameliorated the expression of extracellular matrix proteins of RPMCs induced by high glucose. Additionally, high glucose markedly activated NLRP3 inflammasome in RPMCs that was blunted by mPGES-1 inhibition. Furthermore, silencing NLRP3 with siRNA significantly abrogated the expression of extracellular matrix proteins in RPMCs treated with high glucose. Finally, we observed increased IL-1β and IL-18 levels in the dialysate of incident PD patients, showing a positive correlation with PGE2. Conclusion: These data demonstrate that mPGES-1-derived PGE2 plays a critical role in PD-associated peritoneal fibrosis through activation of the NLRP3 inflammasome. Targeting mPGES-1 may offer a novel strategy to treat peritoneal fibrosis during PD.
Insights
Microsomal prostaglandin E synthase-1 (mPGES-1) drives peritoneal fibrosis in patients undergoing peritoneal dialysis (PD). Inhibiting mPGES-1 reduces fibrosis by blocking NLRP3 inflammasome activation, offering a new therapeutic target for PD patients.
Area of Science:
- Renal Medicine
- Inflammation Research
- Cell Biology
Background:
- Microsomal prostaglandin E synthase-1 (mPGES-1) produces prostaglandin E2 (PGE2), a key inflammatory mediator.
- The role of mPGES-1 in peritoneal dialysis (PD)-associated peritoneal fibrosis remains uninvestigated.
- Peritoneal fibrosis is a serious complication of PD, leading to ultrafiltration failure (UFF).
Purpose of the Study:
- To investigate the role and mechanism of mPGES-1 in PD-associated peritoneal fibrosis.
- To examine the relationship between mPGES-1 expression, PGE2 levels, and peritoneal fibrosis in PD patients.
- To elucidate the signaling pathway involving mPGES-1 and NLRP3 inflammasome in high-glucose-induced peritoneal fibrosis.
Main Methods:
- Assessed mPGES-1 expression and PGE2, IL-1β, IL-18 levels in PD patient peritoneum and dialysate.
- Utilized rat peritoneal mesothelial cells (RPMCs) to study mPGES-1 and NLRP3 inflammasome regulation.
- Employed techniques like Western blotting, qPCR, short hairpin RNA (shRNA), and small interfering RNA (siRNA) for molecular analysis.
Main Results:
- Elevated mPGES-1 and PGE2 levels in PD patients correlated with peritoneal fibrosis and PD duration.
- High glucose induced mPGES-1 expression and PGE2 secretion in RPMCs, promoting extracellular matrix protein synthesis.
- mPGES-1 inhibition and NLRP3 inflammasome silencing significantly reduced high glucose-induced peritoneal fibrosis markers.
Conclusions:
- mPGES-1-derived PGE2 critically contributes to PD-associated peritoneal fibrosis via NLRP3 inflammasome activation.
- Targeting mPGES-1 presents a potential novel therapeutic strategy for treating peritoneal fibrosis in PD patients.
- Increased IL-1β and IL-18 levels in dialysate suggest inflammasome activation in PD patients.
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