Luo Qimei, Hu Qinghua, Zheng Qingkun, Gong Lewei, Su Lijuan, Ren Baojun, Ju Yongle, Jia Zhanjun, Dou Xianrui
Department of Nephrology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China.
Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China.
Front Med (Lausanne). 2021 May 18;8:675363. doi: 10.3389/fmed.2021.675363. eCollection 2021.
Microsomal prostaglandin E synthase-1 (mPGES-1)-derived prostaglandin E (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. 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. 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. 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.
微粒体前列腺素E合酶-1（mPGES-1）衍生的前列腺素E（PGE2）是炎症的主要介质。然而，mPGES-1在腹膜透析（PD）相关腹膜纤维化中的作用和机制尚未得到研究。在PD患者中，检测了腹膜组织中mPGES-1的表达以及透析液中PGE2、IL-1β和IL-18的水平。在大鼠腹膜间皮细胞（RPMCs）中，研究了mPGES-1和NLRP3炎性小体的调节及功能。通过蛋白质免疫印迹法或实时定量PCR检测细胞外基质蛋白的表达及NLRP3炎性小体的成分。在超滤失败（UFF）的PD患者中，腹膜中mPGES-1增强，这与腹膜纤维化程度相关。相应地，新发PD患者的腹腔内PGE2水平也与PD病程、血清C反应蛋白水平和血清肌酐水平呈正相关。在RPMCs中，高糖处理显著诱导mPGES-1表达和PGE2分泌，而不影响mPGES-2和胞质型前列腺素E合酶（cPGES）的表达。通过短发夹RNA抑制mPGES-1可显著改善高糖诱导的RPMCs细胞外基质蛋白的表达。此外，高糖显著激活RPMCs中的NLRP3炎性小体，而mPGES-1抑制可使其减弱。此外，用小干扰RNA（siRNA）沉默NLRP3可显著消除高糖处理的RPMCs中细胞外基质蛋白的表达。最后，我们观察到新发PD患者透析液中IL-1β和IL-18水平升高，与PGE2呈正相关。这些数据表明，mPGES-1衍生的PGE2通过激活NLRP3炎性小体在PD相关腹膜纤维化中起关键作用。靶向mPGES-1可能为治疗PD期间的腹膜纤维化提供一种新策略。
