阿魏酸保护线粒体ETFβ防止糖尿病脂质沉积性肾损伤的研究

Mitochondrial homeostasis is essential for renal tubular survival and function. Electron transfer flavoprotein (ETFβ) is a key transporter in the electron transport process of beta oxidation of fatty acids, which establishes the couple between fatty acid oxidation and mitochondria oxidation by transporting electron to mitochondrial respiratory chain. Lipotoxicity mediates kidney damage in diabetes and emerging evidence demonstrates the implication of lipid deposition in early diabetic kidney injury. Ferulic acid is the main component of Angelica sinensis with beneficial effects on renoprotection. In our early research, sodium ferulate up-regulates ETFβ. Therefore, we hypothesizes that sodium ferulate inhibits mitochondrial oxidative stess via ETFβ over-expression, and prevents lipid deposition in the renal tubule. In the present study, we will investigate the protective effect of sodium ferulate on ETFβ with focus on the regulation of mitochondrial energy metabolism, aiming to elucidate the molecular mechanism through which sodium ferulate blocks lipid deposition in JNK/SREBP signaling cascades by protecting mitochondrial structural and functional integrity. We wish that these findings not only provides a novel insight into the molecular mechanism by which sodium ferulate protected kidney against diabetes, but also suggests that regulation of mitochondrial ETFβ might be a therapeutical targets against early diatetic kidney injury.

线粒体稳态对肾小管正常功能具有重要意义。电子转运黄素蛋白（electron transfer flavoprotein，ETF）是脂肪酸β氧化的关键电子转运体，其中ETFβ将电子传递至呼吸链，构建了脂肪酸氧化与线粒体氧化磷酸化的偶联。新进研究发现肾小管脂质沉积是糖尿病肾损伤的早期主要因素。阿魏酸是当归的主要活性成分，具有肾保护作用。前期研究发现阿魏酸钠能提高ETFβ表达，由此我们推测：阿魏酸钠通过使ETFβ高表达，抑制线粒体氧化应激，防止肾小管脂质沉积。在此研究中，我们将以线粒体稳态为关注点，观察阿魏酸钠通过保护高糖环境下ETFβ的表达，抑制JNK/SREBP途径引起的脂质聚集，防止线粒体结构功能紊乱的作用，藉此确认阿魏酸钠通过维持线粒体稳态，抑制脂质沉积的作用机制。此研究成果将揭示阿魏酸钠发挥肾小管保护作用的分子机制，并提示保护线粒体上ETFβ有可能是防治糖尿病早期肾损伤的治疗靶标。

糖尿病肾病（diabetic nephropathy, DN）是糖尿病最常见的慢性并发症之一，在发达国家和我国发达地区DN已经成为终末期肾病（end stage renal disease，ESRD）的首要原因。随着临床研究的深入，人们发现患者可在早期出现严重的肾脏脂质沉积。过去DN研究以糖毒性为中心的观点发生了转变，更多关注转向糖尿病脂毒性肾损伤的机制。因此，对于尽早诊断、早期干预DN，肾脏脂质沉积可能是重要突破口。.本研究从线粒体稳态角度阐述阿魏酸钠对肾小管上皮细胞的保护作用，建立ETFβ/ROS 途径防止肾小管脂质沉积的功能联系机制，拓展改善脂代谢和线粒体功能对肾小管保护的新认识。以线粒体脂肪酸代谢关键分子ETFβ为枢纽，构建线粒体稳态和细胞存活的联系，克服了以往中药或天然药物肾保护研究中孤立考察和作用路线不明确等缺点。为中药或天然药物改善细胞能量代谢紊乱，防治糖尿病肾损伤的研究提供新的思路。本研究试图在线粒体结构功能紊乱这一病理基础上构建线粒体途径糖毒性与脂毒性的交汇，积极探索对糖尿病肾损伤的新认知，为中药在此邻域的拓展应用提供新的策略。 .重要结果：.①阿魏酸钠减轻高糖引起的肾小管上皮细胞脂质沉积和凋亡；.②氧化应激与脂质生成存在的正反馈调节，建立线粒体ROS 与脂代谢紊乱的关系网络。.③明确阿魏酸钠通过稳定线粒体ETFβ表达改善高糖引起的肾小管上皮细胞线粒体紊乱和脂质沉积。