Hepcidin在体外循环术后急性肾损伤发生发展中的作用机制研究

Acute kidney injury (AKI) associated with cardiopulmonary bypass (CPB) is relatively common complication and the major cause of death. However, due to its pathogenesis has not been fully elucidated, it is difficult for early diagnose and treatment. Recent studies have found that plasma and urine hepcidin concentration correlate with the occurrence of AKI in patients following CPB. Hepcidin is an acute phase reaction protein which plays not only a key role in maintaining iron metabolic but also in modulating inflammatory responses and cell apoptosis. Our previous studies have found that liver, lung and kidney injury were significantly increased in sepsis rat modle with the hepcidin gene Knock-Down and the mortality rate was increased. We hypothesize that hepcidin may has an protective role in AKI after CPB. The present study, based on animal, cell and molecule, will elaborate the important role of hepcidin in AKI after CPB, reveal the molecular mechanism of hepcidin regulating the inflammation and kidney injury flowing CPB and explore the potential therapeutic value of hepcidin in CPB related AKI. Ultimately, our study will clarify the molecular mechanisms of hepcidin in regulating the development of AKI after CPB, provide new molecular targets and strategies in prevention and management of AKI.

急性肾损伤(AKI)是体外循环(CPB)术后主要并发症和死亡原因，由于其发病机制尚未完全阐明，对早期防治造成巨大困难。近年来研究发现CPB术后循环及尿液中hepcidin水平与肾功能损伤发生密切相关。Hepcidin属于急性期反应蛋白，不仅在铁代谢中起着关键作用，而且在调节炎症反应、细胞凋亡中具有重要作用。我们前期研究发现hepcidin基因Knock-Down的脓毒症大鼠模型肝、肺、肾等器官损伤明显加重，死亡率增加。我们推测，hepcidin可能在CPB术后AKI发生发展中具有防护作用。本项目拟从整体、细胞、分子水平，阐述hepcidin在CPB术后AKI中的重要作用；揭示hepcidin调节CPB术后炎症反应和肾损伤的分子机制；探索hepcidin在CPB术后AKI中的潜在防治价值，从而阐明hepcidin在调节AKI发病的分子机制，发现AKI防治新的分子靶标，开辟AKI防治的新途径。

体外循环（CPB）下心内直视手术是目前外科治疗心脏疾病的重要方法，也是导致住院病人发生急性肾损伤（AKI）的主要原因。AKI的发生是直接导致CPB术后病人致残、死亡的主要原因之一。研究显示高达30%-50%的病人CPB术后出现不同程度的肾损伤，其中需要透析治疗的占1.5-6.0%，死亡率高达24-75%，即使轻度的AKI也能够明显增加病人的死亡率。体外循环相关性AKI（CPB-AKI）显著增加患者感染性并发症的发生率，延长呼吸机应用时间、ICU滞留及住院时间，是影响预后的独立危险因素。本项目通过运用小鼠肾脏缺血再灌注急性肾损伤模型和细胞模型，系统阐述hepcidin与CPB术后AKI的发生、炎症细胞浸润和炎症反应程度的相关性。通过干预体内Hepcidin的表达水平，证明Hepcidin对体外循环所致肾损伤的潜在保护作用。Hepcidin基因敲除后巨噬细胞膜上的转铁蛋白明显减少，进而影响巨噬细胞的抗炎反应。并进一步通过临床验证，阐述Hepcidin与体外循环术后急性肾损伤发生发展的相关性。此外，还发现体内Gelsolin水平与体外循环术后急性肾损伤的发生发展明显相关，是体外循环术后急性肾损伤早期诊断的生物学指标。本项目的实施为临床早期诊断和早期干预、治疗急性肾损伤提供新的策略方向和治疗靶点，为开辟AKI防治的新途径提供重要理论基础和科学依据，具有重大的临床价值。