碘造影剂引起急性肾损伤的机制研究和实验性治疗

Iodine contrast-induced acute kidney injury (CI-AKI) is an important clinical problem, but the pathogenesis remains to be elucidated and it is still lack of effective prevention and treatment measures. It is known to all that cyclophilin D (CypD) is an integral part of the mPTP, whose opening leads to cell apoptosis and death, calcium disorder is an important mechanism of opening the mitochondrial membrane permeability transition pore (mPTP) and CaMKII is important for regulating calcium homeostasis and mPTP opening. Our preliminary experiment results reveal that necrosis of renal tubular epithelial cells is an important pathological basis of CI-AKI, and contrast media increases the phosphorylation of CaMKⅡ protein and expression of CypD protein, then decreases mitochondrial membrane potential leading to necrosis-like changes of HK-2 cells. Based on the above findings, we propose a hypothesis that mPTP can be opened by contrast agent due to activating CaMKⅡ, then induce the necrosis of renal tubular epithelial cells and CI-AKI. This project intends to clarify the CaMKⅡ-mPTP pathway mediating the necrosis of renal tubular epithelial cell induced by contrast media in the rat and HK-2 cell CI-AKI model by the strategy of drugs and gene interference, to reveal the molecular basis of CI-AKI, and to investigate the protective effect of nifedipine on patients operated with percutaneous coronary intervention, then to provide the theoretical foundations for the potential new target of clinical treatment for CI-AKI.

碘造影剂致急性肾损伤（CI-AKI）是临床面临的重大难题，但其发生机制不清楚并缺乏有效防治措施。已知亲环素D蛋白构成的线粒体膜通透性转换孔（mPTP）开放与细胞凋亡和坏死密切相关；钙紊乱是引起mPTP开放的重要机制，钙调蛋白依赖性蛋白激酶Ⅱ（CaMKⅡ）对调节钙稳态和mPTP开放均至关重要；本项目前期研究发现肾小管上皮细胞坏死是CI-AKI的重要病理基础，造影剂可上调人肾小管上皮细胞株HK-2细胞CaMKⅡ磷酸化和亲环蛋白D表达、降低线粒体膜电位并使细胞呈坏死改变，提出：造影剂可能通过活化CaMKⅡ使mPTP开放，诱导肾小管上皮细胞坏死，导致CI-AKI。本项目拟在CI-AKI大鼠和HK-2细胞损伤模型，采用药物和基因干预mPTP开放和CaMKⅡ活化，观察大鼠肾功能和细胞损伤的逆转情况，并在临床患者中探讨硝苯地平的防治作用，旨在阐明CI-AKI的发生机制并为其防治寻找有效药物和靶标。

碘造影剂致急性肾损伤（CI-AKI）是临床面临的重大难题，但其发生机制尚不清楚，且目前缺乏有效防治措施。本项研究应用CI-AKI大鼠和细胞模型，初步探讨了造影剂通过激活钙调蛋白依赖性蛋白激酶Ⅱ（CaMKⅡ），促进线粒体膜通透性转换孔（mPTP）开放从而诱导肾小管上皮细胞死亡，最终导致CI-AKI的分子机制。同时本研究也通过体内和体外实验证实钙拮抗剂通过对CaMKⅡ/mPTP通路的调控发挥对CI-AKI的保护作用。此外，我们的临床研究结果首先发现在造影剂暴露之前给予氨氯地平治疗，在保护高血压患者预防造影剂肾病和延长生存期方面发挥了重要作用。我们还基于冠状动脉造影或经皮冠状动脉介入治疗的患者进行了造影前造影剂肾病风险预测模型的验证，开发了造影剂肾病风险预测网站，将研究成果应用于临床实践中。我们的研究为CI-AKI的防治提供新的理论和实验依据。