桑色素调控miR-330抑制SphK1和XO介导炎症信号通路缓解果糖诱导肾损伤机制研究

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.

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

代谢综合征是一组以胰岛素抵抗为中心的代谢紊乱征候群。流行病学研究显示，其发病率持续增涨与长期果糖过量摄入呈正相关。近30年来，含有高果糖谷物糖浆的软饮料、精加工食品等消耗量呈递增趋势，因此，高果糖过量摄入所导致的公共健康问题日益突出。大量临床和实验研究结果表明高果糖摄入与代谢综合征、高尿酸血症、II型糖尿病、肥胖症等密切相关，因此，高果糖摄入诱导机体代谢紊乱的分子病理机制已成为重要的研究热点。高果糖摄入可引起肾脏胰岛素抵抗、氧化应激、炎症反应、组织纤维化与胶原沉积和微量白蛋白尿等损伤，但其分子病理机制尚需进一步阐明。经本项目的运行，我们揭示高果糖可通过下调miR-330水平激活SphK1/S1P/S1PR1/3轴，进而激活NF-κB信号通路和NLRP3炎症小体造成IL-1β水平升高，导致肾脏炎症反应，诱发胰岛素信号通路异常，最终引起肾脏功能损伤。桑色素可以通过上调miR-330水平抑制SphK1/S1P/S1PR1/3轴，从而抑制NF-κB信号通路和NLRP3炎症小体激活，缓解肾脏炎症反应和胰岛素信号通路异常，进而改善肾功能损伤。本项目为桑色素防治代谢性肾损伤提供了重要的实验基础，而其对miRNA的调控功能也为桑色素防治代谢性疾病提供了新的研发角度。同时，我们证实高果糖可引起大鼠肾皮质胰岛素抵抗及肾脏纤维化，并发现TGF-β1/TGFBR1/Smads通路激活是关键的病理环节，会造成近端肾小管EMT及collagen沉积，进而发展为肾脏纤维化。本项目中这些关键靶点的发现，为揭示高果糖摄入引发肾脏炎症反应、胰岛素抵抗和纤维化的分子机制提供重要实验依据，进一步发现了肾保护中药活性成分及其新的分子作用机制，为其临床防治代谢性肾损伤等提供了新思路。