抑制 NLRP3 可减轻草酸钙晶体诱导的肾纤维化和晶体粘附。

IF 2 2区 医学 Q2 UROLOGY & NEPHROLOGY
Yuexian Xu, Guoxiang Li, Wanqing Liu, Defeng Ge, Zongyao Hao, Wei Wang
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引用次数: 0

摘要

肾结石作为泌尿系统最常见的疾病之一,越来越受到人们的关注。在本研究中,我们首先通过腹腔注射乙草酸盐(Gly)构建了小鼠草酸钙(CaOx)晶体沉积模型,发现通过RNA-seq检测,模型组小鼠肾脏中构成NLRP3炎性体的NLRP3、CASP1和ASC及其下游产物IL-1β水平升高。然后,我们通过免疫组织化学、免疫荧光、qPCR和Western blotting检测了人类样本、草酸钙一水(COM)刺激的HK2细胞和通过腹腔注射草酸钙晶体沉积模型中NLRP3的表达。然后,我们构建了系统性NLRP3敲除小鼠,通过RNA-seq发现,敲除NLRP3后,CaOx晶体诱导的肾纤维化和晶体粘连可能减弱。我们通过在体外和NLRP3敲除小鼠中敲除NLRP3进一步证实了这些发现。与此一致的是,我们在体外和体内观察到草酸钙晶体诱导的肾纤维化更加明显,NLRP3过表达后晶体粘附增强。最终,我们利用NLRP3抑制剂MCC950来支持NLRP3作为治疗靶点的潜力。我们的研究发现NLRP3通过减轻CaOx晶体诱导的肾纤维化和晶体粘附在肾结石形成中起关键作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhibition of NLRP3 alleviates calcium oxalate crystal-induced renal fibrosis and crystal adhesion.

Kidney stones are gaining attention as one of the most common urological diseases. In this study, we first constructed a mouse model of calcium oxalate (CaOx) crystal deposition by intraperitoneal injection of glyoxalate (Gly) and found that the levels of NLRP3, CASP1 and ASC, which constitute the NLRP3 inflammasome, as well as the level of its downstream product, IL-1β, were elevated in the kidneys of the model group of mice, as determined by RNA-seq. We then examined NLRP3 expression via immunohistochemistry, immunofluorescence, qPCR, and Western blotting in human samples, calcium oxalate monohydrate (COM)-stimulated HK2 cells, and a model of calcium oxalate crystal deposition via intraperitoneal injection. We then constructed systemic NLRP3 knockout mice and found via RNA-seq that CaOx crystal-induced renal fibrosis and crystal adhesion may be attenuated after the knockout of NLRP3. We further substantiated these findings by knocking down NLRP3 both in vitro and in NLRP3-knockout mice. Consistently, we observed more pronounced calcium oxalate crystal-induced renal fibrosis and enhanced crystal adhesion upon overexpression of NLRP3 in vitro and in vivo. Ultimately, we utilized the NLRP3 inhibitor MCC950 to support the potential of NLRP3 as a therapeutic target. Our research revealed that NLRP3 plays a pivotal role in kidney stone formation by mitigating renal fibrosis and reducing crystal adhesion induced by CaOx crystals.

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来源期刊
Urolithiasis
Urolithiasis UROLOGY & NEPHROLOGY-
CiteScore
4.50
自引率
6.50%
发文量
74
期刊介绍: Official Journal of the International Urolithiasis Society The journal aims to publish original articles in the fields of clinical and experimental investigation only within the sphere of urolithiasis and its related areas of research. The journal covers all aspects of urolithiasis research including the diagnosis, epidemiology, pathogenesis, genetics, clinical biochemistry, open and non-invasive surgical intervention, nephrological investigation, chemistry and prophylaxis of the disorder. The Editor welcomes contributions on topics of interest to urologists, nephrologists, radiologists, clinical biochemists, epidemiologists, nutritionists, basic scientists and nurses working in that field. Contributions may be submitted as full-length articles or as rapid communications in the form of Letters to the Editor. Articles should be original and should contain important new findings from carefully conducted studies designed to produce statistically significant data. Please note that we no longer publish articles classified as Case Reports. Editorials and review articles may be published by invitation from the Editorial Board. All submissions are peer-reviewed. Through an electronic system for the submission and review of manuscripts, the Editor and Associate Editors aim to make publication accessible as quickly as possible to a large number of readers throughout the world.
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