基于整合素连接激酶（ILK）稳态平衡探讨交通心肾法治疗心肾综合征的分子机制

Cardiorenal syndrome is an acute, serious syndrome for final phase of chronic heart failure. We proposed Jiao Tong Xin Shen treatment is basic therapy for cardiorenal syndrom based on traditional theory of failure of the heart to communicating with the kidney, and its clinical application at our hospital for decades is a significant effect, which gave an evidence for antagonized RAAS and overactived immune inflammation. Studies show that imbalance of ILK steady in tissue of heart and kidney is modulated by AngII/AT1T and SDF-1/CXCR4. Hence, this project thinks that the effect of Fu Fang Jiao Tai soup, typical reciept of Jiao Tong Xin Shen treatment, is carried out by interventing the steady of ILK. The rats in this project underwent surgical procedures for the left ascending coronary artery and ligation of the unilateral nephrectomy acted as CRS model and Fu Fang Jiao Tai soup acted as intervention means to verify it with belows observations, the function and pathological patterns of heart and kidney,the time phase expression of ILK modulated by AngII/AT1R、SDF-1/CXCR4, the regulation of PINCH-ILK-parvin complex formation. It explores the molecular mechanism of CRS therapy with Fu Fang Jiao Tai soup, representative of Jiao Tong Xin Shen treatment. On the other hand, it provides an objective evidence for the application of traditional chinese medicine theory and classical famous prescription in emergency with severe rescue.

心肾综合征（CRS）是慢性心衰终末期心肾功能严重衰竭的临床危重症。基于传统"心肾不交"理论，我们提出交通心肾法是CRS的基本治法，临床验证疗效显著，初步证实其是通过拮抗RAAS和免疫炎症过度激活实现的。研究表明二者下游AngII/AT1R、SDF-1/CXCR4介导的心肾组织整合素连接激酶(ILK)稳态失衡是CRS病理核心。故本课题提出："交通心肾法代表方复方交泰汤治疗CRS的疗效机制是进一步干预ILK平衡稳态。"本研究以冠脉结扎联合单侧肾切除制备CRS大鼠模型，以复方交泰汤为干预手段，运用分子免疫、分子生物学等技术，从心肾功能、组织病理、AngII/AT1R、SDF-1/CXCR4介导的ILK表达和时相变化调控的角度，验证假说的客观性，旨在探索交通心肾法及代表方复方交泰汤治疗CRS的分子机制，亦为传统经典理论及名方在危重症抢救中的应用提供依据。

II 型CRS是指CHF引起的进行性肾功能损害，RAAS、免疫炎症反应过度激活是其发病核心。研究表明AngII/AT1R和SDF1/CXCR4介导了心肾组织ILK稳态失衡，导致心肾功能恶化。初步研究显示交通心肾法治疗CRS的可能机制是拮抗RAAS和免疫炎症。本课题以UNX联合MI制备CRS大鼠模型，以复方交泰汤、奥美沙坦酯、AMD3100为干预手段，运用生物化学、分子生物学等技术，从心肾功能、组织病理、AngII/AT1R/Rac1、SDF1/CXCR4/PIP3介导的ILK表达和时相变化几方面探索交通心肾法对CRS大鼠心肾功能及对ILK稳态平衡的影响。现总结如下：1交通心肾法具有改善心脏功能的作用，与RAAS拮抗剂奥美沙坦酯相似。研究表明本法能够降低CRS大鼠BNP水平（P<0.05），降低LVEDD和升高LVEF、LVFS的趋势明显（P>0.05）。本法尚能改善心肌细胞肥大增生，降低CRS大鼠α-MHC和β-MHC，升高α-MHC/β-MHC，这是否与改善心室重构和心功能有关尚需进一步证实。2交通心肾法具有改善CRS大鼠肾功能的作用。研究表明本法能够显著减少CRS大鼠尿量（P<0.05），减少24小时尿蛋白定量（P<0.05），减低肾脏质量（P<0.01）,并具有增加肾动脉、叶间动脉血流速度的趋势（P>0.05）。3 交通心肾法可能具有改善CRS模型大鼠肺功能的作用。研究表明本法能够减低CRS大鼠肺脏质量（P<0.01）。4 交通心肾法、奥美沙坦酯、AMD3100均具有调控CRS大鼠心脏ILK表达的作用。研究表明各治疗组大鼠心脏ILK mRNA从2周开始至第8周持续较高表达，同时伴有PIP3 mRNA表达水平升高和AGT/AT1R、SDF1/CXCR4 mRNA表达水平下降。治疗8周各组心脏组织ILK蛋白表达均显著升高，其中以药物治疗组升高趋势明显（P>0.05）。5交通心肾法、奥美沙坦酯、AMD3100均具有调控CRS大鼠肾脏ILK表达的作用。各治疗组大鼠肾脏第4周、第8周ILK mRNA表达水平升高，第2周ILK蛋白表达水平升高，并伴有AGT/AT1R、SDF1/CXCR4 mRNA表达水平不同程度的升高趋势。总之，交通心肾法能改善CRS模型大鼠心肾功能，参与AngII/AT1R和SDF1/CXCR4介导的心脏、肾脏ILK表达调控。