AMPKα对脂肪酸β氧化的调控信号通路在糖尿病肾脏脂毒性中的作用

Diabetic nephropathy is the leading cause of end stage renal failure (ESRD) and the current intervention methods for diabetic nephropathy are still unsatisfactory. Therefore, a further understanding of the pathogenesis of diabetic nephropathy is still of significance. "Kidney lipotoxocity" is the key pathogenic factor of diabetic nephropathy, while the precise mechanism underlying remains to be elucidated. AMPKα is the key regulator of fatty acid β-oxidation in mammalian cells, mainly via inactivating ACC in a phosphorylation manner and regulating the activity of PPARα. Related studies and our previous studies have demonstrated that the inhibition of AMPKα signaling is the common mechanism of lipotoxicity in both insulin target tissues and islet β cells, and the decreased expression or activity of AMPKα play a key role in peripheral insulin resistance and islet β cells injury. Our previous study also demonstrated that the expression and activity of AMPKα were significantly decreased in mesangial cells after high glucose stimulation. Based on these findings, we hypothesized that altered AMPKα signaling might also participate in kidney lipotoxocity. The present research aimed to investigate the role of AMPKα signal pathway in diabetes-associated kidney lipotoxicity using in-vivo and in-vitro methods. Furthermore, the protective effects of activating AMPKα signaling in diabetic nephropathy will also be evaluated. The present study will not only help to better our understanding of the pathogenesis of diabetic nephropathy, but also be of great significance of in searching novel intervention method of diabetic nephropathy.

糖尿病肾病是导致终末期肾衰竭的首位病因，目前糖尿病肾病还缺乏有效的治疗措施，深入探讨糖尿病肾病的病理生理机制仍然具有重要意义。肾脏脂毒性是糖尿病肾病的重要致病因素，但是具体机制尚不清楚。AMPKα是细胞脂肪酸β氧化的重要调控因子，可通过两条通路调节脂肪酸β氧化：①磷酸化方式修饰乙酰辅酶A羧化酶的活性；②调节PPARα的活性。国内外及我们前期研究证实：AMPKα信号通路被抑制是胰岛素靶器官及胰岛β细胞脂毒性的共同机制，与胰岛素抵抗及胰岛β细胞损伤密切相关。我们前期研究发现，高糖环境可显著降低肾小球系膜细胞AMPKα表达和活性。我们推测，AMPKα对脂肪酸β氧化的调节机制异常也是肾脏脂毒性的重要原因。本项目拟采用体内体外实验相结合的方法，探讨AMPKα对脂肪酸β氧化的调节信号通路在糖尿病肾脏脂毒性的作用，进而寻找并验证可能的干预手段。本研究对于深化理解糖尿病肾病的病理生理机制具有重要意义。

脂毒性是糖尿病肾病的重要治病因素，但其具体机制并不清楚。AMPKa是细胞能量代谢的主要调控器，乙酰辅酶A羧化酶2（Acetyl-CoA carboxylase 2，ACC2）是AMPKa的下游靶点，也是脂肪酸代谢的限速酶。而自噬是维持细胞能量平衡和细胞稳态的一种高度保守的“自我吞噬”机制。本研究通过体外和体内实验观察了糖尿病环境下ACC2与肾脏脂肪酸代谢及肾间质纤维化和脂毒性之间的关联，继而探讨了自噬在该过程起到的作用。结果发现，糖尿病环境能够诱导肾小管上皮细胞脂质沉积增加，促进其EMT转化；下调 ACC2 表达可改善上述效应。体内、外实验中脂质代谢功能障碍时自噬均被激活。干扰脂肪酸b氧化可调节自噬水平，并且影响由棕榈酸诱导的肾小管上皮细胞的脂毒性。这些研究结果表明ACC2在调解肾脏脂毒性过程中起重要作用。自噬是脂肪酸代谢的下游事件，参与了ACC2对肾小管上皮细胞脂肪酸代谢的调节。预示ACC2和自噬是防止糖尿病肾病的新的潜在靶点。