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.