NLRP3 Inflammasome-Mediated Pyroptosis in Diabetic Nephropathy: Pathogenic Mechanisms and Therapeutic Targets.

IF 4.2 2区 医学 Q2 IMMUNOLOGY
Journal of Inflammation Research Pub Date : 2025-06-25 eCollection Date: 2025-01-01 DOI:10.2147/JIR.S524246
Yichao Chen, Riqiu Chen, Xiaozhen Ji, Zhifu Zeng, Changrong Guan
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Abstract

Diabetic nephropathy (DN) is a prevalent microangiopathic manifestation of diabetes mellitus (DM) and a pathological sequela of chronic glycemic disorders, characterized by several pathological features including glomerulosclerosis, podocyte loss, tubular epithelial atrophy and abnormal extracellular matrix accumulation. A growing body of research has underscored that chronic inflammatory microenvironments play a central role in the progression of DN. Pyroptosis, a newly defined form of programmed inflammatory necrosis, operates through the following molecular mechanism: inflammasome activation, gasdermin D (GSDMD)-mediated plasma membrane perforation and pro-inflammatory mediator release. Pyroptosis is triggered by the activation of the NOD-like receptor 3 (NLRP3) inflammasome. Classical (caspase-1) or non-classical (caspase-4/5/11) pathways activate pyroptosis by cleaving GSDMD, inducing enzymatic fragmentation of the GSDMD protein. GSDMD-N-terminal domain oligomerizes to form transmembrane pores, which further disrupt cellular osmotic homeostasis as well as membrane integrity. Inflammatory cascades are triggered when IL-1 and IL-18 are released as a result of subsequent cell lysis. This review systematically elucidates the pathobiological interplay between pyroptosis regulatory networks and the pathogenesis of DN and summarizes potential therapeutic compounds that mitigate pyroptosis by inhibiting NLRP3 inflammasome activation or blocking GSDMD pore formation. Preclinical studies suggest that targeting pyroptosis-related signaling molecules including NLRP3, caspase-1 and GSDMD may alleviate renal injury by suppressing inflammation-driven fibrosis and ameliorating glomerular dysfunction. Current studies emphasize that regulating pyroptosis mechanisms could slow DN progression, providing novel insights into the development of nephroprotective strategies.

NLRP3炎症小体介导的糖尿病肾病焦亡:致病机制和治疗靶点。
糖尿病肾病(DN)是糖尿病(DM)的一种常见微血管病变表现,是慢性血糖紊乱的病理后遗症,以肾小球硬化、足细胞丧失、小管上皮萎缩和细胞外基质异常积累等病理特征为特征。越来越多的研究强调慢性炎症微环境在DN的进展中起着核心作用。焦亡是一种新定义的程序性炎症坏死形式,其分子机制包括:炎性小体激活、气皮蛋白D (GSDMD)介导的质膜穿孔和促炎介质释放。焦亡是由nod样受体3 (NLRP3)炎性体的激活引发的。经典(caspase-1)或非经典(caspase-4/5/11)途径通过切割GSDMD激活焦亡,诱导GSDMD蛋白的酶促断裂。gsdmd - n末端结构域寡聚形成跨膜孔,进一步破坏细胞渗透稳态和膜完整性。当IL-1和IL-18因随后的细胞裂解而释放时,炎症级联反应被触发。本文系统阐述了焦亡调节网络与DN发病机制之间的病理生物学相互作用,并总结了通过抑制NLRP3炎性体激活或阻断GSDMD孔形成来减轻焦亡的潜在治疗化合物。临床前研究表明,靶向NLRP3、caspase-1和GSDMD等与焦热相关的信号分子可通过抑制炎症性纤维化和改善肾小球功能障碍来减轻肾损伤。目前的研究强调,调节焦亡机制可以减缓DN的进展,为肾保护策略的发展提供新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Inflammation Research
Journal of Inflammation Research Immunology and Microbiology-Immunology
CiteScore
6.10
自引率
2.20%
发文量
658
审稿时长
16 weeks
期刊介绍: An international, peer-reviewed, open access, online journal that welcomes laboratory and clinical findings on the molecular basis, cell biology and pharmacology of inflammation.
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