雄激素通过AR-miR-182-TXNRD1/GLRX2/CYB561途径促进维生素C诱导肾草酸钙结石形成的机制研究

尿石症发病率男性高于女性，前期荟萃分析证实维生素C补充与男性肾结石形成显著相关，而与女性无相关性，提示雄激素可能在结石形成中具有重要作用。我们前期实验表明:在小鼠肾草酸钙结石模型中，维生素C显著促进草酸钙结晶的形成，而特异性敲除AR可明显减少结晶的形成，初步证实雄激素促进维生素C诱导的草酸钙结晶形成。进一步研究发现雄激素可能通过抑制TXNRD1、GLRX2、CYB561的表达，继而促进维生素C向草酸转化及促进草酸诱导的肾脏氧化应激损伤，最终导致结石的形成。然而雄激素如何调控上述分子从而促进维生素C向草酸转化及促进草酸诱导肾氧化应激损伤的机制仍不清楚。本项目拟通过多种细胞模型和AR基因敲除小鼠揭示雄激素调控TXNRD1、GLRX2、CYB561，促进维生素C在肝脏的草酸转化及促进草酸诱导的肾脏氧化应激损伤，从而促进肾草酸钙结石形成的作用及具体分子机制，为草酸钙结石的防治提供新干预策略。

Males develop kidney stones far more frequently than age matched females. Our previous research proved that AA supplements was remarkably correlation with higher risk for kidney stones incidence in men, but not in women. The evidence suggested that androgen receptor signaling might play a key role in the development of nephrolithiasis. To explore the biological mechanism of vitamin C in promoting the crystallization and deposition of calcium oxalate. we intraperitoneally injected vitamin C in the glyoxylate-induced kidney CaOx mouse model in vivo and showed that CaOx crystals deposition significant increase in the high-dose vitamin C group was observed compared with that in the low-dose group. It was found that androgen can promote the conversion of vitamin C into oxalic acid in liver epithelial cells and promote oxidative stress injury of oxalic acid in kidney. However, the underlying mechanism how AR regulated TXNRD1/GLRX2/CYB561 and how TXNRD1/GLRX2/CYB561 regulated vitamin C-induced oxalate biosynthesis in liver and oxidative stress induced kidney epithelial cell injury and CaOx crystals formation via using multiple in vitro cell lines and in vivo AR knockout mouse models. This study will provide new experimental evidence for the treatment and prevention of renal calcium oxalate stones.