Cx32介导的线粒体凋亡对肝移植术后急性肾损伤的影响及其机制研究

急性肾损伤是肝移植术后常见的并发症，是患者恢复延迟和术后死亡的主要原因，其机制尚未阐明，并缺乏有效的防治手段。凋亡是细胞损伤的重要形式，主要包括线粒体凋亡和死亡受体凋亡途径。我们前期的研究发现，肝移植术后的肾脏损伤和细胞凋亡与缝隙连接蛋白connexin32（Cx32）的表达高度一致；抑制Cx32的功能可以减轻肾组织的损伤以及线粒体凋亡途径相关蛋白的表达，而对死亡受体凋亡途径的相关蛋白表达无明显影响。因此，我们推测，由Cx32蛋白介导的线粒体凋亡可能在肝移植术后急性肾损伤的过程中扮演着重要的角色。本研究拟采用特异性抑制剂、基因沉默和质粒转染、基因敲除鼠等技术，改变Cx32蛋白的功能，通过在体动物实验和体外细胞学研究，验证其对肝移植术后急性肾损伤的影响，并分析其机制是否与对线粒体凋亡途径的调控有关，以期为阐明肝移植术后急性肾损伤的机制提供新的科学依据，并为其治疗提供一个潜在靶点。

Acute kidney injury (AKI) following orthotopic liver transplantation (OLT) is very common, which not only delays patients’ recovery and raises the cost of hospitalization, but also affects the survival rate of patients, however, underlying mechanism is still unclear and effective therapeutics are lacking. Apoptosis is important for cell damage, which is always mediated by mitochondrial and death receptor. We found that in our present studies, the severity of AKI and apoptosis following OLT is correlated with Cx32 expression on kidneys; AKI and mitochondrial apoptosis could be decreased by Cx32 inhibition, by contrast, apoptosis mediated by death receptor has no changes. Thus, we supposed that Cx32 plays an important role in the development of AKI after OLT, and the mechanisms might be relative with mitochondrial apoptosis regulation. In vivo and in vitro studies, different models will be used to simulate the pathological and physiological process of liver tranplantation. Various methods, such as sepicific inhibitor, gene silencing and Cx32 gene knockout mice, will be applied to change the function of Cx32, in order to clarify its effects and role in the development of AKI following OLT and most importantly to verify whether Cx32 mediates AKI through modulating mitochondrial apoptosis. Through our studies, we aim to provide new scientific basis for elucidating the mechanism of AKI after OLT, and also ofter a new potential target for its treatment.