Shi Yingfeng, Hu Yan, Li Jinqing, Chen Hui, Zhong Qin, Ma Xiaoyan, Li Xialin, Zhang Shasha, Zhuang Shougang, Liu Na
Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, 02902, USA.
Small. 2025 Apr;21(14):e2409362. doi: 10.1002/smll.202409362. Epub 2025 Feb 28.
Pyroptosis, belonging to programmed cell death, is shown to be mediated by gasdermin D (GSDMD) and gains more and more attention in innate immunity and multiple diseases. However, the role of GSDMD-mediated pyroptosis in peritoneal fibrosis (PF) remains unclear. This study observed NLRP3 inflammasome activation and pyroptosis in the peritoneum of long-term peritoneal dialysis (PD) patients with PF. Moreover, it is found that high glucose (HG) can induce the activation of NLRP3 inflammasome by regulating TLR4/NF-κB and JNK/p38 MAPK signaling in human peritoneal mesothelial cells (HPMCs), leading to subsequent Caspase-1 activation. The cleaved Caspase-1 promoted pyroptosis-related transmembrane pore formation through activating GSDMD-N, and stimulated the HPMCs to secrete inflammatory factors including IL-1β and IL-18. GSDMD global deletion or pharmacologic pretreatment with Caspase-1 specific inhibitor VX-765 effectively inhibited the pyroptosis and inflammation, thereby ameliorating PF. Additionally, treatment with VX-765 and transfected with Caspase-1 siRNA or GSDMD siRNA also inhibited the transmembrane pore formation and inflammatory factors secretion in HG-induced HPMCs. Consistent with these results, delayed treatment with VX-765 also alleviated PF, indicating the therapeutic effect of VX-765. Taken together, the results demonstrate that pyroptosis may be a novel therapeutic target for peritoneal fibrosis.
细胞焦亡属于程序性细胞死亡，已被证明由gasdermin D（GSDMD）介导，在固有免疫和多种疾病中受到越来越多的关注。然而，GSDMD介导的细胞焦亡在腹膜纤维化（PF）中的作用仍不清楚。本研究观察了长期腹膜透析（PD）合并PF患者腹膜中NLRP3炎性小体的激活和细胞焦亡情况。此外，研究发现高糖（HG）可通过调节人腹膜间皮细胞（HPMCs）中的TLR4/NF-κB和JNK/p38 MAPK信号通路诱导NLRP3炎性小体激活，进而导致Caspase-1激活。裂解的Caspase-1通过激活GSDMD-N促进细胞焦亡相关跨膜孔的形成，并刺激HPMCs分泌包括IL-1β和IL-18在内的炎性因子。GSDMD基因完全缺失或用Caspase-1特异性抑制剂VX-765进行药物预处理可有效抑制细胞焦亡和炎症，从而改善PF。此外，用VX-765处理并转染Caspase-1 siRNA或GSDMD siRNA也可抑制HG诱导的HPMCs中的跨膜孔形成和炎性因子分泌。与这些结果一致，VX-765延迟治疗也可减轻PF，表明VX-765具有治疗作用。综上所述，这些结果表明细胞焦亡可能是腹膜纤维化的一个新的治疗靶点。
