水通道蛋白在肾间质纤维化中作用机制探讨

Renal Epithelial Mesenchymal transition (EMT) plays a crucial role in the progression of renal interstitial fibrosis, which finally leads to renal failure. This project will use aristolochic acid I (AA-I) and TGF-β1 as tool drugs to establish the renal tubular epithelial cells mesenchymal fibrosis model in vitro and in vivo. Through EMT signal pathway TGF-β / Smads signaling pathways and TGF-β / ERK signaling pathways to study the regulation mechanism of AQPs in the EMT occurring and development. Base on our preliminary experimental study of water channel proteins and the newest cell migration theory, we hypothesis that kidney aquaporins play an important role in the EMT. Aquaporins are newly found cell membrane protein which transport the water throughout the cell membrane , they have many important physiological functions, now days, aquaporins has become a research hotspot, as a potential new target for drug discovery, AQPs will undoubtedly have a broad application prospect in the clinical. Therefore, further revealed AQPs in tubular epithelial cells induced by drugs to the formation of EMT in the mechanism , which is important significant to explore the pathogenesis of chronic renal fibrosis and clinical exploration on new way of treatment.

肾间质纤维化是各种慢性肾病发展为终末肾衰的共同途径，而肾小管上皮细胞间充质转分化（EMT）是这一途径发生发展的重要机制。本课题根据马兜铃酸和TGF-β可导致肾间质纤维化的特点建立肾小管EMT的动物及细胞模型, 通过Smads和非Smads信号通路探索肾脏水通道蛋白（AQPs）在EMT中的作用机制。综合前期实验结果，并根据AQPs生物学最新细胞迁移理论，我们假设AQPs在EMT过程中起关键作用，故AQPs在EMT过程中对信号通路的调控及细胞因子之间相互作用关系，值得我们进一步探讨。AQPs作为新发现的细胞膜上特异性转运水分子的蛋白有许多重要的生理功能，这类蛋白作为一个潜在的药物发现新靶点，目前已成为研究的热点，干预AQPs功能或是表达的药物无疑会有广阔的治疗应用前景。本课题研究结果将深入揭示AQPs与EMT之间的相互作用关系，为AQPs调节剂在临床肾脏纤维化的防治应用提供新的理论依据。

肾间质纤维化是各种慢性肾病发展为终末肾衰的共同途径，而肾小管上皮细胞间充质转分化（EMT）是这一途径发生发展的重要机制。本课题根据小鼠UUO肾脏纤维化模型和马兜铃酸（AA-I和AL-I）及TGF-β所致HK-2细胞EMT的特点建立了肾小管上皮细胞间充质转分化的动物及细胞模型, 通过测定TGF-β / Smads和TGF-β / ERK信号通路探索肾脏水通道蛋白（AQPs）在EMT发生发展中的作用与机制。根据AQP生物学最新细胞迁移理论及实验结果表明，AQP1在EMT过程中起着关键作用，AQP1在EMT过程中与转分化因子（TGF-β等）之间存在相互调控作用。UUO模型引起的肾脏纤维化从体内整体动物方面说明了纤维化过程能够下调AQP1的表达，并且此过程与TGF-β信号通路之间存在某种紧密的联系。AA-I能够在HK-2细胞上通过激活TGF-β/Erk信号通路从而引发EMT过程，从体内外两方面证明了EMT过程能够下调AQP1的表达。AQP1在肾脏纤维化疾病中扮演了一个重要的角色，若AQP1能够影响纤维化损伤，那么将AQP1作为一个潜在的药物靶点，对将来的临床治疗提供了一条新的思路，有着重大的意义和价值。