氟非尼酮治疗糖尿病肾病抗氧化应激的作用机制研究

Diabetic nephropathy (DN) is a major and serious complication of diabetes. Currently, there is no drug that can treat or effectively control DN. Our research groups have recently invented a very promising drug, called AKF-PD (also known as Fluorofenidone), which we have completed preclinical research in treating renal interstitial fibrosis according to the standards of the national drug development program of China. Results are very encouraging. In our research involving mice with DN, we were able to show that AKF-PD is effective in delaying the progression of DN. AKF-PD significantly reduces urinary albumin excretion and mesangial matrix expansion. In vitro, fluorofenidone can inhibited the expression of NADPH oxidase and reactive oxygen species (ROS), AKF-PD may protect against NADPH oxidase /ROS production in diabetic nephropathy. In view of the AGEs and PKC signal pathway plays a central role in expression of NADPH oxidase /ROS , Target to explore the molecular mechanism and treatment of fluorofenidone in diabetic nephropathy.

糖尿病肾病是糖尿病最常见、最严重的并发症之一，临床缺乏有效治疗药物。AKF-PD 是本课题组自主设计的新化合物，按国家I 类新药要求，已完成抗肾间质纤维化的临床前研究。前期研究还观察到AKF-PD 具有治疗糖尿病肾病的作用，AKF-PD可明显减少db/db 小鼠尿白蛋白、减轻肾小球系膜基质增生。体外细胞实验观察到氟非尼酮可抑制NADPH氧化酶及活性氧(reactive oxygen species,ROS)产生，提示抑制NADPH氧化酶/ROS可能是AKF-PD抗氧化应激及糖尿病肾病的重要作用环节。鉴于AGEs及PKC途径信号传导通路在NADPH氧化酶/ROS表达过程中的关键作用，本课题将以此为研究方向，观察氟非尼酮抑制NADPH氧化酶/ROS的作用，探讨氟非尼酮的分子作用机制及其治疗糖尿病肾病的作用靶点。

糖尿病肾病(diabetic nephropathy,DN)是糖尿病最常见而最严重的并发症。针对糖尿病肾病的有效药物很少，氟非尼酮（Fluorofenidone，AKF-PD）是中南大学氟非尼酮课题组自主开发的一种具有广谱抗器官纤维化疗效的吡啶酮类化合物，在治疗糖尿病肾病方案有广阔的前景。本研究初步揭示了AKF-PD治疗糖尿病肾病的抗线粒体氧化损伤的机制。研究证实AKF-PD能明显减少糖尿病肾病小鼠的线粒体氧化应激损伤及肾间质纤维化形成，并通过AGEs/NOX4、PKCa/NOX4及PKCβ1/NOX4多条通路减少线粒体氧化应激损伤。对糖尿病肾病肾间质纤维化及线粒体氧化应激损伤有一定保护作用。