XIST Promote Calcium Oxalate Nephrocalcinosis Induced Renal Inflammatory and Oxidative Injury Via miR-223-NLRP3 Pathway

Abstract

Background: The function of lncRNA X‐inactive specific transcript (XIST) in many diseases, including cancers and inflammatory sickness, has been elucidated in previous papers. But for renal calculus, it remains poorly understood. In this study, we revealed the potential effects of XIST on kidney stones via inflammatory response and oxidative stress. Method: We established a glyoxylate-induced calcium oxalate (CaOx) stone mouse model and exposed HK-2 cells to calcium oxalate monohydrate (COM). The interactions among XIST, miR-223 and NOD‐like receptor protein 3 (NLRP3) and respective effect were studied via the analysis of RNAs and protein expressions, luciferase activity, and immunohistochemistry (IHC). Necrosis and reactive oxygen species (ROS) generation were detected after XIST silence, miR-223 activation and inhibition or both of XIST knock-down and miR-223 activation in vitro and in vivo. Finding: The levels of XIST, NLRP3, Caspase-1 and IL-1β were notably increased in the kidney samples from the glyoxylate-induced CaOx stone mouse model. XIST knockdown significantly suppressed the inflammatory damage and ROS production, and further attenuated kidney stones formation. MiRNA-223 mimics also exerted the same effects. Moreover, we verified the interactions among XIST, miRNA-223 and NLRP3 and the subsequent effects. Interpretation: Our results suggested that lncRNA XIST participated in the formation and progression of renal calculus via interplaying with miR-223 and the NLRP3/Caspase-1/IL-1β pathway to mediate inflammatory response and ROS production. Funding: This study was supported by National Natural Science Foundation of China (8167031233). Declaration of Interest: The authors declare that they have no competing conflicts of interest. Ethical Approval: The animal study was approved by the Ethics Committee of Tongji Hospital.