AMPK通过VEGF通路参与高血压肾病的保护

Renal remodeling is the main pathological process of renal dysfunction, which is an important complication of hypertension. The mechanism of renal remodeling caused by hypertension is not clear: stress load is not the only factor, neurohumoral and other factors are also involved. Recently, the cardioprotective effect of adenosine-activated protein kinase (AMPK) has been confirmed and its extracardiac protection has also been increasingly emphasized. Our previous studies showed that activation of AMPK could reduce renal damage in spontaneously hypertensive rat model(SHR), and stimulate the secretion of VEGF in the kidney. The decrease of VEGF may be a key factor in the occurrence and development of hypertensive nephropathy. We hypothesized that the decrease of renal VEGF might be an important mechanism of renal remodeling in hypertensive rats, and AMPK might inhibit renal remodeling via VEGF signaling pathway. This project intends to identify the change of renal VEGF in persistent hypertension and to elucidate the important role of AMPK/VEGF signaling pathway in hypertensive kidney remodeling, and to reveal the molecular mechanism of sympathetic/β-ARs and renin-angiotensin/AT1 receptors regulating the AMPK/VEGF pathway. This study would provide important insights on the mechanisms of hypertensive renal remodeling and provide a new target for the prevention and treatment of hypertensive renal remodeling.

肾脏重塑是肾脏损害的主要病理过程，是高血压病的重要并发症。高血压所致肾脏重塑的机制尚不明确：它不单纯是压力负荷所致，还有神经体液等因素参与。深入研究高血压肾病的发生机制，是高血压肾病防治的重要策略。近来，“能量代谢感受器”腺苷酸-活化蛋白激酶（AMPK）心脏外的保护作用被日益重视。我们前期研究表明激活AMPK可减轻自发性高血压大鼠的肾脏损害，同时刺激肾脏分泌VEGF，而肾脏VEGF减低可能是高血压肾病发生发展的关键因素，本项目提出肾脏VEGF降低是高血压肾脏重塑的重要机制，AMPK通过VEGF信号通路抑制肾脏重塑的假说。本项目拟查明持续高血压中肾脏VEGF的变化规律，阐明AMPK/VEGF信号通路在高血压肾脏重塑中的重要作用，揭示交感神经/β-AR和肾素-血管紧张素/AT1受体调控AMPK/VEGF通路的分子机制，为认识高血压肾脏重塑的发病机制提出新思路，为高血压肾脏重塑防治提供新靶点。

肾脏重塑是肾脏损害的主要病理过程，是高血压病的重要并发症。高血压所致肾脏重塑的机制尚不明确：它不单纯是压力负荷所致，还有神经体液等因素参与。深入研究高血压肾病的发生机制，是高血压肾病防治的重要策略。近来，“能量代谢感受器”腺苷酸-活化蛋白激酶（AMPK）心脏外的保护作用被日益重视。我们研究表明激活AMPK可减轻自发性高血压大鼠的肾脏损害：10个月的AMPK激动剂二甲双胍的治疗，可以显著改善肾功能，减少了长期高血压引起的蛋白尿。而且随后的研究发现，长期使用二甲双胍，可以刺激肾脏分泌内皮生长因子（VEGF），而肾脏VEGF减低可能是高血压肾病发生发展的关键因素。进一步体外研究发现二甲双胍通过激活缺氧诱导因子-2α（Hif-2α）来增加肾脏足细胞VEGF的分泌。本研究为认识高血压肾脏重塑的发病机制提出新思路，为高血压肾脏重塑防治提供新靶点。