果糖摄入诱发高尿酸血症与肾损伤日益危害人类健康。因对其病理机制缺乏较全面了解，迄今尚无有效治疗策略。桑色素具有降尿酸肾保护作用，但其分子机制尚不明确。我们已证实果糖诱导动物肾损伤与NF-κB和NLRP3炎症小体激活促进IL-1β成熟等炎症反应相关。观察到果糖下调肾脏miR-330表达，而受其调控炎症信号因子SphK1和尿酸生成关键酶XO则被激活；桑色素可抑制肾脏SphK1和XO活性，降低IL-1β水平，减轻肾损伤，这与其上调肾脏miR-330表达一致。本项目拟深入研究果糖诱导肾脏miR-330低表达，激活XO和SphK1介导炎症信号通路及其交互作用而引发肾损伤新途径，及miR-330在其中所起的关键作用；探索桑色素调控miR-330表达，抑制SphK1和XO介导炎症信号通路及其交互作用，缓解果糖诱导肾损伤新机制和新靶点。佐证工作假说，为桑色素治疗肾损伤及相关转化医学研究提供理论和实验基础

High fructose consumption induces hyperuricemia with triggered kidney injury, which seriously harm to the health of human. So far there is no effective prevention and treatment strategy, since little is known about the key pathological mechanism for fructose-induced kidney injury. Morin exhibits anti-hyperuricemia and renal protection. However, its underlying molecular mechanisms are incompletely understood. Our previous studies confirmed that fructose-induced renal NF-κB signaling and NLRP3 inflammasome activation were associated with the enchantment of inflammatory response such as IL-1β maturation. Moreover, fructose was observed to down-regulate expression of renal miR-330, and its targeted genes SphK1 (triggering inflammation) and XO (key enzyme for uric acid production) were subsequently activated in animals. Morin could inhibit renal SphK1 and XO activity to reduce IL-β levels and alleviate kidney injury, which were consistent with kidney miR-330 up-regulation. This project will deeply investigate the new pathway that fructose-induced miR-330 down-expression activates SphK1- or XO-mediated inflammatory signaling pathway and the interaction thereof, and in turn, causes kidney injury. It will also elucidate the key important role of miR-330 in fructose-induced kidney injury. Furthermore, this project will explore new mechanisms and pharmacological targets for the therapeutic intervention of morin on fructose-induced kidney injury via regulating miR-330 to inhibit SphK1- and XO-mediated inflammatory signaling pathway and the cross links between the two signaling pathways. These results will support the hypothesis, and provide theoretical and experimental evidences for the treatment of fructose-induced kidney injury by morin in clinic, as well as the promotion of the translational medicine research.