C5aR通路促Fgl2表达介导缺血再灌注肾损伤的分子机制

Renal ischemia/reperfusion injury is an important cause of acute kidney failure. It is an unavoidable event in organ transplantation and has a major effect on short- and long-term graft survival. The study to provide significant insights into the mechanisms underlying the pathogenesis of the renal ischemia/reperfusion injury will be very important for increasing the kidney survival. The complement system has long been recognized as an important mediator of renal schemia/reperfusion injury, but the regulation mechanism remains unclear. It was found that Fgl2 inhibition resulted in decreased renal injury induced by renal schemia/reperfusion. Compared to the wild type mice, renal schemia/reperfusion-induced renal injury was also reduced, followed by the significant lower in both of the level of Fgl2 and MAC deposition in the murine model of renal schemia/reperfusion injury, suggesting the possibility that C5aR signaling mediates renal injury during renal schemia/reperfusion via the potentiation of coagulation reaction and feedback regulation on C5 activation . In this study, we will define the role of Fgl2 in renal schemia/reperfusion injury and further investigate the cellular mechanisms of C5aR signaling pathway in promoting Fgl2 expression. In addition,we will confirm the feedback regualtion of C5aR signaling on C5 activation,which results in renal injury. Anticipative results will deep our understanding for the pathogenesis of renal ischemia/reperfusion injury, which may ultimately provide effective treatment strategies for clinical disease.

肾缺血再灌注损伤是导致急性肾衰的重要原因，对移植肾的存活起着关键的作用。研究肾缺血再灌注损伤的发病机制无疑对提高移植器官的存活具有重要意义。补体在缺血再灌注损伤中的重要作用已经得到充分认识，但其调控机制尚不清楚。在小鼠肾缺血再灌注损伤模型中我们发现：阻断Fgl2的功能可显著衰减再灌注对肾脏的损伤；与WT小鼠相比，补体C5aRKO小鼠肾损伤显著减轻，Fgl2的表达和MAC的形成明显下降。表明：C5aR通路可能通过凝血系统正反馈调控补体C5的活化来介导缺血再灌注肾损伤。本研究拟进一步明确Fgl2在缺血再灌注肾损伤中的作用；探讨补体C5aR通路促Fgl2表达的信号机制；通过对凝血途径的干预证实补体C5aR通路正反馈调控补体C5的活化介导缺血再灌注肾损伤。预期的研究结果不但可加深对缺血再灌注肾损伤机理的了解，而且有助于补体和凝血系统相互作用认识的深入，并可为临床疾病干预新策略的发展提供理论依据。

肾缺血再灌注损伤是导致急性肾衰的重要原因，对移植肾的存活起着关键的作用。补体在缺血再灌注损伤中的重要作用已经得到充分认识，但其调控机制尚不清楚。本研究发现：缺血再灌注后，肾组织C5aR的表达显著上调；补体C5aR基因缺陷后，缺血再灌注肾损伤显著减轻，Fgl2的表达虽有一定程度的下降，但没有统计学差异，表明其在C5aR通路介导的缺血再灌注肾损伤中作用并不显著。与WT小鼠相比，肾缺血再灌注C5aRKO小鼠肾组织中抗炎分子PGRN的表达显著升高；重组C5a衰减肾小管上皮细胞HK-2中PGRN的表达，C5aR拮抗剂拮抗C5aR通路或抑制NF-κB的活化可逆转C5a的这种效应，表明C5a/C5aR通路以NF-κB依赖的方式抑制PGRN的表达。正常WT小鼠缺血再灌注后，肾组织自噬相关蛋白LC3的表达随时间逐渐升高，但C5aR缺陷可显著下调LC3的表达。与之一致的是，体外重组人C5a促进HK-2细胞LC3的表达，C5aR拮抗剂的加入可逆转这种效应。结论：补体C5a/C5aR通路通过抑制抗炎因子PGRN的表达和上调自噬加速缺血再灌注肾损伤，阻断C5aR通路抑制PGRN的下调有望成为临床缺血再灌注诱发急性肾损伤的治疗策略。

内容获取失败，请点击重试