摘要
Urinary stone is conceptualized as a chronic metabolic disorder punctuated by symptomatic stone events.It has been shown that the occurrence of calcium oxalate monohydrate(COM)during stone formation is regulated by crystal growth modifiers.Although crystallization inhibitors have been recognized as a therapeutic modality for decades,limited progress has been made in the discovery of effective modifiers to intervene with stone disease.In this study,we have used metabolomics technologies,a powerful approach to identify biomarkers by screening the urine components of the dynamic progression in a bladder stone model.By in-depth mining and analysis of metabolomics data,we have screened five differential metabolites.Through density functional theory studies and bulk crystallization,we found that three of them(salicyluric,gentisic acid and succinate)could effectively inhibit nucleation in vitro.We thereby assessed the impact of the inhibitors with an EG-induced rat model for kidney stones.Notably,succinate,a key player in the tricarboxylic acid cycle,could decrease kidney calcium deposition and injury in the model.Transcriptomic analysis further showed that the protective effect of succinate was mainly through anti-inflammation,inhibition of cell adhesion and osteogenic differentiation.These findings indicated that succinate may provide a new therapeutic option for urinary stones.
基金
This study has been jointly sponsored by the National Natural Science Foundation of China(Grant No.32171351)
the“1.3.5”Project for Disciplines of Excellence,West China Hospital,Sichuan University(Grant No.ZYJC18002)
Med-X Innovation Program of Med-X Center for Materials,Sichuan University(Grant No.MCM202104)
the Project funded by China Postdoctoral Science Foundation(2022M722277)
the Sichuan University postdoctoral interdisciplinary Innovation Fund.We thank Ms.Lei Wu and Bo Su from Histology and Imaging Platform,Core Facilities of West China,Sichuan University,Mr.Yun-fei Tian and Shu-guang Yan from the Analytical&Testing Center of Sichuan University,Sichuan University,and Ms.Nian-guo Zhu from Institute of Respiratory Health,West China Hospital,Sichuan University for the technique supports.We thank Xi-jing Yang and Xiao-ting Chen form the Animal Experimental Center of West China Hospital for assistance in animal experiments.
