ALDH2对造影剂肾损伤的影响及其机制

With medical imaging and the development of interventional techniques for diagnosis and treatment, the clinical application of contrast agent is increasing rapidly, and the incidence of contrast induced nephropathy (CIN) has also increased significantly. At present, the effective treatment of CIN is rare, and the key measures far away from CIN lies in prevention before it happens. Therefore, in-depth understanding of CIN genetic risk factors, early identification of high-risk patients, and then precise early and intensive intervention may be an effective strategy to improve the current situation of CIN in china. Recently,some researches including ours have found that aldehyde dehydrogenase 2 (ALDH2) plays an important role in organ protection. Our research team has focused on the field of ALDH2 for more than ten years, and made a lot of creative achievements. Recently, our pre-experiment showed that ALDH2 and its gene Glu504Lys polymorphism were significantly correlated with CIN. Therefore, in this study, we aim to investigate the effect and its underlying vital mechanisms of ALDH2 and its gene polymorphism on CIN with in vivo and in vitro experiments with knockout and transgenic animal models using comparative proteomics and biochip technology,based on the unique advantages of our team. Up to now, no similar research has been reported in the world. Due to high mutation ratio of ALDH2 gene in Chinese Han nationality (30%-50%), our research will have an important clinical value and social significance by improving early identifying, ameliorating early and target intervention and reducing the incidence of CIN and its adverse prognosis,especially in Chinese.

随着介入技术及影像学发展，临床造影剂应用迅猛增长，造影剂肾病（CIN）发病也显著升高，已成为医源性肾衰重要病因。目前，CIN发生后治疗手段匮乏，关键仍在于预防。因此，深入认识CIN遗传危险因素，早期识别高危患者，精准干预，应是改善我国CIN严峻现状的一个有效策略。近年，包括本课题组在内的研究发现，乙醛脱氢酶2（ALDH2）在脏器保护领域发挥重要作用。课题组在ALDH2领域深入研究十余年，取得许多创造性成果，近期预实验提示了ALDH2及其基因多态与CIN的相关性及可能机制。因此，我们拟利用团队在该领域的经验和技术、建立的敲基因和转基因动物模型，应用比较蛋白质组学、生物芯片等技术，深入开展ALDH2及其基因多态对肾损伤的影响及其机制研究。检索文献，迄今尚罕见该方面研究。基于我国汉族ALDH2基因30%-50%的高突变率，本研究将对CIN，尤其是我国CIN，的精准防治提供新的思路和方法。

随着介入技术及影像学发展，临床造影剂应用迅猛增长，作为介入治疗潜在的严重并发症，造影剂肾损伤（CI-AKI）发病率也显著升高，已成为医源性肾衰重要病因。尽管已有学者针对这一并发症的防治进行研究，但最近的大规模随机对照试验数据提示，现有防治手段没有使患者明显获益，并未降低发生率，这表明需要进一步探索CI-AKI发病机制并开发新防治靶点。我们利用乙醛脱氢酶2（ALDH2）基因编辑小鼠（ALDH2 KO、ALDH2 OE小鼠），以及小鼠肾小管上皮原代细胞和人肾近曲小管上皮细胞，明确了过表达ALDH2可减少肾小管上皮细胞活性氧（ROS）生成，在CI-AKI中发挥保护作用。在此基础上，我们通过分析CI-AKI模型小鼠的肾皮质转录组学测序数据，发现Beclin-1信号通路可能参与ALDH2的肾脏保护，并通过后续一系列细胞和动物实验进一步明确ALDH2可通过增加Beclin-1表达及竞争性结合Beclin-1，上调Beclin-1信号通路，进而减少ROS生成，抑制AKI的发生。此外，我们还构建了另一种AKI模型——小鼠肾脏缺血再灌注损伤模型，再次验证上述结果。基于中国汉族人群ALDH2基因高突变率这一特点，本研究为此类人群AKI的精准防治提供了新的理论依据和防治靶点，具有重要意义。