脓毒症急性肾损伤(acute kidney injury，AKI)是重症医学中常见的问题，死亡率高，其机制不甚清楚。本课题组首次发现尿金属蛋白酶组织抑制因子2（tissue inhibitor of metalloproteinase 2，TIMP-2）在脓毒症AKI患者增高，但与脓毒症AKI发生发展的关系尚无报道。我们研究表明调控TIMP-2引起细胞周期改变，大鼠模型中发现TIMP-2与预后相关。我们推测脓毒症AKI诱导TIMP-2表达，导致细胞周期停滞，从而影响肾功能及预后，这可能是该疾病的新机制及潜在的干预靶点。本课题拟探讨脓毒症小管细胞中TIMP-2与细胞周期、肾损伤的关系；观察脓毒症小鼠尿TIMP-2的浓度时间变化；通过注射沉默TIMP-2慢病毒和基因敲除小鼠研究调控TIMP-2对肾功能变化和预后的影响。该研究有助于理解脓毒症AKI机制，为判断预后、靶向治疗提供新的理论依据。

Sepsis complicated with acute kidney injury (AKI) is a common problem with high mortality in Critical Care Medicine. The exact pathophysiology of septic AKI is unknown. Recently, our team first found that the urine levels of tissue inhibitor of metalloproteinase 2(TIMP-2) were increased from patients with AKI, but it is unclear how the TIMP-2 plays a role on the mechanism of AKI. Our study demonstrated that TIMP-2 induced the cell cycle arrest. TIMP-2 was associated with prognosis in rats. We speculate that sepsis increases TIMP-2 expression and induces cell cycle arrest; and subsequently affect renal function and outcome. This might be the new mechanism of septic AKI and potential intervention target. Therefore, this project is to explore the relationship among tubular TIMP-2 expression, cell cycle and kidney injury in sepsis. We will observe the TIMP-2 level changes with time in septic mice. The effects of regulating TIMP-2 levels on renal function and outcome in septic mice will be carried out by injecting lentivirus into kidney to knock down TIMP-2 or using TIMP-2 knock-out mice. This study helps to understand the mechanism of septic AKI, and provides a new theoretical basis for prognosis and target therapy.