Williams B M, Cliff C L, Lee K, Squires P E, Hills C E
School of Life Sciences, University of Lincoln, Lincoln, United Kingdom.
Lincoln County Hospital, Lincoln, United Kingdom.
Front Physiol. 2022 Jun 9;13:907504. doi: 10.3389/fphys.2022.907504. eCollection 2022.
The NOD-like receptor protein 3 (NLRP3) inflammasome is a multi-protein signalling complex integral to the chronic inflammatory response, activated in response to sterile and non-sterile cellular damage. The assembly and activation of the NLRP3 inflammasome comprise a two-step process involving nuclear factor kappa B (NFkB)-mediated priming, followed by canonical, non-canonical or alternative signalling pathways. These result in the maturation and release of inflammatory cytokines interleukin 1 beta (IL1ß) and interleukin-18 (IL18), which are associated with chronic inflammatory conditions including diabetic kidney disease. Diabetic nephropathy is a condition affecting ∼40% of people with diabetes, the key underlying pathology of which is tubulointerstitial inflammation and fibrosis. There is growing evidence to suggest the involvement of the NLRP3 inflammasome in this chronic inflammation. Early deterioration of kidney function begins in the glomerulus, with tubular inflammation dictating the progression of late-stage disease. Priming and activation of the NLRP3 inflammasome have been linked to several clinical markers of nephropathy including proteinuria and albuminuria, in addition to morphological changes including mesangial expansion. Treatment options for diabetic nephropathy are limited, and research that examines the impact of directly targeting the NLRP3 inflammasome, or associated downstream components are beginning to gain favour, with several agents currently in clinical trials. This review will explore a role for NLRP3 inflammasome activation and signalling in mediating inflammation in diabetic nephropathy, specifically in the glomerulus and proximal tubule, before briefly describing the current position of therapeutic research in this field.
NOD样受体蛋白3（NLRP3）炎性小体是慢性炎症反应不可或缺的多蛋白信号复合物，可响应无菌和非无菌性细胞损伤而被激活。NLRP3炎性小体的组装和激活包括两步过程，涉及核因子κB（NFκB）介导的启动，随后是经典、非经典或替代信号通路。这些导致炎性细胞因子白细胞介素1β（IL1β）和白细胞介素-18（IL18）的成熟和释放，它们与包括糖尿病肾病在内的慢性炎症性疾病相关。糖尿病肾病是一种影响约40%糖尿病患者的疾病，其关键的潜在病理是肾小管间质炎症和纤维化。越来越多的证据表明NLRP3炎性小体参与了这种慢性炎症。肾功能的早期恶化始于肾小球，肾小管炎症决定了晚期疾病的进展。NLRP3炎性小体的启动和激活除了与包括系膜扩张在内的形态学变化有关外，还与肾病的几个临床标志物有关，如蛋白尿和白蛋白尿。糖尿病肾病的治疗选择有限，研究直接靶向NLRP3炎性小体或相关下游成分的影响开始受到青睐，目前有几种药物正在进行临床试验。本综述将探讨NLRP3炎性小体激活和信号传导在介导糖尿病肾病炎症中的作用，特别是在肾小球和近端小管中的作用，然后简要描述该领域治疗研究的现状。
