Xu Yuexian, Li Guoxiang, Liu Wanqing, Ge Defeng, Hao Zongyao, Wang Wei
Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230001, Anhui, China.
Institute of Urology, Anhui Medical University, Hefei, 230001, Anhui, China.
Urolithiasis. 2025 Mar 4;53(1):44. doi: 10.1007/s00240-025-01716-1.
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.
肾结石作为最常见的泌尿系统疾病之一正日益受到关注。在本研究中，我们首先通过腹腔注射乙醛酸（Gly）构建了草酸钙（CaOx）晶体沉积的小鼠模型，并通过RNA测序发现，在模型组小鼠的肾脏中，构成NLRP3炎性小体的NLRP3、CASP1和ASC的水平及其下游产物IL-1β的水平均升高。然后，我们通过免疫组织化学、免疫荧光、qPCR和蛋白质免疫印迹法检测了人类样本、一水合草酸钙（COM）刺激的HK2细胞以及腹腔注射草酸钙晶体沉积模型中的NLRP3表达。接着，我们构建了全身性NLRP3基因敲除小鼠，并通过RNA测序发现，敲除NLRP3后，CaOx晶体诱导的肾纤维化和晶体黏附可能会减弱。我们通过在体外和NLRP3基因敲除小鼠中敲低NLRP3进一步证实了这些发现。同样，我们观察到，在体外和体内过表达NLRP3时，草酸钙晶体诱导的肾纤维化更明显，晶体黏附增强。最终，我们使用NLRP3抑制剂MCC950来支持NLRP3作为治疗靶点的潜力。我们的研究表明，NLRP3通过减轻肾纤维化和减少CaOx晶体诱导的晶体黏附，在肾结石形成中起关键作用。
