苍术、厚朴调控免疫代谢减轻代谢综合征足细胞损伤“化湿”功效的作用机制和物质基础

Metabolic syndrome is a major disease which seriously endangers human health, and increases the risk of developing chronic kidney disease. Podocyte injury is an early warning sign for the development of chronic kidney disease. Traditional Chinese medicine treats kidney disease from Spleen theory, the clinical applications of Rhizoma Atractylodis (Atractylodes Lancea), Cortex Magnoliae Officinalis (Magnolia officinalis) and their combinations, which are aromatic traditional Chinese medicines with removing dampness, have unique therapeutic effects. However, the mechanism of action and material basis should be elucidated. The previous results from our research group confirmed that oxidative stress, NLRP3 inflammasome activation and inflammation, insulin signal transduction impairment and lipid metabolic disorder changed immunometabolism in podocytes of metabolic syndrome. Some of traditional Chinese medicines reserved these disturbances. This project will investigate new ways to regulate immunometabolism and alleviate podocyte injury by Rhizoma Atractylodis, Cortex Magnoliae Officinalis and their combinations, in rat model of metabolic syndrome, as well as cell model of metabolic and immune inducing factors-exposed podocytes. Subsequently, this project will analyze the ingredients of Rhizoma Atractylodis, Cortex Magnoliae Officinalis and their combinations, and explore the mechanism of the regulation of immunometabolism involving in the inhibition of oxidative stress and inflammatory response, and the regulation of insulin signal transduction and lipid metabolism, and finally determine their active compounds. This project will reveal the action mechanism and material basis of resolving Dampness by which Rhizoma Atractylodis and Cortex Magnoliae Officinalis regulate immunometabolism to alleviate podocyte injury in metabolic syndrome. Moreover, this project will provide scientific basis for the effective treatment of metabolic syndrome with aromatic traditional Chinese medicines in clinic. These results are expected to promote the development of new drugs of Chinese medicine, and to have profound influences on the development of traditional Chinese medicine discipline.

代谢综合征为严重危害人类健康的重大疾病，增加慢性肾病发生的风险，足细胞损伤是其早期发生预警信号。中医“化湿”从脾论治肾，芳香化湿中药苍术、厚朴及配伍临床疗效独特，但其作用机制和物质基础亟待阐明。课题组前期工作证实氧化应激、NLRP3炎症小体激活和炎症、胰岛素信号转导和脂代谢异常改变了代谢综合征肾小球足细胞免疫代谢，促进其损伤；部分中药具逆转作用。本项目拟在代谢综合征大鼠模型、代谢和免疫诱导因子刺激足细胞模型上，深入研究苍术、厚朴及配伍调控免疫代谢减轻足细胞损伤新途径；继之分析苍术、厚朴及配伍化学成分，探讨其抑制氧化应激和炎症反应，调节胰岛素信号及脂代谢等免疫代谢调控机制，确定其有效成分与组分。该工作将揭示苍术、厚朴调控免疫代谢减轻代谢综合征足细胞损伤“化湿”功效的作用机制和物质基础，为芳香化湿中药临床有效治疗代谢综合征提供科学依据，推动相关中药新药创制，对中药学学科发展将产生较深远的影响。

代谢综合征能引发或加剧肾小球足细胞损伤。免疫代谢调节机体稳态以维持正常生理功能，但代谢综合征肾脏免疫代谢紊乱研究较为薄弱。芳香类中药苍术、厚朴“化湿”功效显著，其调控肾小球足细胞免疫代谢的机制和物质基础研究尚需积极开拓。本项目在课题组前期工作基础上，进一步证实高果糖摄入可促进代谢综合征肾小球足细胞免疫代谢紊乱，佐证了饮食失节所致代谢综合征肾小球足细胞损伤系“内湿”病机表现形式之一。苍术、厚朴及其配伍各有侧重改善代谢综合征病理特征，并有效调节肾小球足细胞免疫代谢以维持其结构完整性，具有一定协同配伍效应；揭示了苍术、厚朴及其配伍调节免疫代谢保护代谢综合征足细胞损伤新机制，如抑制IL-6/STAT3炎症信号减轻肾小球足细胞肥大、上调Sirt1遏止p53介导miR-221改善肾小球足细胞胰岛素信号紊乱等，表明苍术、厚朴“化湿”功效可保护代谢综合征肾小球足细胞损伤，其中苍术素、厚朴酚与和厚朴酚等可作为“化湿”功效成分以调节免疫代谢保护足细胞损伤。发现了Hmgcs2促进脂肪酸降解驱动足细胞线粒体代谢重编程、SSBP1激活DNA-PK/p53通路诱导足细胞铁死亡、果糖代谢介导O-GlcNAcylation抑制组蛋白H1.4加剧足细胞炎症等代谢综合征足细胞损伤新机制和新途径，为调控免疫代谢保护代谢综合征足细胞损伤提供了潜在的药物靶标。这些研究结果佐证了本项目所提出的工作假说，为芳香化湿中药苍术、厚朴治疗代谢综合征足细胞损伤提供科学依据，有助于指导中医临床用药；也为科学诠释饮食失节所致“内湿”病机及推进芳香化湿中药转化医学研究提供实验基础。相关研究成果发表在Signal Transduct Target Ther、Redox Biol等学术刊物上，受邀发表本领域综述1篇。负责人连续入选Elsevier中国高被引学者榜单，获2019年度高等学校科学研究优秀成果奖（科学技术）自然科学一等奖。